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Pulmonary Embolism

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Pulmonary Embolism Second Edition by

Paul D. Stein,

MD

Director of Research Education St. Joseph Mercy-Oakland Pontiac, Michigan, USA Professor, Full Time Affiliate Department of Medicine Wayne State University School of Medicine Detroit, Michigan, USA Adjunct Professor of Medical Physics Oakland University Rochester, Michigan, USA

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 C 1996 by Williams & Wilkins, Maryland  C 2007 by Paul D. Stein

Published by Blackwell Publishing Blackwell Futura is an imprint of Blackwell Publishing Blackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Blackwell Science Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia All rights reserved. No part of this publication may be reproduced in any form or by any electronic or mechanical means, including information storage and retrieval systems, without permission in writing from the publisher, except by a reviewer who may quote brief passages in a review. First published 1996 Second edition 2007 1

2007

ISBN: 978-1-4051-3807-9 Library of Congress Cataloging-in-Publication Data Stein, Paul D. Pulmonary embolism / by Paul D. Stein. – 2nd ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-3807-9 (alk. paper) 1. Pulmonary embolism. I. Title. [DNLM: 1. Pulmonary Embolism. WG 420 s819p

2007]

RC776.P85s74 2007 616.2 49–dc22 2007005029 A catalogue record for this title is available from the British Library Commissioning Editors: Steve Korn and Gina Almond Development Editor: Beckie Brand Editorial Assistant: Victoria Pittman Set in 9/12 Minion and Frutiger by Aptara Inc., New Delhi, India Printed and bound in Singapore by Markono Print Media Pte. Ltd. Cost for publication of this book was supported in part by unrestricted grants from Diatide, Inc., Londonderry, New Hampshire and Dupont Pharmaceuticals Co., Wilmington, Delaware. For further information on Blackwell Publishing, visit our website: www.Blackwellmedicine.com The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards. Blackwell Publishing makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check that any product mentioned in this publication is used in accordance with the prescribing information prepared by the manufacturers. The author and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this book.

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Contents

Preface, ix Part I Prevalence, risks, and prognosis of pulmonary embolism and deep venous thrombosis

1 Pulmonary embolism and deep venous thrombosis at autopsy, 3 2 Incidence of pulmonary embolism and deep venous thrombosis in hospitalized patients, 16 3 Case fatality rate and population mortality rate from pulmonary embolism and deep venous thrombosis, 19 4 Prognosis in acute pulmonary embolism based on right ventricular enlargement, prognostic models, and biochemical markers, 24 5 Changing risks of untreated deep venous thrombosis and acute pulmonary embolism, 31 6 Resolution of pulmonary embolism, 35 7 Upper extremity deep venous thrombosis, 37 8 Thromboembolic disease involving the superior vena cava and brachiocephalic veins, 41 9 Venous thromboembolic disease in the four seasons, 44 10 Regional differences in the United States of rates of diagnosis of pulmonary embolism and deep venous thrombosis and mortality from pulmonary embolism, 47 11 Venous thromboembolism in the elderly, 52

12 Pulmonary thromboembolism in infants and children, 66 13 Venous thromboembolism in men and women, 68 14 Comparison of the diagnostic process in black and white patients, 72 15 Pulmonary thromboembolism in Asians/Pacific Islanders, 76 16 Pulmonary thromboembolism in American Indians and Alaskan Natives, 83 17 Venous thromboembolism in patients with cancer, 85 18 Venous thromboembolism in patients with heart disease, 93 19 Venous thromboembolism in patients with ischemic and hemorrhagic stroke, 98 20 Pulmonary embolism and deep venous thrombosis in hospitalized adults with chronic obstructive pulmonary disease, 101 21 Pulmonary embolism and deep venous thrombosis in hospitalized patients with asthma, 107 22 Deep venous thrombosis and pulmonary embolism in hospitalized patients with sickle cell disease, 109 23 Venous thromboembolism in pregnancy, 113 24 Air travel as a risk for pulmonary embolism and deep venous thrombosis, 119 25 Estrogen-containing oral contraceptives and venous thromboembolism, 122

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26 Obesity as a risk factor in venous thromboembolism, 125 27 Hypercoagulable syndrome, 128 Part II Diagnosis of deep venous thrombosis

28 Deep venous thrombosis of the lower extremities: clinical evaluation, 139 29 Clinical model for assessment of deep venous thrombosis, 144 30 Clinical probability score plus single negative ultrasound for exclusion of deep venous thrombosis, 147 31 D-dimer for the exclusion of acute deep venous thrombosis, 149 32 D-dimer combined with clinical probability assessment for exclusion of acute deep venous thrombosis, 158 33 D-dimer and single negative compression ultrasound for exclusion of deep venous thrombosis, 160

Contents

42 The history and physical examination in all patients irrespective of prior cardiopulmonary disease, 192 43 Clinical characteristics of patients with acute pulmonary embolism stratified according to their presenting syndromes, 197 44 Clinical assessment in the critically ill, 203 45 The electrocardiogram, 206 46 The plain chest radiograph, 216 47 Arterial blood gases and the alveolar–arterial oxygen difference in acute pulmonary embolism, 221 48 Fever in acute pulmonary embolism, 229 49 Leukocytosis in acute pulmonary embolism, 232 50 Alveolar dead-space in the diagnosis of pulmonary embolism, 234 51 Neural network computer-assisted diagnosis, 236

34 Contrast venography, 161

52 Empirical assessment and clinical models for diagnosis of acute pulmonary embolism, 239

35 Compression ultrasound for the diagnosis of deep venous thrombosis, 164

53 D-dimer for the exclusion of acute pulmonary embolism, 243

36 Impedance plethysmography and fibrinogen uptake tests for diagnosis of deep venous thrombosis, 168

54 D-dimer combined with clinical probability for exclusion of acute pulmonary embolism, 250

37 Computed tomography for diagnosis of deep venous thrombosis, 171

55 D-dimer in combination with amino-terminal pro-B-type natriuretic peptide for exclusion of acute pulmonary embolism, 253

38 Magnetic resonance angiography for diagnosis of deep venous thrombosis, 175 39 P-selectin and microparticles to predict deep venous thrombosis, 179

56 Low tissue plasminogen activator plasma levels and low plasminogen activator inhibitor-1 levels as an aid in exclusion of acute pulmonary embolism, 254

Part III Diagnosis of acute pulmonary embolism

57 Echocardiogram in the diagnosis and prognosis of acute pulmonary embolism, 255

40 Clinical characteristics of patients with no prior cardiopulmonary disease, 183

58 Trends in the use of diagnostic imaging in patients hospitalized with acute pulmonary embolism, 260

41 Relation of right-sided pressures to clinical characteristics of patients with no prior cardiopulmonary disease, 190

59 Techniques of perfusion and ventilation imaging, 262


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Contents

60 Ventilation–perfusion lung scan criteria for interpretation prior to the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED), 267 61 Observations from PIOPED: ventilation–perfusion lung scans alone and in combination with clinical assessment, 271 62 Ventilation–perfusion lung scans in patients with a normal chest radiograph, patients with no prior cardiopulmonary disease, patients with any prior cardiopulmonary disease, and patients with chronic obstructive pulmonary disease, 278 63 Perfusion lung scans alone in acute pulmonary embolism, 280 64 Probability interpretation of ventilation–perfusion lung scans in relation to largest pulmonary arterial branches in which pulmonary embolism is observed, 282 65 Revised criteria for evaluation of lung scans recommended by nuclear physicians in PIOPED, 284

72 Prevalence of acute pulmonary embolism in central and subsegmental pulmonary arteries, 318 73 Quantification of pulmonary emboli by conventional and CT angiography, 319 74 Complications of pulmonary angiography, 321 75 Contrast-enhanced spiral CT for the diagnosis of acute pulmonary embolism before the Prospective Investigation of Pulmonary Embolism Diagnosis, 325 76 Methods of PIOPED II, 340 77 Multidetector spiral CT of the chest for acute pulmonary embolism: results of the PIOPED II trial, 348 78 Outcome studies of pulmonary embolism versus accuracy, 355 79 Contrast-induced nephropathy, 357 80 Radiation exposure and risk, 359 81 Magnetic resonance angiography for the diagnosis of acute pulmonary embolism, 364

66 Criteria for very low probability interpretation of ventilation–perfusion lung scans, 288

82 Serial noninvasive leg tests in patients with suspected pulmonary embolism, 371

67 Probability assessment based on the number of mismatched segmental equivalent perfusion defects or number of mismatched vascular defects, 294

83 Predictive value of diagnostic approaches to venous thromboembolism, 373

68 Probability assessment based on the number of mismatched vascular defects and stratification according to prior cardiopulmonary disease, 298 69 The addition of clinical assessment to stratification according to prior cardiopulmonary disease further optimizes the interpretation of ventilation–perfusion lung scans, 304 70 Single photon emission computed tomographic perfusion lung scan, 310 71 Standard and augmented techniques in pulmonary angiography, 311

84 Diagnostic approaches to acute pulmonary embolism, 376 Part IV Prevention and treatment of deep venous thrombosis and pulmonary embolism

85 New and old anticoagulants, 389 86 Prevention of deep venous thrombosis and pulmonary embolism, 405 87 Treatment of deep venous thrombosis and acute pulmonary embolism, 414 88 Withholding treatment of patients with acute pulmonary embolism who have a high risk of bleeding provided and negative serial noninvasive leg tests, 422


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89 Thrombolytic therapy in acute pulmonary embolism, 425 90 Thrombolytic therapy for deep venous thrombosis, 437 91 Inferior vena cava filters: trends in use, complications, indications, and use of retrievable filters, 444 92 Catheter-tip embolectomy in the management of acute massive pulmonary embolism, 454

Contents

93 Pulmonary embolectomy, 459 94 Chronic thromboembolic pulmonary hypertension and pulmonary thromboendarterectomy, 464 Index, 467


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Preface

Since the first edition of Pulmonary Embolism was published in 1996, major strides have been made in many aspects of pulmonary embolism and its immediate cause, deep venous thrombosis. The purpose of this second edition is to provide detailed, in depth information on pulmonary embolism in a format that is readily usable by practicing physicians, and at the same time, provide fully referenced data that can serve as a resource for physicians with a deeper interest in the field. Many associates contributed to the investigations upon which much of the information in this book is based. The PIOPED I investigators supplied data for an impeccable database used for much of what we know about the accuracy of clinical assessment as well as ventilation–perfusion lung scans. The PIOPED II investigators supplied an equally impeccable database upon which much of what we know about the accuracy of multidetector CT angiography is based. This database is just beginning to be examined for useful information on a variety of additional subjects. The PIOPED III investigators are just starting to evaluate magnetic resonance angiography, and hope to acquire an equally impressive database. Grants from the National Institutes of Health, National Heart Lung and Blood Institute (NHLBI) made all of this possible. Guidance by representatives of the NHLBI contributed to the success of the study. Many of the investigators who participated in PIOPED I continued through PIOPED II and into PIOPED III. Some even participated in the Urokinase-Pulmonary Embolism Trial, published in 1973, which contributed a huge amount of information about pulmonary embolism, beyond that which was learned about thrombolytic therapy. Investigators with preferences for diverse approaches to the diagnosis and management of pulmonary embolism subverted their personal interests to collabo-

rate on scientific levels. This resulted in collaborations with only one goal: advancement of the field. The investigators, including physicians, statisticians, nursecoordinators, and technicians, often contributed long and hard hours with little reward. I am thankful for their efforts, and for the deep friendships with many that have resulted from these collaborations. Another database that was used extensively for epidemiological information related to pulmonary embolism and deep venous thrombosis was The National Hospital Discharge Summary. This database is available to the general public. Many details about its correct use, however, required consultation with representatives of the National Center for Health Statistics, and this assistance was graciously given. Several bright young men have worked with me over the years. Jerald W. Henry, MD, worked for several years on obtaining data from PIOPED I before going to medical school. He is now a practicing radiologist. More recently, Kalpesh C. Patel, MBBS, and Neeraj K. Kalra, MD, assisted. They are now finishing subspecialty training. Fadi Kayali, MD, did dedicated and superior work. He has been accepted into fellowship training. Afzal Beemath, MD, is a brilliant former fellow. He not only contributed importantly to several investigations, but also helped in a major way in the completion of this book. Nikunj Patel, MD, also worked long hours in assisting in the preparation of this book, as did his brother Hiren who assisted for a few months. Fadi Matta, MD, and Abdo Yaekoub, both of whom recently started with me, have done a sensational job. Finally, thanks to Steven Korn, formerly of Futura Publishing Company and Beckie Brand of Blackwell Publishing Company for encouraging me to complete this labor.

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PART I

Prevalence, risks, and prognosis of pulmonary embolism and deep venous thrombosis

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CHAPTER 1

Pulmonary embolism and deep venous thrombosis at autopsy

Prevalence of pulmonary embolism at autopsy The prevalence of pulmonary embolism (PE) at autopsy varies according to the age and morbidity of the population studied. Dalen and Alpert in 1975 estimated that 15% of deaths in acute general hospitals and 25% of deaths in nursing homes or chronic hospitals were due to PE [1]. In more recent years, with more extensive use of antithrombotic prophylaxis, PE at autopsy was shown with similar prevalences among patients who died in acute care hospitals (24%) and patients who died in chronic care hospitals (22%) [2]. Outpatients, however, had a lower prevalence of PE at autopsy (5%) [2]. The prevalence of PE at autopsy of patients in general hospitals and in entire communities, with one exception, ranged from 9 to 28% and has not changed in over 60 years [2–21] (Table 1.1). One study, however, reported gross PE in 55% of patients at autopsy [10]. On average, PE at autopsy occurred in 7031 of 55,090 patients (13%) (Table 1.1, Figure 1.1).

Small PE at autopsy In an autopsy study that employed postmortem pulmonary arteriography as well as gross dissection and microscopic examination, gross dissection showed PE in 34 of 225 (15%) of autopsied patients [4]. Among these, PE was limited to muscular pulmonary artery branches (0.1–1 mm diameter) in 26 of 34 patients (76%) and PE was in elastic pulmonary artery branches (>1 mm diameter) in 8 of 34 patients (24%) [4]. Microscopic examination showed PE in pulmonary arterioles in 13 of 34 patients (38%) with grossly visible PE. The smallest PE that have been identified in living patients were with wedge pulmonary arteriography, which showed PE in 1–2-mm-diameter pulmonary artery branches [24] (see Chapter 71). Fibrous bands, webs, and intimal fibrosis have been interpreted as the final state of organization of PE and these have been reported by some to indicate old PE at autopsy [7]. Meticulous dissection and microscopic examination for minute and barely visible fragments showed traces of fresh or old PE at autopsy in 52% and 64% of patients [7, 8].

Large or fatal PE at autopsy Large or fatal PE in patients at autopsy in general hospitals or communities from 1939 to 2000 occurred in 2264 of 54,364 patients (4%) (range 0.3–24%) [2, 3, 8–11, 13–19, 21, 22] (Table 1.1, Figure 1.1). In most studies, the prevalence of large or fatal PE ranged from 3 to 10%. In elderly institutionalized patients, the rate of fatal PE at autopsy was within that range, 18 of 234 (8%) [23]. Data on institutionalized patients are not included in Table 1.1. A sudden increase in the rate of PE at autopsy was observed in London in 1940 due to cramped conditions in air raid shelters [22]. These rates also are not included in Table 1.1.

Unsuspected PE at autopsy Pulmonary embolism was unsuspected or undiagnosed antemortem in 3268 of 3876 patients in general hospitals or communities who had PE at autopsy (84%) (range 80–93%) [3, 5, 8, 11, 12, 16, 18] (Table 1.2, Figure 1.2). Remarkably, even in patients with large or fatal PE at autopsy, the majority, 1902 of 2448 (78%), were unsuspected or undiagnosed antemortem [2, 11, 12, 14–16, 18, 19, 25] (Table 1.2, Figure 1.2). In our experience, PE at autopsy caused death in 5%, contributed to death in 0.5%, and was incidental in 9.2% of 404 autopsies, and the distribution, according

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PART I

Prevalence, risks, and prognosis of PE and DVT

Table 1.1 Prevalence of pulmonary embolism at autopsy in general hospitals and communities. Any PE/No autopsies (%)

Fatal or large PE/No autopsies (%)

Study years

First author, year [Ref] Simpson, 1940 [22]

4/242 (2)

1939

606/4391 (14)

1945–1954

Coon, 1959 [3]

34/225 (15)

1960–1961

Smith, 1964 [4]

118/981 (12)

1956–1960

Uhland, 1964 [5]

17/61 (28)*

1951–1959

Freiman, 1965 [6]

55/263 (21)†

1964–1965

Morrell, 1968 [7]

567/4600 (12)

202/4600 (4)

1964–1974

Coon, 1976 [8]

319/1350 (24)

1976

Schwarz, 1976 [9]

280/508 (55)‡

92/508 (18)

1969–1970

Havig, 1977 [10]

216/1455 (15)

54/1455 (4)

1973–1974

Goldhaber, 1982 [11]

389/2398 (16)

1966–1976

Dismuke, 1984 [12]

105/1133 (9)

1966–1970

Dismuke, 1986 [13]

53/1124 (5)

1971–1975

””

43/1128 (4)

1976–1980

””

44/1276 (3)

1980–1984

313/2388 (13)

239/2388 (10)

1979–1983

Rubenstein, 1988 [14] Sandler, 1989 [15]

1934/21,529 (9)

67/21,529 (0.3)

1960–1984

Karwinski, 1989 [16] Linblad, 1991 [17]

161/766 (21)

68/766 (9)

1957

250/1117 (22)

93/1117 (8)

1964

””

346/1412 (25)

83/1412 (6)

1975

””

260/994 (26)

93/994 (9)

1987

59/404 (15)

20/404 (5)

1985–1986

Stein, 1995 [18]

””

92/2427 (4)

1985–1989

Morgenthaler, 1995 [19]

288/3334 (9)§

1966–1974

Mandelli, 1997 [20]

182/1144 (16)§

1989–1994

431/2356 (18)

178/2356 (8)

1987

Nordstrom, 1998 [2]

525/3764 (14)

221/3764 (6)

1980–2000

Pheby, 2002 [21]

””

* An additional 22/61 (36%) showed traces of residual pulmonary embolism (PE), fibrous bands, or webs. †

An additional 31% had had fibrous bands or intimal fibrosis indicative of old PE. An additional 72 of 508 (14%) were visible only by microscopy. § Massive and submassive PE.

PE, DVT at autopsy (%)

50 45 40 35 30 25 20 15 10 5 0

43

13 4

Any PE

Large or fatal PE

Any DVT

Figure 1.1 Prevalence of pulmonary embolism (PE) and deep venous thrombosis (DVT) at autopsy.


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PE and DVT autopsy

Table 1.2 Unsuspected pulmonary embolism at autopsy. Any unsuspected or

Unsuspected or

undiagnosed PE

undiagnosed minor or

Unsuspected or undiagnosed fatal or large PE

[unsuspected PE/total

small PE [unsuspected

[unsuspected large PE/total

PE (%)]

small PE/total PE (%)]

PE (%)]

Study years

First author, year [Ref]

563/606 (93)

1945–1954

Coon, 1959 [3]

91/107 (85)

1955–1960

Uhland, 1964 [5]

514/567 (91)

1964– 1974

Coon, 1976 [8]

199/217 (92)

161/162 (99)

38/54 (70)

1973–1974

Goldhaber, 1982 [11]

310/389 (80)

219/244 (90)

91/145 (63)

1966–1976

Dismuke, 1984 [12]

30/44 (68)

1980–1984

Rubenstein, 1988 [14]

186/195 (95)

1979–1983

Sandler, 1989 [15]

1619/1934 (84)

436/484 (90)

1183/1450 (82)

1960–1984

Karwinski, 1989 [16] Stein, 1995 [18]

52/59 (88)

36/37 (97)

14/20 (70)

1985–1986

47/92 (51)

1985–1989

Morgenthaler, 1995 [19]

189/279 (68)

1987

Nordstrom, 1998 [2]

124/169 (73)

1995–2002

Attems, 2004* [25]

* All patients ≥70 years old. PE, pulmonary embolism.

to whether diagnosed and treated, suspected but not diagnosed or treated, or unsuspected is shown in Table 1.3 [18]. Many patients with unsuspected large or fatal PE had advanced associated disease [18]. Patients who suffer sudden and unexplained catastrophic events in the hospital are a group in whom the diagnosis might be suspected more frequently if physicians maintain a high index of suspicion [18].

Rate and sequence of organization of thromboemboli

Unsuspected PE/total PE (%)

A thrombus contains extensive regions of masses of agglutinated platelets [26]. Platelets are deposited first,

Figure 1.2 Prevalence of unsuspected pulmonary embolism (PE) at autopsy.

90

followed by leukocytes, followed after a variable period of time by fibrin with trapped red cells and a few scattered leukocytes [26]. The rate of organization of thromboemboli has been assessed in rabbits [27, 28]. The following results were shown [27, 28]: 8 minutes. Thrombus covered by an eosinophilic rim of platelets. Small amounts of fibrin were interspersed among the platelets at the edge of the thrombus [28]. 3 days. Thrombi contained masses of red cells, fibrin, platelets, and white cells together with a number of macrophages. Parts of the surface not in contact with the vessel wall were covered by flattened cells and in places these were buttressed by a layer of elongated cells beneath. Platelets were particularly

84 78

75 60 45 30 15 0

Patients with any unsuspected PE

Patients with unsuspected large or fatal PE


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PART I

Prevalence, risks, and prognosis of PE and DVT

Table 1.3 Autopsy patients ≥18 years old (n = 404). PE caused death (%)

PE contributed to death (%)

PE incidental (%)

PE total (%)

Diagnosed and treated

3 (0.7)

0 (0)

1 (0.2)

4(1.0)

Suspected but not

3 (0.7)

0 (0)

0 (0)

3 (0.7)

Unsuspected

14 (3.5)

2 (0.5)

36 (8.9)

52(12.9)

Total

20 (5.0)

2 (0.5)

37 (9.2)

59 (14.6)

diagnosed or treated

Modified from Stein and Henry [18] and reproduced with permission. PE, pulmonary embolism.

Table 1.4 Deep venous thromboses; autopsies with full limb dissection. DVT n/N (%)

Site (number of thrombi)

95/324 (29)

Site (number of patients)

First author, year [Ref]

Thighs or pelvis 7

Rossle, 1937 [29]

Thighs and Calves 38 Calves only 50 100/165 (61)

Thighs 22

Neumann, 1938 [30]

Calves 87 Ankle 17 Foot 71 88/200 (44)

Thighs only 3

Hunter, 1945 [31]

Thighs and Calves 28 Calves only 57 35/130 (27) 32/100 (32)*

Raeburn, 1951 [32] Thighs only 18

McLachin, 1962 [33]

Thighs and Calves 10 Calves only 4 149/253 (59)

Thighs only 24

Gibbs, 1957 [34]

Thighs and Calves 39 Calves only 86 13/27 (48)

IVC 1

Thighs only 1

Pelvic 1

Thighs and Calves 7

Thigh 23

Calves only 5

Stein, 1967 [35]

Calves 35† 540/1350 (40)

Pelvic 41‡

Schwarz, 1976 [9]

Thigh 21 Calves 74 161/261 (62)

IVC 8 Pelvic 31 Thigh 129 Calves 128 Foot 87

* Males >40 years old. †

Calf 11 microscopic thrombi in addition. Sample of 37 patients. DVT, deep venous thrombosis; n, number of patients with DVT; N, number of patients necropsied. ‡

Havig, 1977 [10]


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Figure 1.3 Extensive antemortem thrombus located in popliteal and calf veins. Previously unpublished figure from Stein and Evans [35].

prevalent near the thrombus–vessel wall junction. Mononuclear cells were prominent [27]. 5 and 7 days. Beginnings of vascularization were apparent. Capillaries were within the thrombus mass and in cellular areas of attachment to the intima. The central area of the thrombus showed mainly debris [27]. 7 days. Occluding thrombi had retracted in places and were covered by flattened cells, and showed one or more firm cellular attachments to the intima. Macrophages were conspicuous and contained lipid, fibrin, and cellular debris together with fibroblastic cells [27]. 14 days. Thrombi consisted of cellular masses containing small clumps of fibrin and variable amounts of fat and fibrous tissue [27]. 20 days. Some thrombi appeared as polypoid masses protruding into the lumen and containing variable amounts of fat, fibrous, and elastic tissue, and on occasion calcium, while others showed lipid within foamy cells and a fibrous tissue cap containing fibroblasts, collagen, and elastic tissue [27]. 30 days. Thromboemboli were converted to eccentric fibrofatty thickenings of the intima [27].

Deep venous thrombosis at autopsy Data on patients who had complete dissection of the lower extremities at autopsy are from prior decades,

and before the general use of antithrombotic prophylaxis [10, 29–36]. Among patients at autopsy who had full limb dissection, 1213 of 2810 (43%) showed deep venous thrombosis (DVT) [10, 29–36] (Table 1.4, Figures 1.1 and 1.3). Among 161 patients with DVT at autopsy, 7 patients had thrombi in the common iliac vein and 22 had thrombi in the external iliac vein. Each of these patients also showed DVT in the femoral vein [10]. The external iliac vein showed thrombi in 12 of 161 patients (7%) without femoral vein involvement. In 4 of these patients, the calf veins showed DVT, but not the femoral veins [10]. Deep venous thrombosis affected the veins of the calves more frequently than the veins of the thighs, and both were more frequently affected than the veins of the pelvis. The distribution of 601 thrombi found in 311 patients who had dissection of the pelvic, thigh, and calf veins was 54% in the veins of the calves, 32% in the veins of the thighs, 12% in the pelvic veins, and 1% in the inferior vena cava [10, 30, 35, 36] (Figure 1.4). The distribution of 563 thrombi among 261 necropsied patients who had dissection of the veins of the foot as well as the veins of the calf, thigh, and pelvis was 28% in the veins of the foot, 38% in the calf, 27% in the thigh, 6% in the pelvic veins, and 1% in the inferior vena cava (IVC) [10, 30] (Figure 1.5). Among 282 necropsied patients who had complete dissection of the veins of the thighs and veins of the calves, the thrombi were located only in the veins of the calves in 54% of patients [31, 33–35] (Figure 1.6).


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60

54

Thrombi (%)

50 40 32 30 20 12 10 0

1 IVC

Pelvis

Calf

Thigh

40

Figure 1.4 Distribution of deep venous thrombosis among patients at autopsy in whom pelvic, thigh, and calf veins were dissected.

38

35 Thrombi (%)

30

28

27

25 20 15 10 6 5 1 0 IVC

Pelvis

Thigh

Calf

Foot

Figure 1.5 Distribution of deep venous thrombosis among patients at autopsy in whom veins of the foot as well as pelvic, thigh, and calf veins were dissected.

Patients (%)

60

54

50 40 30

30 20

16

10 0 Thigh only

Thighs and calves

Calves only

Figure 1.6 Percentage of patients at autopsy with deep venous thrombosis who had involvement of veins of thigh only, veins of thighs and calf veins, and veins of calf only.

Figure 1.7 Normal postmortem venogram of calf (lateral projection) showing anterior tibial (AT), posterior tibial (PT), and peroneal (Pe) veins. The deep veins are paired. (Reproduced from Stein and Evans [35], with permission.)

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Both the veins of the thighs and calves were affected in 30% of patients. Only the veins of the thighs showed DVT in 16% of patients. Bilateral DVT was observed in 81 of 96 patients (84%) with extensive DVT at autopsy and in 26 of 65 (40%) of patients with minor DVT at autopsy [10]. Postmortem venography illustrates the extent and location of DVT at autopsy in unselected patients [35]. For comparison, normal postmortem venograms of the calf and thighs are shown (Figures 1.7 and 1.8). Postmortem venograms of DVT involving the veins of the thighs are shown in Figures 1.9 and 1.10. Figure 1.8 Normal postmortem venogram of the thighs (anteroposterior projection) showing the femoral (F), deep femoral (DF), greater saphenous (GS), and popliteal (P) veins. Valve pockets are shown. (Reproduced from Stein and Evans [35], with permission.)

Figure 1.9 Postmortem venogram of the veins of both thighs. Extensive thrombosis of the femoral, deep femoral, and popliteal veins was found by dissection of the left thigh. The venogram of the left thigh shows absence of filling of the popliteal and deep femoral veins and only a faint outline of the femoral vein (F). The left greater saphenous vein is dilated and joined by numerous collateral vessels. The veins of the right thigh were normal. (Reproduced from Stein and Evans [35], with permission.)

Figure 1.10 Postmortem venogram of right thigh. The femoral vein has not filled with contrast material because of a completely occluding thrombus. The greater saphenous (GS) vein is distended. Collateral vessels formed at the site of an occluding thrombus in the greater saphenous vein (arrow). (Reproduced from Stein and Evans [35], with permission.)


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PART I

Prevalence, risks, and prognosis of PE and DVT

Figure 1.11 Organized thrombus in anterior tibial vein (same patient as Figure 1.12). This thrombus is older than the thrombus in the femoral vein, and there is no phlebitis here. Hematoxylin and eosin ×40. (Previously unpublished figure from Stein and Evans [35].)

Forward thrombosis versus retrograde thrombosis

Thrombophlebitis and phlebothrombosis

In every case that we examined in which the veins of the thigh and the calf showed DVT in continuity, the thrombi in the calf were older than those in the thigh [35] (Figures 1.11 and 1.12). This supports the concept that forward thrombosis is more common than retrograde thrombosis.

The terms “thrombophlebitis” and “phlebothrombosis” in prior years were used to distinguish between DVT associated with inflammation (thrombophlebitis) and DVT not associated with inflammation (phlebopthrombosis). These are outdated terms. Histological investigations have not supported a distinction between the clinical diagnoses of thrombophlebitis and phlebothrombosis. Thrombosis of the veins of the lower extremities usually occurs without inflammation [35] (Figures 1.11 and 1.14–1.16). Inflammation of the walls of the veins, when it occurs (Figure 1.12), is usually secondary to the thrombosis [35]. No clear evidence indicates that inflammation

Collateral veins around occlusions Clinically unsuspected DVT at autopsy was often extensive, causing collateral circulation around occlusions and dilatation of collateral veins [35] (Figures 1.10 and 1.13).

Figure 1.12 Thrombus attached to femoral vein (same patient as Figure 1.11). Lymphocytic infiltrate is shown throughout the wall of the vein. The patient had signs and symptoms of deep venous thrombosis. Hematoxylin and eosin ×13. (Previously unpublished figure from Stein and Evans [35].)


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Figure 1.13 Postmortem venogram of the thighs. There is definite radiographic evidence of occlusion of the femoral vein between points 1 and 2. There is no filling of the femoral vein (F) between these points. Dilated and tortuous collaterals pass around the site of occlusion. No thrombus was found on dissection of the veins of the thigh of this patient, presumably because dissection was carried out along the collateral vessels in this area rather than the femoral vein. (This apparent femoral vein occlusion was not included among the positive cases reported in Stein and Evans [35].)

Figure 1.14 Recent thrombus attached in vein of soleal plexus. Hematoxylin and eosin ×16. (Previously unpublished figure from Stein and Evans [35].)

11

of the veins prevents embolization, or that embolization is more frequent in those patients with thrombi not associated with venous inflammation. The distinction between “thrombophlebitis” and “phlebothrombosis” is of no clinical consequence [35]. A thrombus can induce inflammation in the underlying wall of the vein, and this inflammation in some patients is extensive enough to produce pain, tenderness, swelling, and fever compatible with the clinical diagnosis of thrombophlebitis [36]. However, the underlying pathogenic mechanism is primary thrombosis and not primary phlebitis [36]. The following historical background explains the evolution of these outdated diagnostic terms. John Hunter, after studying infected venesections in human beings and in horses, attributed the thrombosis to phlebitis [37]. Virchow, however, observed that the cellular reaction in the wall of the vein usually does not occur until after the thrombus has been laid down [38]. Welch [39], in studying DVT in patients with infectious diseases such as typhoid fever, found an inflammatory lesion beneath the endothelium in which he could not demonstrate any organisms. He termed this “toxic endophlebitis” and attributed some instances of DVT to inflammation of the veins. Subsequently, patients were described who had clinical evidence of thrombosed leg veins and also had clinical signs of inflammation (warmth, redness, tenderness). A diagnosis of thrombophlebitis was made. In view of Welch’s observations, it was concluded that the primary event was inflammation of the wall of the vein. In contrast, asymptomatic patients were later described who had thrombosis of


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Prevalence, risks, and prognosis of PE and DVT

Figure 1.15 Fresh unattached thrombus in fomoral vein. Lines of Zahn distinguish this from postmortem clot. Hematoxylin and eosin ×4. (Previously unpublished figure from Stein and Evans [35].)

Figure 1.16 Photomicrograph showing thrombus originating in valve pocket of a posterior tibial vein. The well-organized fibrous point of attachment is capped by a fresh red cell, platelet, and fibrin clot. There is no inflammation of the vein. Hematoxylin and eosin ×4. (Previously unpublished figure from Stein and Evans [35].)

Figure 1.17 Thrombus attached to valve pocket in femoral vein and propagating along the vein. Venous valve is shown (arrow). Hematoxylin and eosin ×10. (Previously unpublished figure from Stein and Evans [35].)


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13

Figure 1.18 Section of left posterior tibial vein. An antemortem thrombus, 0.2 cm in largest dimension, is located within a valve pocket. (Previously unpublished figure from Stein and Evans [35].)

the lower extremities that resulted in PE [40]. These patients, because of the lack of leg signs, were said to have phlebothrombosis. Although there are situations in which phlebitis is primary and thrombosis is secondary (such as mechanical and chemical injury) [36], these are rarely compared with the incidence of thrombosis without inflammation [31, 36]. In patients with DVT at autopsy, fresh components of the thrombus as well as older components were shown, indicating that the thrombosis was continuing [35] (Figure 1.16). None of the patients were diagnosed antemortem as having DVT. A patient with clinical signs and symptoms of DVT showed lymphocytic infiltration in the media of the veins (Figure 1.12). The inflammation occurred not only at the sites of attachment of the thrombus, but also where the thrombus was apposed to the endothelium without being attached, suggesting that the thrombus induced the inflammation.

Valve pockets as site of origin of DVT The valve pockets were a frequent site of origin of thrombi (Figures 1.16–1.18). Thrombi located in valve pockets consisted of organized fibrous points of attachment capped by fresh fibrin and red cell clot [35] (Figure 1.16). Dilated veins and enlarged valve pockets were frequently seen (Figure 1.19). There was no correlation of either of these abnormalities with the presence of thrombosis [35].

Figure 1.19 Postmortem venogram showing dilated valve pocket in femoral (F) vein of left thigh (arrow). The deep femoral vein (DF) is also shown. (Reproduced from Stein and Evans [35], with permission.)


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References

18 Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 1995; 108: 978–981. 19 Morgenthaler TI, Ryu JH. Clinical characteristics of fatal pulmonary embolism in a referral hospital. Mayo Clin Proc 1995; 70: 417–424. 20 Mandelli V, Schmid C, Zogno C, Morpurgo M. “False negatives” and “false positives” in acute pulmonary embolism: a clinical–postmortem comparison. Cardiologia 1997; 42: 205–210. 21 Pheby DF, Codling BW. Pulmonary embolism at autopsy in a normal population: implications for air travel fatalities. Aviat Space Environ Med 2002; 73: 1208–1214. 22 Simpson K. Shelter deaths from pulmonary embolism. Lancet 1940; 2: 744. 23 Gross JS, Neufeld RR, Libow LS, Gerber I, Rodstein M. Autopsy study of the elderly institutionalized patient. Review of 234 autopsies. Arch Intern Med 1988; 148: 173–176. 24 Stein PD. Wedge arteriography for the identification of pulmonary emboli in small vessels. Am Heart J 1971; 82: 618–623. 25 Attems J, Arbes S, Bohm G, Bohmer F, Lintner F. The clinical diagnostic accuracy rate regarding the immediate cause of death in a hospitalized geriatric population; an autopsy study of 1594 patients. Wien Med Wochenschr 2004; 154; 159–162. 26 Poole JC, French JE, Cliff WJ. The early stages of thrombosis. J Clin Pathol 1963; 16: 523–528. 27 Still WJ. An electron microscopic study of the organization of experimental thromboemboli in the rabbit. Lab Invest 1966; 15: 1492–1507. 28 Thomas DP, Gurewich V, Ashford TP. Platelet adherence to thromboemboli in relation to the pathogenesis and treatment of pulmonary embolism. N Engl J Med 1966; 274: 953–956. 29 Rossle R. Uber die Bedeutung und die entstehung der wadenvenenthrombosen. Virchow Arch Path Anat 1937; 300: 180–189. 30 Neumann R. Ursprungszentren und entwicklungsformen der bein-thrombose. Virchow Arch Path Anat 1938; 301: 708–735. 31 Hunter WC, Krygier JJ, Kennedy JC, Sneeden VD. Etiology and prevention of thrombosis of the deep leg veins: a study of 400 cases. Surgery 1945; 17: 178–190. 32 Raeburn C. The natural history of venous thrombosis. BMJ 1951; 2: 517–520. 33 McLachlin J, Richards T, Paterson JC. An evaluation of clinical signs in the diagnosis of venous thrombosis. Arch Surg 1962; 85: 738–744. 34 Gibbs NM. Venous thrombosis of the lower limbs with particular reference to bed-rest. Br J Surg 1957; 45: 209– 236.

1 Dalen JE, Alpert JS. Natural history of pulmonary embolism. Prog Cardiovas Dis 1975; 17: 259–270. 2 Nordstrom M, Lindblad B. Autopsy-verified venous thromboembolism within a defined urban population— the city of Malmo, Sweden. Acta Path Microbiol Immunol Scand 1998; 106: 378–384. 3 Coon WW, Coller FA. Clinicopathologic correlation in thromboembolism. Surg Gynecol Obstet 1959; 109: 259– 269. 4 Smith GT, Dammin GJ, Dexter L. Postmortem arteriographic studies of the human lung in pulmonary embolization. JAMA 1964; 188: 143–151. 5 Uhland H, Goldberg LM. Pulmonary embolism: a commonly missed clinical entity. Dis Chest 1964; 45: 533–536. 6 Freiman DG, Suyemoto J, Wessler S. Frequency of pulmonary thromboembolism in man. N Engl J Med 1965; 272: 1278–1280. 7 Morrell MT, Dunnill MS. The post-mortem incidence of pulmonary embolism in a hospital population. Br J Surg 1968; 55: 347–352. 8 Coon WW. The spectrum of pulmonary embolism: twenty years later. Arch Surg 1976; 111: 398–402. 9 Schwarz N, Feigl W, Neuwirth E, Holzner JH. Venous thromboses and pulmonary emboli in autopsy material. Wien Klin Wochenschr 1976; 88: 423–428. 10 Havig O. Deep venous thrombosis and pulmonary embolism. Chapters 2, 4: Pulmonary thromboembolism. Acta Chir Scand 1977; 478(suppl): 4–11, 24–37. 11 Goldhaber SZ, Hennekens CH, Evans DA, Newton EC, Godleski JJ. Factors associated with correct antemortem diagnosis of major pulmonary embolism. Am J Med 1982; 73: 822–826. 12 Dismuke SE, VanderZwaag R. Accuracy and epidemiological implications of the death certificate diagnosis of pulmonary embolism. J Chronic Dis 1984; 37: 67–73. 13 Dismuke SE, Wagner EH . Pulmonary embolism as a cause of death. The changing mortality in hospitalized patients. JAMA 1986; 255: 2039–2042. 14 Rubenstein I, Murray D, Hoffstein V. Fatal pulmonary emboli in hospitalized patients—an autopsy study. Arch Int Med 1988; 148: 1425–1426. 15 Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis? J R Soc Med 1989; 82: 203–205. 16 Karwinski B, Svendsen E. Comparison of clinical and post-mortem diagnosis of pulmonary embolism. J Clin Pathol 1989; 42: 135–139. 17 Lindblad B, Sternby NH, Bergqvist D. Incidence of venous thromboembolism verified by necropsy over 30 years. BMJ 1991; 302: 709–711.

Prevalence, risks, and prognosis of PE and DVT


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35 Stein PD, Evans H. An autopsy study of leg vein thrombosis. Circulation 1967; 35: 671–681. 36 Allen EV, Barker NW, Hines EA, Jr. Peripheral Vascular Diseases. WB Saunders, Philadelphia, 1962: 559– 569. 37 Hunter J. Observation on the inflammation of the internal coats of veins. Trans Soc Imp Med Chir Knowl 1793; 1: 18. Quoted by Stein and Evans in Reference [35].

15

38 Virchow R. Cellular Pathology as Based Upon Physiological and Pathological Histology. J. & A. Churchill, Ltd., London, 1860: 197–203. Quoted from Gibbs NM in Reference [34]. 39 Welch WH. Thrombosis. In: Allbutt TC, ed. A System of Medicine, Vol. 6. Macmillan, New York, 1899: 180. 40 Homans J. Thrombosis of the deep veins of the lower leg causing pulmonary embolism. New Engl J Med 1934; 211: 993.


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Incidence of pulmonary embolism and deep venous thrombosis in hospitalized patients

Introduction In 1999, 140,000 patients were discharged from nonfederal short-stay hospitals in the United States with a diagnosis of pulmonary embolism (PE) and 370,000 patients were discharged with deep venous thrombosis (DVT) [1]. In 2001, the number of patients diagnosed with PE increased to 156,000, and the number discharged with DVT remained the same [2]. Either PE or DVT was diagnosed in 466,000 hospitalized patients [2]. Throughout the entire United States, from 1979 to 2001, the number of patients discharged from short-stay nonfederal hospitals with PE was 2,741,000, with DVT 6,475,000, and with either venous thromboembolism (VTE) (either PE or DVT) 8,575,000 [3]. During this 23-year period, the average populationbased rate of diagnosis of PE in hospitalized patients was 47/100,000 population, the population-based rate of diagnosis of DVT was 112/100,000 population, and for VTE it was 148/100,000 population [2].

Incidence of PE in hospitals The National Hospital Discharge Survey showed the prevalence of PE in patients ≥20 years of age averaged over a 21-year period of study from 1979 to 1999 of 0.40% [4] (Figure 2.1). During this period there were 612,000,000 short-stay nonfederal hospital admissions throughout the United States [4]. These data were based entirely on discharge codes. The results were comparable to the incidence of PE in hospitalized patients as was shown by much smaller but more rigidly defined retrospective evaluations (0.27–0.4%) [5–8]. (National Hospital Discharge Survey. Available at: http://www.cdc.gov/nchs/about/major/hdasd/nhds .htm.)

16

The incidence of PE in hospitalized patients did not change over 21 years [4] (Figure 2.2). The incidence of PE in hospitalized patients was nearly the same in men and women (relative risk of men to women 1.11) [4] (Figure 2.3). The incidence of PE in hospitalized patients was the same in white and black patients (relative risk of white patients to black patients 1.00) [4] (Figure 2.4). The prevalence of PE in a general hospital, based on clinical diagnoses, many of which were confirmed at autopsy, in an era prior to pulmonary angiography or ventilation–perfusion scans was 0.2% [9]. The prevalence of acute PE in patients in a clinic of digestive surgery, diagnosed by pulmonary angiography, high probability V-Q scans or autopsy was 0.3% [10]. Using comparable criteria, we found the same prevalence (0.3%) [8]. The inclusion of patients estimated to have PE based on non-high-probability interpretations of the ventilation–perfusion lung scans and the inclusion of patients with clinically undiagnosed PE at autopsy caused the estimated prevalence of PE to be higher, 1.0% [5]. There are, in addition, patients with silent PE, the frequency of which is undetermined. On average, PE occurs in 13% of patients at autopsy, among whom the diagnosis was unsuspected antemortem in 84% (Chapter 1).

Incidence of DVT in hospitals Based on results of the National Hospital Discharge Survey, the prevalence of DVT in patients ≥20 years of age averaged over the 21-year period of study was 0.93% [4] (Figure 2.1). Venous thromboembolic disease (VTE), defined as PE and/or DVT, occurred in 1.24% [4] (Figure 2.1). The incidence of DVT in


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17

PE and DVT in hospitalized patients

0.5 0.40

PE

VTE

2

VTE

1.5 DVT 1 0.5

PE

0 99

97

95

93

91

89

87

85

83

81

VTE, DVT, PE in hospitalized adults (%)

DVT

1.8 1.6

Male

1.4

DVT

1.2 Female

1 0.8

Male

0.6

PE

0.4

Female

0.2 99

97

95

93

91

89

87

85

83

81

PE and DVT in hospitalized adults according to sex (%)

Year

Year

2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2

White patients Black patients White patients Black patients

99

97

95

93

Year

91

89

87

85

83

81

79

Figure 2.4 Incidences of pulmonary embolism (PE) and deep venous thrombosis (DVT) in hospitalized adults from 1979 to 1999 according to race. The incidences in black and white patients were the same for PE and nearly the same for DVT. (Reprinted from Stein et al. [4], with permission from Elsevier.)

0.93

79

Figure 2.3 Incidences of pulmonary embolism (PE) and deep venous thrombosis (DVT) in hospitalized adults from 1979 to 1999 according to sex. The incidences in men and women were nearly the same. (Reprinted from Stein et al. [4], with permission from Elsevier.)

1.24

1

79

Figure 2.2 Incidences of pulmonary embolism (PE), deep venous thrombosis (DVT), and venous thromboembolism (VTE) in hospitalized adults from 1979 to 1999. The incidence of DVT increased (slope = 0.028%/year, r = 0.92, P < 0.0005). The incidence of PE did not change. The incidence of VTE increased in parallel to the incidence of DVT. (Reprinted from Stein et al. [4], with permission from Elsevier.)

1.5

0

PE and DVT in hospitalized adults according to race (%)

Figure 2.1 Prevalence of pulmonary embolism (PE), deep venous thrombosis (DVT) and either PE or DVT, venous thromboembolism (VTE) in hospitalized adults (â&#x2030;Ľ20 years). (Data from Stein et al. [4].)

PE and DVT in hospitalized adults (%)

2


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PART I

hospitalized patients increased from 239,000 of 30,771,000 (0.8%) in 1979 to 363,000 of 28,504,000 (1.3%) in 1999 and the incidence of VTE increased in parallel (Figure 2.2). The incidence of DVT in hospitalized patients was nearly the same in men and women (relative risk of men to women 1.05) [4] (Figure 2.3). The incidence of DVT in hospitalized patients was nearly the same for white and black patients (relative risk 1.05) [4] (Figure 2.4). The increasing incidence of DVT in hospitalized patients from 1979 to 1999 may represent an increasing availability and use of venous ultrasound during much of that period [1]. Early diagnosis and treatment of DVT may have prevented a parallel increase in the incidence of PE in hospitalized patients. Whether the trend toward an increasing incidence of DVT in hospitalized patients will continue is uncertain, particularly in view of outpatient treatment of DVT, which was introduced in 1996 and 1997 [11–13]. The reported incidence of DVT in hospitals, 0.1– 3.17%, ranged more widely than the incidence of PE [14–17]. In Asian hospitals the prevalence of DVT was lower [18, 19], but VTE has been reported to be uncommon among Asians [20, 21] (see Chapter 15).

7 Proctor MC, Greenfield LJ. Pulmonary embolism: diagnosis, incidence and implications. Cardiovasc Surg 1997; 5: 77–81. 8 Stein PD, Patel KC, Kalra NJ et al. Estimated incidence of acute pulmonary embolism in a community/teaching general hospital. Chest 2002; 121: 802–805. 9 Hermann RE, Davis JH, Holden WD. Pulmonary embolism. A clinical and pathologic study with emphasis on the effect of prophylactic therapy with anticoagulants. Am J Surg 1961; 102: 19–28. 10 Huber O, Bounameaux H, Borst F et al. Postoperative pulmonary embolism after hospital discharge: an underestimated risk. Arch Surg 1992; 127: 310–313. 11 The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 337: 657–662. 12 Levine M, Gent M, Hirsh J et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677–681. 13 Koopman MMW, Prandoni P, Piovella F et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334: 682–687. 14 Klatsky AL, Armstrong MA, Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in AsianAmericans. Am J Cardiol 2000; 85: 1334–1337. 15 Igbinovia A, Malik GM, Grillo IA et al. Deep venous thrombosis in Assir region of Saudi Arabia. Case–control study. Angiology 195; 46: 1107–1113. 16 Schuurman B, den Heijer M, Nijs AM. Thrombosis prophylaxis in hospitalized medical patients: does prophylaxis in all patients make sense? Neth J Med 2000; 56: 171–176. 17 Stein PD, Patel KC, Kalra NK et al. Deep venous thrombosis in a general hospital. Chest 2002; 122: 960–962. 18 Liam CK, Ng SC. A Review of patients with deep vein thrombosis diagnosed at university hospital, Kuala Lumpur. Ann Acad Med Singapore 1990; 19: 837–840. 19 Kueh YK, Wang TL, Teo CP et al. Acute deep vein thrombosis in hospital practice. Ann Acad Med Singapore 1992; 21: 345–348. 20 Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asian/Pacific Islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med 2004; 116: 435–442. 21 White RH, Zhou H, Romano PS. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann Intern Med 1998; 128: 737–740.

References 1 Stein PD, Hull RD, Ghali WA et al. Tracking the uptake of evidence: two decades of hospital practice trends for diagnosing deep venous thrombosis and pulmonary embolism. Arch Intern Med 2003; 163: 1213–1219. 2 Unpublished data from Stein PD, Kayali F, Olson RE. Regional differences in rates of diagnosis and mortality of pulmonary thomboembolism. Am J Cardiol 2004; 93: 1194–1197. 3 Stein PD, Kayali F, Olson RE. Regional differences in rates of diagnosis and mortality of pulmonary thomboembolism. Am J Cardiol 2004; 93: 1194–1197. 4 Stein PD, Beemath A, Olson RE. Trends in the incidence of pulmonary embolism and deep venous thrombosis in hospitalized patients. Am J Cardiol 2005; 95: 1525– 1526. 5 Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 1995; 108: 978–981. 6 Stein PD, Huang H, Afzal A et al. Incidence of acute pulmonary embolism in a general hospital: relation to age, sex and race. Chest 1999; 116: 909–913.

Prevalence, risks, and prognosis of PE and DVT


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CHAPTER 3

Case fatality rate and population mortality rate from pulmonary embolism and deep venous thrombosis

Overview

Untreated patients

Among all patients with pulmonary embolism (PE) throughout the United States, irrespective of treatment or the severity of the PE, the estimated case fatality rate (death from PE/100 patients with PE) in 1998 was 7.7% [1]. The case fatality rate from untreated clinically apparent PE, obtained before anticoagulant therapy was universally used, was 26â&#x20AC;&#x201C;37% [2, 3]. In recent years, however, the case fatality rate from mild untreated PE, based on a small number of patients was 5% [4]. The case fatality rate from acute PE in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) was 2.5% [5]. This rate applies to patients who were well enough to be recruited into an investigation of the diagnostic validity of ventilationâ&#x20AC;&#x201C; perfusion lung scans [5]. Most fatalities from PE occur within the first 2.5 hours after the diagnosis is made [6]. Such patients could not have been included in PIOPED. Case fatality rates from PE in trials of treatment with low-molecular-weight heparin were 0.6â&#x20AC;&#x201C; 1.0% [7, 8]. In such trials patients with massive PE requiring thrombolytic therapy, and patients at risk of bleeding, among others, were excluded. The most important factor affecting mortality is shock due to right ventricular failure secondary to PE [9]. In patients with over 50% occlusion of the pulmonary circulation who were in shock, the case fatality rate was 32%, whereas in those with over 50% occlusion of the pulmonary circulation who were not in shock, the case fatality rate was 6% [9].

Regarding untreated patients with acute PE in decades before diagnostic imaging tests were available, Barritt and Jordan reported a 26% mortality from the initial PE [3]. Some of these patients perhaps died from recurrent PE [3]. The diagnosis was made on the basis of clinical features that included evidence of right ventricular failure, pulmonary infarction, or both. Clinical features of pulmonary infarction included pleuritic pain, hemoptysis, pleural friction rub, loss of resonance at the lung base, rales, and the chest radiograph. Features that they relied upon for the detection of acute right ventricular failure were faintness, chest pain, fall of blood pressure, rise of jugular venous pressure, and the electrocardiogram. In 1961, Hermann and associates calculated a 37% case fatality rate from the initial PE [2] (Figure 3.1). The diagnosis was based on clinical features, and autopsy among those who died. The treatment of these patients was not reported, although data were collected between 1943 and 1957 and anticoagulant therapy was not in general used before 1947 [2]. Hermann and associates also reported a 36% frequency of fatal recurrent PE. The total estimated frequency of death that included the original PE and recurrent PE was 73% (Figure 3.1). There was, in addition, a 21% frequency of nonfatal recurrent PE among untreated patients with clinically diagnosed PE (Figure 3.2). Presumably, PE was severe among these patients with apparent clinical features.

19


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Untreated fatal PE Initial and recurrent 73%

80 60

Initial 37%

Treated patients in the modern era Case fatality rates (PE deaths/100 PE) have been reported in regional surveys [10], regional estimates [11], registries [12], and prospective investigations [5]

Non-fatal recurrent PE (%)

Untreated PE 40 30

21% 20

5%

10 0

Clinically apparent initial PE

Mild initial PE

Figure 3.2 Nonfatal recurrent pulmonary embolism (PE) among untreated patients diagnosed on the basis of clinical findings (clinically apparent PE) and among patients with mild PE diagnosed by objective tests. (Data from Hermann et al. [2] and Stein and Henry [4].)

1997

We evaluated the 20 patients who received no treatment for PE during the first 3 months of follow-up of PIOPED [4]. Only 1 of these patients (5%) died of PE [4] (Figure 3.1). These 20 patients from PIOPED are described in Chapter 5.

1995

Figure 3.1 Fatal initial pulmonary embolism (PE) and fatal initial and recurrent PE among untreated patients diagnosed on the basis of clinical findings (clinically apparent PE) and among patients with mild PE diagnosed by objective tests. (Data from Hermann et al. [2] and Stein and Henry [4].)

1993

Mild PE

1991

Clinically apparent PE

1989

Clinically apparent PE

0 1987

0

4

1985

Initial & recurrent 5%

20

8

1983

40

12

1981

Mortality (%)

100

Prevalence, risks, and prognosis of PE and DVT

1979

Fatal PE/all PE (%)

PART I

Year Figure 3.3 Estimated case fatality rate for pulmonary embolism (PE) from 1979 to 1998. (Reprinted from Stein et al. [1], with permission from Elsevier.)

where the number of deaths was in the hundreds, and in elderly patients [13] where the number of deaths was several thousand. We calculated case fatality rates of PE from a database with 194,000 PE deaths, based on the entire population of the United States from 1979 to 1998 [1]. The estimated case fatality rate from PE increased from 6.7% in 1979 to 10.5% in 1989 (Figure 3.3). From 1989 to 1998 the estimated case fatality rate decreased to 7.7 PE deaths/100 PE. The estimated case fatality rate in the Minneapolis-St. Paul metropolitan area in 1995 ranged from approximately 2 to 6% depending on age [11]. As in our investigation, these are estimated rates [11]. The case fatality rate in short-stay hospitals in metropolitan Worcester in 1985â&#x20AC;&#x201C;1986 (12%) was somewhat higher than what we calculated during those years [10]. The estimated case fatality rate from PE increased with age (Figure 3.4). The relation of case fatality to age was described by an exponential function. The higher case fatality rate with age is concordant with regional investigations [10, 11] and studies in individual hospitals [2, 14]. The estimated case fatality rate from PE over the 20year interval of observation was higher among African Americans than Caucasians (Figure 3.5). The rate ratio of African Americans to Caucasians was 1.43. Others observed a higher case fatality rate among elderly African Americans than elderly Caucasians [13]. The estimated case fatality rate was comparable in men and women (Figure 3.6) as had been shown in regional studies [10, 11]. Among the patients â&#x2030;Ľ65 years of age, we showed no difference in the case fatality rate between men and women. In an investigation of Medicare patients aged 65â&#x20AC;&#x201C;74 years, the case fatality


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Case fatality rate and population mortality rate

20

Figure 3.4 Estimated case fatality rates for pulmonary embolism (PE) according to decades of age. The estimated case fatality rates are the average of yearly values over a 20-year period. (Reprinted from Stein et al. [1], with permission from Elsevier.)

Fatal PE/all PE (%)

17.4 15 10.9 10

8.2 3.6

5

6.9

5.5

0 25−34 35−44

45−54 55−64 65−74 75−84

>85

Age group (years)

rate in 1991 of 10.0% in white men and 9.4% in white women [13] was comparable to our estimated case fatality rates of 7.3 and 9.2% in white men and women aged 65 years or older the same year. The case fatality rate in black females aged 65 years or older in 1991 was virtually identical in both studies (11.4 and 11.1%), but we calculated a higher rate in black males (20.9% versus 13.5%).

Massive PE: hypotensive patients Among patients with massive PE, defined as a systolic arterial pressure <90 mm Hg, death from PE within 90 days occurred in 35 of 108 (32%) [15] (Figure 3.7). Among patients with systolic arterial pressure ≥90 mm Hg, death from PE within 90 days occurred in 119 of 2284 (5%).

Treated patients with PE compared with treated patients with deep venous thrombosis (DVT) Pooled data among treated patients with PE and treated patients with DVT showed higher death rates from recurrent PE among the PE patients [16]. Among 2429 patients with DVT treated 5 days to 3 months with anticoagulants, death from PE occurred in 0.3% (Figure 3.8). Among 949 patients with PE treated 5 days to 3 months, death from recurrent PE occurred in 1.4%. The death rates from PE excluded deaths within the first 5 days of diagnosis [16]. Patients treated with thrombolytic agents or inferior vena cava filters were also excluded.

Population mortality rate from PE The number of patients who died from PE in 1998 based on death certificates was 24,947 [17]. With a

Caucasians 1997

1995

1993

1991

1989

1987

1985

1983

1981

Male

8

Female

4 0

1997

1995

1993

1991

1989

1987

1985

1983

1981

Figure 3.5 Case fatality rate from pulmonary embolism (PE) among African Americans and Caucasians. The estimated case fatality rate from PE was higher among African Americans than Caucasians over the 20-year period of observation (P = 0.014). (Reprinted from Stein et al. [1], with permission from Elsevier.)

12

1979

Year

Fatal PE/all PE (%)

African American

20 16 12 8 4 0 1979

Fatal PE/all PE (%)

4.7

Year Figure 3.6 Case fatality rate according to sex. The estimated case fatality rate among males and females was comparable. (Reprinted from Stein et al. [1], with permission from Elsevier.)


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22

PART I

40 35 30 25 20 15 10 5 0

32%

5%

PE BP < 90 mm Hg

PE BP > 90 mm Hg

Figure 3.7 Death rates from pulmonary embolism (PE) within 90 days among patients with massive PE, defined as a systolic arterial pressure (BP) <90 mm Hg, and patients with nonmassive PE (systolic arterial pressure ≥90 mm Hg). (Data are from Kucher et al. [15].)

population of 270,299,000 in 1998, this would amount to 9 PE deaths/100,000 population. Assuming that death certificates are only 26.7% accurate for the diagnosis of fatal PE [18], the estimated number of deaths from PE in 1998 may be 93,000 and the death rate may be 34 PE deaths/100,000 population. Over the last two decades the population mortality rate from PE (deaths from PE/100,000 population) decreased [17, 19]. This could be a consequence of a declining incidence of PE (diagnoses of PE/100,000 population) or a declining case fatality rate from PE (deaths from PE/100 cases of PE) or the combination. For the interval 1979–1989, our data showed no decline in the case fatality rate (Figure 3.3), which suggests that

1.4%

Fatal PE (%)

1.5

1

0.5

n = 949 0.3%

n = 2429 0 DVT

PE

Figure 3.8 Pooled data among patients with pulmonary embolism (PE) and patients with deep venous thrombosis (DVT) treated 5 days to 3 months with anticoagulants. The death rate from recurrent PE was higher in patients with PE than the death rate from PE in patients with DVT. (Data are from Douketis et al. [16].)

Prevalence, risks, and prognosis of PE and DVT

the declining population mortality rate from PE was largely due to a declining incidence of PE. From 1979 to 1999, the incidence of diagnosis has, in fact, decreased [20]. Improved prevention of PE may have been a key factor. From 1989 to 1998, the declining population mortality rate appears to be largely due to a declining case fatality rate. The rate of diagnosis of PE no longer declined during this interval [20], but the population mortality rate continued to decline [17]. The estimated case fatality rate also declined during this period (Figure 3.3). The declining population mortality rate during this period, therefore, reflected a decreased case fatality rate. Earlier diagnosis and improved management rather than improved prevention would account for the decreased population mortality rate during this period. The trends in estimated case fatality that we showed were concordant with trends from the Minneapolis-St. Paul metropolitan area [21]. Both databases showed either an increasing or unchanging case fatality rate from 1979 to the mid- or late 1980s [21] followed by a declining case fatality rate.

References 1 Stein PD, Kayali F, Olson RE. Estimated case fatality rate of pulmonary embolism, 1979–1998. Am J Cardiol 2004; 93: 1197–1199. 2 Hermann RE, Davis JH, Holden WD. Pulmonary embolism: a clinical and pathologic study with emphasis on the effect of prophylactic therapy with anticoagulants. Am J Surg 1961; 102: 19–28. 3 Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet 1960; 1: 1309–1312. 4 Stein PD, Henry JW, Relyea B. Untreated patients with pulmonary embolism: outcome, clinical and laboratory assessment. Chest 1995; 107: 931–935. 5 Carson JL, Kelley MA, Duff A et al. The clinical course of pulmonary embolism. New Engl J Med 1992; 326: 1240– 1245. 6 Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 1995; 108: 978–981. 7 The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 337: 657–662. 8 Simonneau G, Sors H, Charbonnier B et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESSE Study Group. N Engl J Med 1997; 337: 663–669.


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Case fatality rate and population mortality rate

9 Alpert JS, Smith R, Carlson J et al. Mortality in patients treated for pulmonary embolism. JAMA 1976; 236: 1477– 1480. 10 Anderson FA, Wheeler HB, Goldberg RJ et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933–938. 11 Janke RM, MCGovern PG, Folsom AR. Mortality, hospital discharges, and case fatality for pulmonary embolism in the twin cities: 1980–1995. J Clin Epidemiol 2000; 53: 103–109. 12 Goldhaber SZ, Visani L, De Rosa M, for ICOPER. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353: 1386–1389. 13 Siddique RM, Siddique MI, Conners AF, Jr, Rimm AA. Thirty-day case-fatality rates for pulmonary embolism in the elderly. Arch Intern Med 1996; 156: 2343–2347. 14 Byrne JJ. Phlebitis: a study of 748 cases at the Boston City Hospital. New Engl J Med 1955; 253: 579–586. 15 Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation 2006; 113: 577–582.

23

16 Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998; 279: 458– 462. 17 Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979–1998: an analysis using multiple-cause mortality data. Arch Intern Med 2003; 163: 1711–1717. 18 Attems J, Arbes S, Bohm G, Bohmer F, Lintner F. The clinical diagnostic accuracy rate regarding the immediate cause of death in a hospitalized geriatric population; an autopsy study of 1594 patients. Wien Med Wochenschr 2004; 154: 159–162. 19 Lilienfeld DE. Decreasing mortality from pulmonary embolism in the United States, 1979–1996. Int J Epidemiol 2000; 29: 465–469. 20 Stein PD, Hull RD, Patel KC et al. Venous thromboembolic disease: comparison of the diagnostic process in men and women. Arch Intern Med 2003; 163: 1689–1694. 21 Lilienfeld DE, Godbold JH, Burke GL, Sprafka JM, Pham DL, Baxter J. Hospitalization and case fatality for pulmonary embolism in the twin cities: 1979–1984. Am Heart J 1990; 120: 392–395.


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CHAPTER 4

Prognosis in acute pulmonary embolism based on right ventricular enlargement, prognostic models, and biochemical markers

Right ventricular enlargement and prognostic models The prognosis in acute pulmonary embolism (PE) depends on the severity of the PE and the prior cardiorespiratory condition of the patient. The size of the PE has been assessed by the pulmonary angiogram, CT angiogram (Chapter 73), and perfusion lung scans [1]. Indices of severity include shock, pulmonary hypertension, right ventricular dilatation, and Pa O2 . Elderly patients had a worse prognosis than young patients (Chapter 3). Literature review of the prognostic value of echocardiographically assessed right ventricular dysfunction showed that short-term PE-related deaths occurred in 4–14% more patients with right ventricular dysfunction than in those without right ventricular dysfunction [2]. Among normotensive patients, the short-term mortality was 4 and 5% higher among those with right ventricular dysfunction [2]. Others, in a review, found a short-term mortality of 5% in normotensive patients with ventricular dysfunction [3]. Among patients with PE in whom the right ventricular to left ventricular short-axis ratio (RV/LV) was measured by CT, the positive predictive value of death from PE in 3 months was 10% in 69 patients with RV/LV > 1 and it was zero among 51 patients with RV/LV ≤ 1 [4]. However, among patients with PE in PIOPED II who were treated only with anticoagulants and/or an inferior vena cava filter, who were not hypotensive, in shock, critically ill, on ventilatory support, did not have a myocardial infarction within the previous month, and did not have an episode of ven-

24

tricular tachycardia or ventricular fibrillation within the previous 24 hours, in-hospital outcome was the same in those with and those without an enlarged right ventricle (Stein PD, Beemath A, Matta F, et al., unpublished data from PIOPED II). The in-hospital mortality from PE on in these patients with an RV/LV short axis dimension ratio >1 measured on CT angiograms was 0 of 76 (0%) versus 1 of 79 (1.3%) in those with an RV/LV dimension ratio ≤1. The in-hospital all cause mortality in those with an RV/LV dimension ratio >1 was 2 of 76 (2.6%) versus 2 of 79 (2.5%) in those with an RV/LV dimension ratio ≤1. The case fatality rate in hypotensive patients and in patients with right ventricular enlargement or dysfunction is described in Chapter 89. Correlation of pulmonary artery mean pressure with angiographic severity was low (r = 0.38) as was the correlation of Pa O2 (r = −0.34) [5]. Prognostic models based on weighting of several indices of severity have been described [6–8]. The most recent consists of 11 routinely available predictors of 30-day all-cause mortality [6]. These were age, male sex, cancer heart failure, chronic lung disease, pulse ≥110/min, respiratory rate ≥30/min, temperature <36◦ C, altered mental status (disorientation, lethargy, stupor, or coma), and oxygen saturation <90 mm Hg [6]. These were assigned point scores as shown in Table 4.1. Validation in a subsequent investigation showed a 30-day all-cause mortality of 0, 1.0, 3.1, 10.4, and 24.4% in the respective five classes of risk, which did not differ from the original derivation values [9]. Several laboratory tests were also independently associated with 30-day all-cause mortality [9].


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Table 4.1 Predictors of 30-day mortality. Predictor

Point Score

Age

1 point/yr

Male

10

Cancer

30

Heart failure

10

Chronic lung disease

10

Pulse >110/min

20

Systolic blood pressure <100 mm HG

30

Respiratory rate ≥30/min

20

Temperature <36◦ C

20

Disorientation, lethargy, stupor, or coma

60

Oxygen saturation <90 mm Hg

20

Risk

Point Score

very low

≤65

low intermed

66–85 86–105

high

106–125

very high

>125

Table base on Aujesky et al. [9].

These included hemoglobin <12 g/dL, white blood cell count <4000 or >12,000/mm3 , platelets <100,000/mm3 , sodium <130 or >150 meq/L, blood urea nitrogen ≥30 mg/dL, arterial pH 7.25, and Pa CO2 <25 or >55 mm Hg [9]. The more complex model that included laboratory findings showed 30-day mortalities that were similar to mortalities with the less complex model [9].

Cardiac troponins Cardiac troponins are regulatory proteins of the thin actin filaments of the cardiac muscle [10]. They control the calcium-mediated interaction of actin and myosin [11]. Troponin T and troponin I are highly sensitive and specific markers of myocardial injury [10]. The release of cardiac troponin from the myocyte to the blood can be due to reversible or irreversible cell damage [11]. Ischemia without coronary stenosis (demand ischemia), resulting from a mismatch between myocardial oxygen supply and demand, may occur [11]. This may cause increased membrane permeability and release of smaller troponin fragments into the systemic circulation [11]. It has been thought for many years that some of the electrocardiographic changes in acute PE reflect myocardial ischemia [12–14]. Myocardial

25

infarction has been shown at autopsy of patients who died of PE and had normal coronary arteries [12, 13, 15, 16]. In fact, investigations in dogs [17] and in pigs [18] with experimentally induced PE showed that blood flow increased in both the right and left coronary arteries. Coronary blood flow increased concordantly with increasing pulmonary artery pressure and decreasing PaO2 [17, 18]. The troponin complex consists of three subunits: troponin T, which binds to tropomyosin and facilitates contraction; troponin I, which binds to actin and inhibits actin–myosin interactions; and troponin C, which binds to calcium ions [11]. The amino acid sequences of the skeletal and cardiac isoforms of cardiac troponin T and troponin I are sufficiently dissimilar and therefore detectable by monoclonal antibodybased assays [11]. Troponin C is not used clinically because both cardiac and smooth muscle share troponin C isoforms. In-hospital, all-cause mortality among patients with acute PE who had an elevated troponin I ranged from 14 to 36% and in patients with a normal troponin I, in-hospital mortality ranged from 2 to 7% [19–26] (Table 4.1). Pooled data among patients with an elevated troponin I showed an in-hospital mortality 24 of 109 (22%) versus 17 of 291 (6%) among patients with a normal troponin I. Patients with a markedly elevated troponin I level above 1.5 ng/mL had a higher mortality from PE (22% mortality) than those with a modest elevation of 0.07–1.5 ng/mL (10% mortality) [20]. Among unselected PE patients with an elevated troponin T, in-hospital, all-cause mortality was 13 of 57 (23%) versus 3 of 105 (3%) [20, 24] among patients with a normal troponin T (Table 4.2).

Troponin levels in combination with right ventricular dysfunction or right ventricular dilatation Acute right ventricular dilatation or dysfunction has been shown to indicate a poor prognosis by several investigators. This is reviewed in Chapter 57. Patients with right ventricular dysfunction in combination with an elevated troponin I [23] or troponin T [27] showed high rates of in-hospital mortality compared with those in whom the right ventricle was normal and troponin level was not elevated (Table 4.3). In-hospital mortality, however, was the same in patients with


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PART I

Prevalence, risks, and prognosis of PE and DVT

Table 4.2 Mortality and troponin levels in patients with acute pulmonary embolism. Troponin I

Cutoff

Abnormal, mortality

Normal, mortality

value

Cause of

Follow-up

First author [Ref]

n/ N (%)

n/ N (%)

(ng/mL)

death

duration

Yalamanchili [19]

8/24 (33)

All cause

In-hospital

Unselected

7/43 (16)*

9/123 (7) 1/63 (2)*

≥2.0

Konstantinides [20]

≥0.07

All cause

In-hospital

Unselected

Kucher [21]

4/28 (14)

1/63 (2)

≥0.06

All cause

In-hospital

Unselected

La Vecchia [22]

5/14 (36)

1/42 (2)

>0.6

All cause

In-hospital

Unselected

Scridon [23]

23/73 (32)*

5/68 (7)*

>0.1

All cause

30 days

Unselected

Troponin T

Selection

Cutoff

Abnormal, mortality

Normal, mortality

value

Cause of

Follow-up

First author [Ref]

n/ N (%)

n/ N (%)

(ng/mL)

death

duration

Konstantinides [20]

5/39 (13)*

2/67 (3)*

≥0.04

All cause

In-hospital

Unselected

Giannitsis [24]

8/18 (44)

1/38 (3)

≥0.1

All cause

In-hospital

Unselected

Selection

Pruszczyk [25]

8/32 (25)

0/32 (0)

>0.01

All cause

In-hospital

Normotensive

Pruszczyk [26]

6/24 (25)

1/22 (5)

>0.01

All cause

In-hospital

RV Dilatation

* Estimated from authors’ graphs.

elevations of troponin, irrespective of right ventricular function.

Myoglobin Myoglobin is a low-molecular-heme protein that is found in both cardiac and skeletal muscle and, therefore, is not cardiac specific [28, 29]. It is among the earliest markers released into the circulation [30], and may be detected as early as 2 hours after the onset of myocardial necrosis [28]. Serum myoglobin after myocardial infarction increases even before a detectable rise of cardiac troponin levels occurs [29]. Myoglobin measurement for the diagnosis of the acute coronary syndrome is most efficient when measured within 6 hours after the onset of myocardial infarc-

tion [28]. Literature on myoglobin levels in pulmonary embolism is sparse. Among patients with PE who had right ventricular distention and an elevated myoglobin level, in-hospital, all-cause mortality was 7 of 21 (33%) versus 0 of 25 (0%) among such patients who had a normal myoglobin level [16] (Table 4.4).

Natriuretic peptides The natriuretic peptides are useful diagnostic and prognostic biomarkers for patients with congestive heart failure [31]. In contrast to atrial natriuretic peptide that originates mainly from atrial tissue, brain natriuiretic peptide (BNP) is produced to a large degree from ventricular myocytes [31]. The principal stimulus for BNP synthesis and secretion is cardiomyocyte

Table 4.3 Mortality and right ventricular dysfunction with elevated troponin levels in patients with acute pulmonary embolism. RV dysfunction

RV normal and

and elevated

troponin not

troponins

elevated

[mortality

[mortality

First author [Ref]

n/N (%)]

n/N (%)]

Scridon [23]

17/45 (38)

Binder [27] ∗

3/16 (19)*

Estimated from authors’ graphs.

Troponin type

Cutoff value

Cause of

Follow-up

(ng/mL)

death

duration

— (5)

Trop I

>0.1

All cause

30 days

0/53 (0)

Trop T

≥0.04

All cause

In-hospital


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Prognosis in acute pulmonary embolism

Table 4.4 Mortality and myoglobin levels in patients with acute pulmonary embolism. Myoglobin High, mortality

Normal, mortality

Cutoff value

Cause of

Follow-up

First author [Ref]

n/N (%)

n/N (%)

(ng/mL)

death

duration

Selection

Pruszczyk [20]

7/21 (33)

0/25 (0)

>0.01

All cause

In-hospital

RV dilatation

stretch [31]. Brain natriuretic peptide is a 32-amino acid peptide hormone first isolated from porcine brain tissue [31]. In plasma, the intact 108 amino acid prohormone (proBNP), the biologically active 32-amino acid BNP, and the remaining part of the prohormone, N-terminal (NT)-proBNP, which is 76 amino acids, can be measured by immunoassay [31]. Prohormones in normal ventricular myocytes are not stored to a significant amount. Therefore, it takes several hours for the plasma natruiretic levels to increase significantly after the onset of stretch [32]. This process includes BNP messenger ribonucleic acid synthesis, prohormone synthesis, and prohormone release into the circulation. Elevations in BNP [33] and NT-proBNP [34] are associated with right ventricular dysfunction in acute PE. Natriuretic peptide levels are also increased in patients with right ventricular pressure overload due to causes other than PE, including primary pulmonary hypertension, chronic thromboembolic hypertension, congenital heart disease, and chronic lung disease [35–38].

Brain natriuretic peptides in patients with PE, when low, predict a benign clinical outcome, with few inhospital deaths from PE [31]. There were no inhospital deaths among 70 patients with PE who had a low NT-proBNP level [28, 39] and 2 in-hospital deaths among 66 patients with PE who had a low BNP level [40, 41] (Table 4.5). Published cutoff values for NT-proBNP [27, 34, 39] and for BNP [40–42] vary (Table 4.4). Because BNP release into the circulation may take several hours after the onset of myocardial injury, a second measurement should be obtained 6– 12 hours after an initially negative test in a PE patient with a symptom duration <6 hours [31].

Serum uric acid Uric acid is the final product of purine nucleotide degradation. Tissue hypoxia depletes adenosine triphosphate (ATP) and activates the purine nucleotide degradation pathway to uric acid, resulting in urate overproduction [43, 44]. Serum uric acid level is therefore determined by the imbalance between

Table 4.5 Mortality, brain natriuretic peptide, and N-terminal pro-brain natriuretic peptide levels in patients with acute pulmonary embolism. Natriuretic peptide

Peptide and

First author

High, mortality

Normal, mortality

cutoff value

Cause of

Follow-up

[Ref]

n/N (%)

n/N (%)

(pg/mL)

death

duration

Selection

Binder [27]

7/67 (10)*

0/57 (0)

NT-proBNP

All cause

In-hospital

Unselected

All cause

In-hospital

Unselected

Pulmonary

In-hospital

Unselected

In-hospital

Unselected

3 months

Unselected

≥1000 Pruszczyk [39]

15/66 (23)

0/13 (0)

NT-proBNP 88–334†

Kruger [40]

1/17 (6)

1/25 (4)

BNP >90

embolism Kucher [41]

4/32 (13)

1/41 (2)

BNP ≥90

Pulmonary embolism

ten Wolde [42]

4/36 (11)

1/74 (1)

BNP >21.7 pmol/L

Pulmonary embolism

Estimated from authors’ graphs. NT-proBNP cutoff level age and sex dependent. NT-proBNP, N-terminal pro-brain natriuretic peptide; BNP, brain natriuretic peptide. †


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PART I

production and excretion and is increased in hypoxic states such as left ventricular failure, cyanotic heart disease, and obstructive pulmonary disease [45–50]. Among 71 patients with acute PE, serum uric acid was elevated (mean ± SD 6.2 ± 2.3 mg/dL) compared with 62 age- and sex-matched controls (4.5 ± 0.9 mg/dL) [51]. Serum uric acid was higher in the 27 patients who died from PE during hospitalization than in the remaining survivors (8.3 ± 2.2 versus 6.5 ± 2.2 mg/dL). After treatment including thrombolysis and pulmonary embolectomy, serum uric acid level significantly decreased in patients with PE from 6.7 ± 2.0 to 5.8 ± 1.9 mg/dL.

10 Ammann P, Pfisterer M, Fehr T, Rickli H. Raised cardiac troponins: causes extend beyond acute coronary syndromes. BMJ 2004; 328: 1028–1029. 11 Ammann P, Maggiorini M, Bertel O et al. Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes. J Am Coll Cardiol 2003; 41: 2004–2009. 12 Horn H, Dack S, Friedberg CK. Cardiac sequelae of embolism of the pulmonary artery. Arch Int Med 1939; 64: 296. 13 Dack S, Master AM, Horn H, Grishman A, Field LE. Acute coronary insufficiency due to pulmonary embolism. Am J Med 1949; 7: 464. 14 Weber DM, Phillips JH, Jr. A re-evaluation of electrocardiographic changes accompanying acute pulmonary embolism. Am J Med Sci 1966; 251: 381–398. 15 Currens J, Barnes AR. The heart in pulmonary embolism. Arch Int Med 1943; 71: 325. 16 Coma-Canella I, Gamallo C, Martinez Onsurbe P, LopezSendon J. Acute right ventricular infarction secondary to massive pulmonary embolism. Eur Heart J 1988; 9: 534– 540. 17 Stein PD, Alshabkhoun S, Hatem C et al. Coronary artery blood flow in acute pulmonary embolism. Am J Cardiol 1968; 21: 32–37. 18 Stein PD, Alshabkhoun S, Hawkins HF, Hyland JW, Jarrett CE. Right coronary blood flow in acute pulmonary embolism. Am Heart J 1969; 77: 356–362. 19 Yalamanchili K, Sukhija R, Aronow WS, Sinha N, Fleisher AG, Lehrman SG. Prevalence of increased cardiac troponin I levels in patients with and without acute pulmonary embolism and relation of increased cardiac troponin I levels with in-hospital mortality in patients with acute pulmonary embolism. Am J Cardiol 2004; 93: 263– 264. 20 Konstantinides S, Geibel A, Olschewski M et al. Importance of cardiac troponins I and T in risk stratification of patients with acute pulmonary embolism. Circulation 2002; 106: 1263–1268. 21 Kucher N, Wallmann D, Carone A, Windecker S, Meier B, Hess OM. Incremental prognostic value of troponin I and echocardiography in patients with acute pulmonary embolism. Eur Heart J 2003; 24: 1651– 1656. 22 La Vecchia L, Ottani F, Favero L et al. Increased cardiac troponin I on admission predicts in-hospital mortality in acute pulmonary embolism. Heart 2004; 90: 633– 637. 23 Scridon T, Scridon C, Skali H, Alvarez A, Goldhaber SZ, Solomon SD. Prognostic significance of troponin elevation and right ventricular enlargement in acute pulmonary embolism. Am J Cardiol 2005; 96: 303– 305.

References 1 The Urokinase Pulmonary Embolism Trial: A National Cooperative Study. Perfusion lung scanning. Circulation 1973; 47(2, suppl): II46–II50. 2 ten Wolde M, Sohne M, Quak E, Mac Gillavry MR, Buller HR. Prognostic value of echocardiographically assessed right ventricular dysfunction in patients with pulmonary embolism. Arch Intern Med 2004; 164: 1685–1689. 3 Gibson NS, Sohne M, Buller HR. Prognostic value of echocardiography and spiral computed tomography in patients with pulmonary embolism. Curr Opin Pulmon Med 2005; 11: 380–384. 4 van der Meer RW, Pattynama PM, van Strijen MJ et al. Right ventricular dysfunction and pulmonary obstruction index at helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embolism. Radiology 2005; 235: 798–803. 5 The Urokinase Pulmonary Embolism Trial: A National Cooperative Study. Interrelationships of pulmonary angiograms, lung scans, hemodynamic measurements, and fibrinolytic findigs. Circulation 1973; 47(2, suppl): II73– II80. 6 Aujesky D, Obrosky DS, Stone RA et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005; 172: 1041–1046. 7 Wicki J, Perrier A, Perneger TV, Bounameaux H, Junod AF, Predicting adverse outcome in patients with acute pulmonary embolism: a risk score. Thromb Haemost 2000; 84: 548–552. 8 Nendaz MR, Bandelier P, Aujesky D et al. Validation of a risk score identifying patients with acute pulmonary embolism, who are at low risk of clinical adverse outcome. Thromb Haemost 2004; 91: 1232–1236. 9 Aujesky D, Roy PM, Le Manach CP et al. Validation of a model to predict adverse outcomes in patients with pulmonary embolism. Eur Heart J 2006; 27: 476–481.

Prevalence, risks, and prognosis of PE and DVT


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24 Giannitsis E, Muller-Bardorff M, Kurowski V et al. Independent prognostic value of cardiac troponin T in patients with confirmed pulmonary embolism. Circulation 2000; 102: 211–217. 25 Pruszczyk P, Bochowicz A, Torbicki A et al. Cardiac troponin T monitoring identifies high-risk group of normotensive patients with acute pulmonary embolism. Chest 2003; 123: 1947–1952. 26 Pruszczyk P, Bochowicz A, Kostrubiec M et al. Myoglobin stratifies short-term risk in acute major pulmonary embolism. Clin Chim Acta 2003; 338: 53– 56. 27 Binder L, Pieske B, Olschewski M et al. N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratification of acute pulmonary embolism. Circulation 2005; 112: 1573– 1579. 28 Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol, 2000: 36: 970– 1062. 29 de Lemos JA, Morrow DA, Gibson M et al. The prognostic value of serum myoglobin in patients with nonST-segment elevation acute coronary syndromes. Results from the TIMI 11B and TACTICS-TIMI 1B Studies. J Am Coll Cardiol 2002; 40: 238–244. 30 Mair J, Wagner I, Jakob G et al. Different time courses of cardiac contractile proteins after acute myocardial infarction. Clin Chim Acta 1994; 231: 47–60. 31 Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism. Circulation 2003; 108: 2191–2194. 32 Hama N, Itoh H, Shirakami G et al. Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction. Circulation 1995; 92: 1558–1564. 33 Tulevski II, Hirsch A, Sanson BJ et al. Increased brain natriuretic peptide as a marker for right ventricular dysfunction in acute pulmonary embolism. Thromb Haemost 2001; 86: 1193–1196. 34 Kucher N, Printzen G, Doernhoefer T, Windecker S, Meier B, Hess OM. Low pro-brain natriuretic peptide levels predict benign clinical outcome in acute pulmonary embolism. Circulation 2003; 107: 1576–1578. 35 Nagaya N, Nishikimi T, Okano Y et al. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998; 31: 202– 208.

29

36 Nagaya N, Nishikimi T, Uematsu M et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000; 102: 865–870. 37 Bando M, Ishii Y, Sugiyama Y, Kitamura S. Elevated plasma brain natriuretic peptide levels in chronic respiratory failure with cor pulmonale. Respir Med 1999; 93: 507–514. 38 Tulevski II, Groenink M, van Der Wall EE et al. Increased brain and atrial natriuretic peptides in patients with chronic right ventricular pressure overload: correlation between plasma neurohormones and right ventricular dysfunction. Heart 2001; 86: 27–30. 39 Pruszczyk P, Kostrubiec M, Bochowicz A et al. Nterminal pro-brain natriuretic peptide in patients with acute pulmonary embolism. Eur Respir J 2003; 22: 649– 653. 40 Kruger S, Graf J, Merx MW et al. Brain natriuretic peptide predicts right heart failure in patients with acute pulmonary embolism. Am Heart J 2004; 147: 60–65. 41 Kucher N, Printzen G, Goldhaber SZ. Prognostic role of brain natriuretic peptide in acute pulmonary embolism. Circulation 2003; 107: 2545–2547. 42 ten Wolde M, Tulevski II, Mulder JW et al. Brain natriuretic peptide as a predictor of adverse outcome in patients with pulmonary embolism. Circulation 2003; 107: 2082–4208. 43 Fox AC, Reed GE, Meilman H, Silk BB. Release of nucleosides from canine and human hearts as an index of prior ischemia. Am J Cardiol 1979; 43: 52–58. 44 Mentzer RM, Jr, Rubio R, Berne RM. Release of adenosine by hypoxic canine lung tissue and its possible role in pulmonary circulation. Am J Physiol 1975; 229: 1625– 1631. 45 Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP et al. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J 1997; 18: 858–865. 46 Anker SD, Leyva F, Poole-Wilson PA, Kox WJ, Stevenson JC, Coats AJ. Relation between serum uric acid and lower limb blood flow in patients with chronic heart failure. Heart 1997; 78: 39–43. 47 Hayabuchi Y, Matsuoka S, Akita H, Kuroda Y. Hyperuricaemia in cyanotic congenital heart disease. Eur J Pediatr 1993; 152: 873–876. 48 Hasday JD, Grum CM. Nocturnal increase of urinary uric acid:creatinine ratio: a biochemical correlate of sleepassociated hypoxemia. Am Rev Respir Dis 1987; 135: 534– 538. 49 Braghiroli A, Sacco C, Erbetta M, Ruga V, Donner CF. Overnight urinary uric acid:creatinine ratio for detection of sleep hypoxemia: validation study in chronic


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obstructive pulmonary disease and obstructive sleep apnea before and after treatment with nasal continuous positive airway pressure. Am Rev Respir Dis 1993; 148: 173– 178. 50 Elsayed NM, Nakashima JM, Postlethwait EM. Measurement of uric acid as a marker of oxygen tension

in the lung. Arch Biochem Biophys 1993; 302: 228– 232. 51 Shimizu Y, Nagaya N, Satoh T et al. Serum uric acid level increases in proportion to the severity of pulmonary thromboembolism. Circulation 2002; 66: 571– 575.

Prevalence, risks, and prognosis of PE and DVT


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CHAPTER 5

Changing risks of untreated deep venous thrombosis and acute pulmonary embolism

Introduction The frequency of fatal pulmonary embolism (PE) in patients with untreated deep venous thrombosis (DVT) has diminished as diagnostic tests have made it possible to diagnose mild DVT [1]. Prior to the use of venography and of sensitive noninvasive tests for the early detection of DVT, the risk of fatal PE in untreated patients with clinically apparent DVT was 37% [2] (Figure 5.1). In pooled data of patients with un-

100

60 Clinical DVT (%)

Fatal PE (%)

80

treated DVT identified by radioactive fibrinogen scintiscans, most of which was distal and subclinical, fatal PE occurred in 5% [3]. It is apparent that the risk of fatal PE was greater among patients with more severe DVT. The percentage of patients with acute PE who have clinically detectable DVT has diminished as physicians have developed the ability to diagnose subtle PE [2]. Among patients who died from acute PE, 53% had clinically identified DVT [4] (Figure 5.2). In an investigation of patients with massive or submassive angiographically diagnosed acute PE (the Urokinase Pulmonary Embolism Trial), 34% of patients had clinically identifiable DVT [5]. Among patients with mild as well as severe acute PE (PIOPED), only 15% of patients had clinically apparent DVT [6] and 47% had signs of DVT in PIOPED II [7].

40

20

60 53 34 20 15 0

0 Clinical DVT

Subclinical DVT

Figure 5.1 Frequency of fatal pulmonary embolism (PE) in untreated patients with clinically apparent deep venous thrombosis (DVT), and patients, most of whom had subclinical DVT diagnosed by radioactive fibrinogen scintiscans. (Data are from Byrne [2] and Collins et al. [3]. Reprinted from Stein [1] with permission.)

47

40

Fatal PE

Massive Massive or Massive or or mild PE mild PE submassive (PIOPED) (PIOPED II) PE

Figure 5.2 Frequency of clinically apparent deep venous thrombosis (DVT) among patients with fatal acute pulmonary embolism (PE), massive or submassive pulmonary embolism, or massive or mild pulmonary embolism. (Data are based on Byrne and Oâ&#x20AC;&#x2122;Neil [4], the Urokinase Pulmonary Embolism Trial [5], Stein [6] and Stein et al. [7].)

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In the present era of early diagnosis of acute PE, the risk of fatal recurrent PE as well as the risk of death from the initial PE in untreated patients is lower than in patients with severe PE reported in prior years [1]. Among untreated patients with acute PE diagnosed on the basis of clinical features that included evidence of right ventricular failure, pulmonary infarction, or both, Barritt and Jordan reported a 26% mortality from the initial PE, although some of these patients, perhaps died from recurrent PE [8] (see Chapter 3, untreated patients). In 1961, Hermann and associates [9] calculated a 37% mortality from the initial PE and a 36% frequency of fatal recurrent PE (see Chapter 3, untreated patients).

Untreated patients in present era of early diagnosis In an investigation of the clinical course of acute PE, Carson and associates observed that in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED), 24 patients escaped treatment in the hospital [10]. However, 4 patients were begun on anticoagulant therapy during the first month after discharge. We evaluated the 20 patients who received no treatment for PE during the first 3 months of follow-up [11]. Only 1 of these patients died of PE [10, 11]. In the era of early diagnosis by ventilation–perfusion lungs scans and pulmonary angiography, mortality from the initial PE and from recurrent PE among patients with untreated mild PE was 1 of 20 (5%) (Figure 5.3) [11]. The circumstances involving no therapy in these 20 patients from PIOPED are as follows: 19 had pulmonary angiograms interpreted as showing no PE by the local radiologist, but the interpretation of no PE was reversed in 18 following reevaluation by the central panel of angiogram readers [11]. The diagnosis of no PE was reversed in 1 patient because PE was found at autopsy 6 days after the pulmonary angiogram. One patient had no pulmonary angiogram; the patient died of unrelated causes 4 days after a ventilation– perfusion lung scan and autopsy showed small peripheral PE. The untreated patient who died was a 33-year-old woman with underlying primary pulmonary hypertension with right ventricular failure [11]. Organized

PART I

Prevalence, risks, and prognosis of PE and DVT

100

Fatal initial and recurrent PE (%)

BLUK077-Stein

80

60

40

20

0 Clinically apparent PE

Mild PE

Figure 5.3 Fatal initial and fatal recurrent pulmonary embolism (PE) among untreated patients. Comparison is made between patients in whom the diagnosis was clinically apparent, and presumably pulmonary embolism was severe and patients in whom pulmonary embolism was mild. (Data are from Hermann et al. [9], and Stein and Henry [11]. Reprinted from Stein [1] with permission.

and fresh pulmonary emboli were shown at autopsy 6 days after a pulmonary angiogram that failed to show PE. Whether this death resulted from the original PE or recurrent PE is uncertain. In regard to the course of untreated mild PE over 1 year, there were no instances of fatal recurrent PE [11]. This assumes that the cause of death in the only patient who died was the original PE. Fatal recurrent PE, therefore, was 0 of 19 (0%) among untreated survivors of mild PE during months 4–12 of observation [11]. One patient died of aspiration pneumonia following hysterectomy for endometrial carcinoma 4 days after an intermediate probability ventilation–perfusion lung scan was obtained [11]. Multiple small thromboemboli in peripheral branches were observed at autopsy. These thromboemboli did not contribute to death. Based on clinical assessment, recurrent PE was thought to have occurred. The frequency of nonfatal recurrent PE among survivors of the first PE was 1 of 19 (5.3%).


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100 90 80 Fatal initial PE and fatal and nonfatal recurrent PE (%)

33

Changing risks of untreated DVT and acute PE

70 60 50 40 30 20 10 0 Clinical PE

Mild PE

Figure 5.4 Fatal initial pulmonary embolism (PE), fatal recurrent PE, and nonfatal recurrent PE among patients with clinically apparent severe PE and patients with mild PE. (Data are from Hermann et al. [8] and Stein and Henry [10]).

The frequency of fatal initial PE, fatal recurrent PE, and nonfatal recurrent PE over the course of 1 year among untreated patients with acute PE was 2 of 20 (10%) (Figure 5.4). Untreated patients with PE had mild PE as suggested by the following data. Among patients who had measurements of the PaO2 while breathing room air, the PaO2 was lower in untreated patients compared to treated patients (39 ± 16 versus 55 ± 31 mm Hg) (P < 0.001) [11]. The pulmonary artery mean pressure did not show a statistically significant difference between untreated and treated patients (23 ± 13 mm Hg versus 24 ± 10 mm Hg). Ventilation–perfusion (V–Q) lung scans were interpreted as high probability in a smaller percent of untreated patients with PE than treated patients, 0 of 20 (0%) versus 160 of 376 (43%) [11]. Low probability, nearly normal, or normal ventilation–perfusion scans were more frequent among untreated patients 10 of 20 (50%) versus 58 of 376 (15%). Ventilation– perfusion lung scans among untreated patients more

often showed no mismatched segmental equivalent perfusion defects than among treated patients, 14 of 20 (70%) versus 122 of 376 (32%) [11]. All untreated patients, 20 of 20 (100%) showed fewer than 3 mismatched segmental equivalent perfusion defects compared with 227 of 376 (60%) among treated patients. Pulmonary angiograms at the time of PIOPED entry were obtained in 19 of the untreated patients [11]. Thromboemboli involved only segmental pulmonary arteries or smaller branches in 16 of 19 (84%) of untreated patients compared with 132 of 362 (36%) treated patients. Thromboemboli were not observed on the angiogram of 1 untreated patient, but were shown at autopsy 6 days later. The frequency of fatal initial and fatal recurrent PE in untreated patients with mild PE (5.0%) is strikingly lower than the mortality from untreated PE reported in past decades among patients who presumably had severe PE [8, 9]. This lower mortality appears to relate to the milder severity of PE in these untreated patients. The mortality of untreated patients with mild PE is comparable to the mortality from fatal PE in untreated patients with subtle DVT, approximately 5% [3].

Rates of recurrent PE in untreated patients with PE based on calculations in patients with suspected PE and negative serial noninvasive leg tests The estimated frequency of PE during the 3-month follow-up of untreated patients with nonmassive PE and serial noninvasive leg tests was between 3 and 9%. The estimated frequency of fatal PE was 1% [12] (see Chapter 88).

References 1 Stein PD. Changing patterns of risk of untreated thromboembolic disease. Semin Respir Crit Care Med 1996; 17: 3–6. 2 Byrne JJ. Phlebitis: a study of 748 cases at the Boston City Hospital. New Engl J Med 1955; 253: 579–586. 3 Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. New Engl J Med 1988; 318: 1162–1173.


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4 Byrne JJ, O’Neil EE. Fatal pulmonary emboli. A study of 130 autopsy-proven fatal emboli. Am J Surg 1952; 83: 47–49. 5 A National Cooperative Study. Clinical and electrocardiographic observations. The Urokinase Pulmonary Embolism Trial. Circulation 1973; 47/48(suppl II): II-60– II-65. 6 Stein PD. Unpublished data from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). 7 Stein PD, Beemath A, Matta F, et al. Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med 2007 (In press). 8 Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet 1960; 1: 1309–1312.

PART I

Prevalence, risks, and prognosis of PE and DVT

9 Hermann RE, Davis JH, Holden WD. Pulmonary embolism: a clinical and pathologic study with emphasis on the effect of prophylactic therapy with anticoagulants. Am J Surg 1961; 102: 19–28. 10 Carson JL, Kelley MA, Duff A et al. The clinical course of pulmonary embolism. New Engl J Med 1992; 326: 1240– 1245. 11 Stein PD, Henry JW, Relyea B. Untreated patients with pulmonary embolism: outcome, clinical and laboratory assessment. Chest 1995; 107: 931–935. 12 Stein PD, Hull RD, Raskob GE. Withholding treatment in patients with acute pulmonary embolism who have a high risk of bleeding and negative serial noninvasive leg tests. Am J Med 2000; 109: 301– 306.


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CHAPTER 6

Resolution of pulmonary embolism

Pulmonary emboli resolve because of natural thrombolytic processes [1, 2]. The rate of resolution of perfusion defects, calculated as a percent of the pretreatment defect among 70 patients treated with anticoagulants in the Urokinase Pulmonary Embolism Trial [1], is shown in Figure 6.1. After 24 hours, there was only a 7% mean resolution of the pretreatment perfusion scan defect [1] (Figure 6.1). By 2 days, there was 16% mean resolution. The mean resolution progressively increased to 75% by 3 months, and thereafter, increased only slightly. Among patients with no prior cardiopulmonary disease, ≥90% resolution was shown at 1 year in 29 of 32 (91%) [1] (Figure 6.2).

However, among patients who had prior cardiopulmonary disease, ≥90% resolution was shown at 1 year in only 13 of 18 (72%). Others showed complete clearing of the perfusion scan in 7 of 10 (70%) patients with no prior cardiopulmonary disease [3], and in 22 of 33 (67%), many of who had prior cardiopulmonary disease [4]. In the Urokinase Pulmonary Embolism Trial, the proportion of patients with ≥90% resolution of the perfusion defect was similar in those treated with anticoagulants and those treated with Urokinase in both patients with prior cardiopulmonary disease and patients with no prior cardiopulmonary disease [1] (Figure 6.3).

Figure 6.2 Proportion of patients with <10% residual perfusion defects after 1 year of treatment with anticoagulants according to whether they had cardiopulmonary disease (CPD) or no cardiopulmonary disease. (Data from the Urokinase Pulmonary Embolism Trial [1].)

Mean resolution (%)

60

77

53 42

40

32 16

20

21

7 0 24hrs day 2

Percent of patients with <10% residual perfusion defects

Figure 6.1 Mean resolution of perfusion defects shown as a percentage (%) of pretreatment defects in relation to time of treatment. Hrs = hours, mos = months. (Data from the Urokinase Pulmonary Embolism Trial [1].)

77

75

80

day 3

100 80

day 5

day 7 day 14 3 mos 6 mos 12 mos

91 72

60 40 20 0 CPD (n=18)

No CPD (n=32)

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Percent of patients with <10% residual perfusion defects

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PART I

100 80

AC 72

UK 77

AC 91

Prevalence, risks, and prognosis of PE and DVT

UK 88

60 40 20 0

CPD (n=18)

CPD (n=22)

No CPD No CPD (n=32) (n=37)

Using newer scintigraphic techniques than used in the Urokinase Pulmonary Embolism Trial, and somewhat different methods of calculating the improvement of perfusion, de Groot showed a mean rate of improvement of the perfusion scan of 4% in 2–4 days [5]. Importantly, a high probability interpretation of the lung scan remained high probability in 77 of 79 patients (97%) during the 2–4 day period. The V–Q scan became nondiagnostic in 1 of 79 (1%) and it became normal in 1 of 79 (1%) [5]. Resolution of acute PE based on pulmonary angiograms obtained 1 to 7 days after the initial angiogram in 6 patients showed no change in 1 and minimal resolution with persistent marked abnormalities in 5 [2]. Ten to 21 days after the initial pulmonary angiogram, among 10 patients, no resolution was shown in 1, minimal resolution in 2, moderate resolution with persistent minimal abnormalities in 5, and complete resolution (normal angiogram) in 2. After 34 days, among 2 patients, 1 showed minimal resolution and 1 showed complete resolution. The pulmonary diffusing capacity of carbon monoxide (DLCO) after 1 year was only 72% of predicted among 21 patients with PE and no prior cardiopulmonary disease, who were treated with anticoagulants [6]. Others also observed a continuing impairment of DLCO in 10 patients treated with anticoagulants, although the perfusion lung scans tended to return to normal [3]. Among 11 patients such pa-

Figure 6.3 Percent of patients with <10% residual perfusion defects after treatment with anticoagulants (AC) or Urokinase (UK) according to whether they had cardiopulmonary disease (CPD) or no cardiopulmonary disease. (Data from The Urokinase Pulmonary Embolism Trial [1].)

tients followed a mean of 7.4 years, mean pulmonary artery pressure (22 mm Hg) was somewhat elevated and pulmonary vascular resistance at rest was also elevated (171 dyne –sec/cm−5 ) [7].

References 1 The Urokinase Pulmonary Embolism Trial. A national cooperative study. Perfusion lung scanning. Circulation 1973; 47(2 suppl): II46–II50. 2 Dalen JE, Banas JS, Jr, Brooks HL, Evans GL, Paraskos JA, Dexter L. Resolution rate of acute pulmonary embolism in man. N Engl J Med 1969; 280: 1194–1199. 3 Wimalaratna HS, Farrell J, Lee HY. Measurement of diffusing capacity in pulmonary embolism. Respir Med 1989; 83: 481–485. 4 Paraskos JA, Adelstein SJ, Smith RE et al. Late prognosis of acute pulmonary embolism. N Engl J Med 1973; 289: 55–58. 5 de Groot MR, Oostdijk AH, Engelage AH, van Marwijk Kooy M, Buller HR. Changes in perfusion scintigraphy in the first days of heparin therapy in patients with acute pulmonary embolism. Eur J Nucl Med 2000; 27: 1481– 1486. 6 Sharma GV, Burleson VA, Sasahara AA. Effect of thrombolytic therapy on pulmonary–capillary blood volume in patients with pulmonary embolism. N Engl J Med 1980; 303: 842–845. 7 Sharma GV, Folland ED, McIntyre KM, Sasahara AA. Long-term benefit of thrombolytic therapy in patients with pulmonary embolism. Vasc Med 2000; 5: 91–95.


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CHAPTER 7

Upper extremity deep venous thrombosis

Prior to 1967, thrombosis of the upper extremities constituted less than 2% of cases of deep venous thrombosis (DVT) [1]. Since the 1970s, there has been an increased recognition of upper extremity DVT [2–6]. The incidence of upper extremity DVT in a community teaching general hospital was reviewed during the 2-year period, July 1998 through June 2000 [7]. The incidence of upper extremity DVT in adults (≥20 years) was 64 of 34,567 hospital admissions (0.19%). The incidence of upper extremity DVT that we observed among hospitalized patients was the same as reported by Kroger and associates (0.2%) [3]. Upper extremity DVT in adults was accompanied by proximal DVT of the lower extremity in 2 of 64 patients [7] (see Figure 7.1). Upper extremity DVT involved the subclavian vein in 48 patients (75%) and the axillary vein in 25 patients (39%) [7]. The internal jugular vein was included among patients with upper extremity DVT, and it involved 29 patients (45%) [7]. Nine patients (14%) had involvement only of a deep distal vein (brachial

Figure 7.1 Patient with upper extremity deep venous thrombosis (DVT). (Courtesy of Syed Mustafa, MD, St. Joseph Mercy-Oakland Hospital, Pontiac Michigan.)

veins in 6 patients, ulnar vein alone in 1 patient, radial vein alone in 1 patient, and both radial and ulnar veins in 1 patient). In 7 patients, the upper extremity DVT was shown by venography to extend proximally to the brachiocephalic vein. Among these, 2 extended to the superior vena cava. In addition to these patients with DVT of the upper extremity, 16 patients had involvement only of the superficial veins of the upper extremity. These patients are not included in the various computations. All the patients with upper extremity DVT received therapy with anticoagulants [7]. None developed pulmonary embolism (PE). Cancer was diagnosed in 30 of 65 (46%). Upper extremity DVT in the past had been considered to be benign and self-limited [8]. More recent data suggest that this is not the case [8–11]. Systematic review of the literature in 1991 showed a 9% incidence of symptomatic PE in patients with upper extremity DVT, half of which was diagnosed by objective tests [12]. Review in 1991 by others showed a 7% incidence of symptomatic PE in patients with upper extremity DVT, none of which was confirmed by objective tests [13]. More recently, symptomatic PE diagnosed by ventilation–perfusion lung scans was observed in 7% of patients with upper extremity DVT [8]. Most PE (94%) in patients with upper extremity DVT occurred in untreated patients [9]. Fatal PE in patients with upper extremity DVT has been reported [10]. Routine ventilation/perfusion lung scans in patients with upper extremity DVT were high probability for PE in 13% [13]. The increased incidence of upper extremity DVT has been attributed to the use of central venous catheters and transvenous pacemakers [2]. As the use of central venous lines and pacemaker wires has increased, their role in the etiology of upper extremity DVT has become prominent [3, 14–17]. The incidence of central venous catheter-related DVT assessed by venography has been reported in 27–66% of patients [18]. Most of

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the thrombi in these cases were asymptomatic. The reported incidence of symptomatic catheter-related DVT in adults ranged from 0.3 to 28.3% [18]. In the series we reported, central venous access lines on the side of the upper extremity DVT were inserted in 39 of 65 (60%) [7]. Nearly the same percentage (55%) of upper extremity DVT was associated with central venous access lines in the experience of others [19]. Others reported the use of indwelling catheters in 28–33% of patients with upper extremity DVT [3, 9, 14]. Six patients in our series had arteriovenous shunts on the side of the upper extremity DVT [7]. There were 3 additional patients who had thrombosis only of the arteriovenous shunt without involvement of contiguous veins. These patients were not included among the patients we reported. Nineteen patients (29%) had no apparent cause, although all patients developed upper extremity DVT in the hospital and had received intravenous infusions of medications. Three of 39 patients (8%) who had central venous access lines had been on antithrombotic prophylaxis with lowdose warfarin (1–2 mg/day) prior to developing upper extremity DVT. Among 30 patients with venous access lines and upper extremity DVT in whom there was data, the lines had been inserted 3–14 days in 90%. Swelling of the arm was the most frequent sign, and was present in all patients with upper extremity DVT. Pain was present in 26 of 65 (40%) patients. Some discomfort due to the swelling was present in all. Four of 65 (6%) had erythema over the affected site. One patient with internal jugular vein thrombosis had swelling of the neck. He also had thrombosis of the superior vena cava. Campbell and associates, among 25 patients with upper extremity DVT, observed swelling in 96%, pain in 76%, discoloration in 52%, prominent veins in 52%, and a palpable cord in 8% [2].

We observed an association of malignancy with upper extremity DVT in 29 of 65 (45%) [7]. Among these patients, 23 also had a central line. An association of upper extremity DVT with malignancy is well established [20] and was reported in 64% by Baarslag et al. [19]. A hypercoagulable state may also be associated with proximal upper vein thrombosis [21], but our patients generally were not evaluated for this. During the 2-year period of this investigation, 10 of 34,567 patients (0.03%) had thrombosis of the superior vena cava or brachiocephalic vein, unaccompanied by DVT of the subclavian or axillary veins or more distal veins of the upper extremity and unaccompanied by proximal DVT of the lower extremity [22] (Figure 7.2). During the same period, proximal DVT of the lower extremity was diagnosed in 271 of 34,567 patients (0.78%) [23] (Figure 7.2). Deep venous thrombosis of the upper extremity, sometimes accompanied by thrombosis of the superior vena cava or brachiocephalic vein, but unaccompanied by proximal DVT of the lower extremity, was observed in 62 of 34,567 adult patients (0.18%) [7]. Among all patients with symptomatic DVT, thrombosis of the superior vena cava or brachiocephalic vein alone constituted 10 of 343 (3%) [7, 22, 23] (Figure 7.3). Upper extremity DVT, unaccompanied by proximal lower extremity DVT but sometimes accompanied by thrombosis of the superior vena cava or brachiocephalic vein, constituted 62 of 343 (18%), and proximal lower extremity DVT constituted 271 of 343 (79%). More recently, a prospective registry of 324 patients with central venous catheter-associated upper extremity DVT and 268 patients with noncentral venous catheter-associated upper extremity DVT was published [24]. An indwelling central venous catheter was

Prevalence, risks, and prognosis of PE and DVT

DVT in hosp pts (%)

1 0.8 0.6

0.78%

0.4 0.18%

0.2

0.03%

0 Lower extremity

Upper extremity, SVC, or brachioceph

SVC or brachioceph

Figure 7.2 Prevalence in hospitalized (hosp) patients (pts) of proximal lower extremity deep venous thrombosis (DVT), upper extremity, superior vena cava (SVC) or brachiocephalic (brachioceph) DVT unaccompanied by lower extremity DVT, and isolated SVC or brachiocephalic DVT. (Data from Mustafa et al. [7], Otten et al. [22], and Stein et al. [23].)


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Upper extremity deep venous thrombosis

SVC or brachiocephalic 3%

Upper extremity 18%

Lower extremity 79%

Figure 7.3 Proportion of patients with proximal deep venous thrombosis (DVT) of lower extremities, upper extremity DVT, unaccompanied by proximal lower extremity DVT but sometimes accompanied by thrombosis of the superior vena cava or brachiocephalic vein. (Data from Mustafa et al. [7], Otten et al. [22], and Stein et al. [23].)

the strongest independent predictor of upper extremity DVT. Only 20% of patients with upper extremity DVT who did not have a contraindication to anticoagulation were receiving anticoagulant prophylaxis at the time of diagnosis of upper extremity DVT [24]. Frequent risk factors in patients with central venous catheter-associated upper extremity DVT and in patients with noncentral venous catheter-associated upper extremity DVT were cancer, personal history, or family history of venous thromboembolism (VTE). Surgery or immobilization within 30 days, and ongoing chemotherapy were frequent risk factors in patients with central venous catheter-associated upper extremity DVT. Ongoing chemotherapy was a frequent risk factor in patients with noncentral venous catheterassociated upper extremity DVT [24]. Among 324 patients with upper extremity DVT, 25% had upper extremity swelling, 11% had upper extremity discomfort, and 4% had erythema [24]. Pulmonary embolism at the time of diagnosis of upper extremity DVT was confirmed in 0.9%.

References 1 Coon WW, Willis PW, III. Thrombosis of axillary and subclavian veins. Arch Surg 1967; 94: 657–663. 2 Campbell CB, Chandler JG, Tegtmeyer CJ, Bernstein EF. Axillary, subclavian, and brachiocephalic vein obstruction. Surgery 1977; 82: 816–826.

39

3 Kroger K, Schelo C, Gocke C, Rudofsky G. Colour Doppler sonographic diagnosis of upper limb venous thromboses. Clin Sci 1998; 94: 657–661. 4 Huber P, Hauptli W, Schmitt HE, Widmer LK. [Axillary and subclavian vein thrombosis and its sequelae]. Internist (Berl) 1987; 28: 336–343. 5 Theis W, Zaus M, Klefhaber M et al. Primare und sekundare Schultergurtelvenenthrombose; eine Analyse von 227 Patienten [Abstract]. VASA 1994; l43(suppl): 167– 169. 6 Layher T, Heinrich F. Retrospektive Betrachtung von Arm- bzw-Schultervenenthrombosen am Krankenhaus Bruchsal im Zeitraum von 1973 und 1993 [Abstract]. VASA 1994; 43(suppl): 169. 7 Mustafa S, Stein PD, Patel KC, Otten TR, Holmes R, Silbergleit A. Upper extremity deep venous thrombosis. Chest 2003; 123: 1953–1956. 8 Hingorani A, Ascher E, Lorenson E et al. Upper extremity deep venous thrombosis and its impact on morbidity and mortality rates in a hospital-based population. J Vasc Surg 1997; 26: 853–860. 9 Horattas MC, Wright DJ, Fenton AH et al. Changing concepts of deep venous thrombosis of the upper extremityreport of a series and review of the literature. Surgery 1988; 104: 561–567. 10 Monreal M, Raventos A, Lerma R et al. Pulmonary embolism in patients with upper extremity DVT associated to venous central lines—a prospective study. Thromb Haemost 1994; 72: 548–550. 11 Prandoni P, Polistena P, Bernardi E et al. Upperextremity deep vein thrombosis. Risk factors, diagnosis, and complications. Arch Intern Med 1997; 157: 57–62. 12 Becker DM, Philbrick JT, Walker FB, IV. Axillary and subclavian venous thrombosis. Prognosis and treatment. Arch Intern Med 1991; 151: 1934–1943. 13 Monreal M, Lafoz E, Ruiz J, Valls R, Alastrue A. Upperextremity deep venous thrombosis and pulmonary embolism. A prospective study. Chest 1991; 99: 280– 283. 14 Timsit JF, Farkas JC, Boyer JM et al. Central vein catheterrelated thrombosis in intensive care patients: incidence, risks factors, and relationship with catheter-related sepsis. Chest 1998; 114: 207–213. 15 Haire WD, Lieberman RP, Edney J et al. Hickman catheter-induced thoracic vein thrombosis. Frequency and long-term sequelae in patients receiving high-dose chemotherapy and marrow transplantation. Cancer 1990; 66: 900–908. 16 Ryan JA, Jr, Abel RM, Abbott WM et al. Catheter complications in total parenteral nutrition. A prospective study of 200 consecutive patients. N Engl J Med 1974; 290: 757–761.


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17 Dollery CM, Sullivan ID, Bauraind O et al. Thrombosis and embolism in long-term central venous access for parenteral nutrition. Lancet 1994; 344: 1043–1045. 18 Verso M, Agnelli G, Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 2003; 21: 3665–3675. 19 Baarslag HJ, van Beek EJ, Koopman MM, Reekers JA. Prospective study of color duplex ultrasonography compared with contrast venography in patients suspected of having deep venous thrombosis of the upper extremities. Ann Intern Med 2002; 136: 865–872. 20 Prandoni P, Bernardi E. Upper extremity deep vein thrombosis. Curr Opin Pulm Med 1999; 5: 222–226.

21 Martinelli I, Cattaneo M, Panzeri D, Taioli E, Mannucci PM. Risk factors for deep venous thrombosis of the upper extremities. Ann Intern Med 1997; 126: 707–711. 22 Otten TR, Stein PD, Patel KC, Mustafa S, Silbergleit A. Thromboembolic disease involving the superior vena cava and brachiocephalic veins. Chest 2003; 123: 809– 812. 23 Stein PD, Patel KC, Kalra NK et al. Deep venous thrombosis in a general hospital. Chest 2002; 122: 960–962. 24 Joffe HV, Kucher N, Tapson VF, Goldhaber SZ; for the deep vein thrombosis (DVT) FREE Steering Committee. Upper-extremity deep vein thrombosis: a prospective registry of 592 patients. Circulation 2004; 110: 1605–1611.

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CHAPTER 8

Thromboembolic disease involving the superior vena cava and brachiocephalic veins

Isolated venous thromboembolic disease of the brachiocephalic veins and superior vena cava (SVC) was observed in hospitalized adults ≥20 years old in 10 of 34,567 (0.03%) [1] (see Chapter 7). It was accompanied by deep venous thrombosis (DVT) at other sites in an additional 13 patients (0.04%). Previous data are limited to 2 case reports [2, 3]. Thrombosis of the SVC is an uncommon cause of the SVC syndrome [4–6]. Rarely, pulmonary embolism (PE) with the SVC syndrome has been observed at autopsy [7, 8]. It was suggested, however, that SVC thrombosis may pose a significant risk for PE [9]. Brachiocephalic vein thrombosis was observed in 22 patients and SVC thrombosis was observed in 6 patients [1]. The number of patients with brachiocephalic vein thrombosis alone or in combination with SVC thrombosis or with thrombosis of the subclavian or axillary veins is shown in Table 8.1 [1]. The diagnosis was made by contrast venography in 21 patients, and by contrast enhanced spiral CT in 2 patients. All 6 patients with SVC thrombosis showed incomplete obstruction of the SVC. Among the 22 patients with brachiocephalic vein involvement, 13 showed total occlusion or occlusion sufficient to produce collateral veins.

Table 8.2 Predisposing factors among patients with brachiocephalic or superior vena cava thrombosis (n = 23).

Table 8.1 Vessels showing thrombosis (n = 23). SVC only

Two of 23 (8.7%) patients had nonfatal PE, both of which were diagnosed by high-probability ventilation– perfusion lung scans [1]. One patient had brachiocephalic vein thrombosis and, in addition, had bilateral thrombosis of the axillary, subclavian, and internal jugular veins. The PE occurred before the venous thrombosis was diagnosed and treated. The other patient had brachiocephalic vein thrombosis with no other upper body DVT, but in addition had proximal lower extremity DVT. The PE occurred while on treatment for lower extremity DVT. This was the only patient with coincident DVT of the lower extremities. To our knowledge, only one case of PE from brachiocephalic thrombosis has been reported previously [10]. Predisposing factors for patients with thrombosis of the SVC or brachiocephalic vein are shown in Table 8.2 [1]. Among patients who had central venous access lines, 10 had Groshong catheters, 4 had Infusaports, and 1 had a PICC line (peripherally inserted central catheter) (all from Bard Access Systems, Salt Lake City, Utah). An association of use of central venous access lines with thrombosis has been described [11–15]. Three patients with brachiocephalic vein thrombosis had neither cancer nor central venous lines, but had

1

Number

Percent

SVC + brachiocephalic

1

Cancer and central venous access line

14

61

SVC + brachiocephalic + subclavian or axillary

4

Cancer alone

3

13

Brachiocephalic only

9*

Central venous access line alone

1

4

Brachiocephalic + subclavian or axillary

8

External mechanical compression;

1

4

4

17

not cancer * One of these patients also had DVT of a lower extremity.

Cause not apparent

SVC, superior vena cava. Reprinted with permission from Otten et al. [1].

Reprinted with permission from Otten et al. [1].

41


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Table 8.3 Signs and symptoms, SVC and/or brachicephalic vein thrombosis.

2 Kwong T, Leonidas JC, Ilowite NT. Asymptomatic superior vena cava thrombosis and pulmonary embolism in an adolescent with SLE and antiphospholipid antibodies. Clin Exp Rheum 1994; 12: 215–217. 3 Goldstein MF, Nestico P, Olshan AR et al. Superior vena cava thrombosis and pulmonary embolus: association with right atrial mural thrombus. Arch Intern Med 1982; 142: 1726–1728. 4 Gucalp R, Dutcher J. Oncologic emergencies. In: Braunwald E, Fauci AS, Kasper DL et al., eds. Harrison’s Principles of Internal Medicine, 15th edn. McGraw-Hill, New York, 2001: 642–650. 5 Abner A. Approach to the patient who presents with superior vena cava obstruction. Chest 1993; 103: 394S–397S. 6 Salsali M, Cliffton EE. Superior vena caval obstruction with lung cancer. Ann Thorac Surg 1968; 6: 437–442. 7 Maddox A-M, Valdivieso M, Lukeman J et al. Superior vena cava obstruction in small cell bronchogenic carcinoma. Clinical parameters and survival. Cancer 1983; 52: 2165–2172. 8 Ryan JA, Abel RM, Abbott WM et al. Catheter complications in total parenteral nutrition. A prospective study of 200 consecutive patients. N Engl J Med 1974; 290: 757– 761. 9 Adelstein DJ, Hines JD, Carter SG et al. Thromboembolic events in patients with malignant superior vena cava syndrome and the role of anticoagulation. Cancer 1988; 62: 2258–2262. 10 Black MD, French GJ, Rasuli P et al. Upper extremity deep venous thrombosis. Underdiagnosed and potentially lethal. Chest 1993; 103: 1887–1890. 11 Prandoni P, Polistena P, Bernardi E et al. Upper-extremity deep vein thrombosis. Risk factors, diagnosis, and complications. Arch Intern Med 1997; 157: 57–62. 12 Torosian MH, Meranze S, McLean G et al. Central venous access with occlusive superior central venous thrombosis. Ann Surg 1986; 203: 30–33. 13 Haire WD, Lieberman RP, Edney J et al. Hickman catheter- induced thoracic vein thrombosis. Frequency and long-term sequelae in patients receiving high-dose chemotherapy and marrow transplantation. Cancer 1990; 66: 900–908. 14 Gore JM, Matsumoto AH, Layden JJ et al. Superior vena cava syndrome. Its association with indwelling ballooning-tipped pulmonary artery catheters. Arch Intern Med 1984; 144: 506–508. 15 Dollery CM, Sullivan ID, Bauraind O. Thrombosis and embolism in long-term central venous access for parenteral nutrition. Lancet 1994; 344: 1043–1045. 16 Knudson GJ, Wiedmeyer DA, Erickson SJ et al. Color Doppler sonographic imaging in the assessment of upperextremity deep venous thrombosis. Am J Roentgenol 1990; 154: 399–403.

Number (percent) All patients

Brachiocephalic vein

(n = 23)

only* (n = 9)

Arm edema

18 (78)

7 (78)

Pain/discomfort

15 (65)

5 (56)

Head/neck edema

10 (43)

3 (33)

Distended veins

7 (30)

2 (22)

Erythema

5 (22)

2 (22)

2 (9)

0 (0)

1 (4)

1 (11)

CNS symptoms None (incidental finding)

* Patients with accompanying thrombosis of axillary, subclavian, or internal jugular vein were excluded. CNS, central nervous system. Reprinted with permission from Otten et al. [1].

arteriovenous shunts for renal dialysis [1]. There was no evidence of thrombosis of the shunts. One of these patients had subclavian vein thrombosis in addition to thrombosis of the brachiocephalic vein. The other 2 patients had no evidence of thrombosis at other sites. The patient who had SVC thrombosis alone had no clear cause for the thrombosis. She was taking estrogen replacement therapy following menopause. Signs and symptoms observed in all patients with SVC thrombosis and/or brachiocephalic vein thrombosis and in 9 patients who showed involvement only of a brachiocephalic vein are shown in Table 8.3 [1]. In the latter group, the thrombosis caused partial occlusion in 6 of 9 (67%). Three of those with partial occlusion showed collateral vessels. Contrast venography is the most conclusive test [16–20]. Helical computed tomographic phlebography [21], magnetic resonance angiography [19, 20], and gadolinium-enhanced magnetic resonance venography [22] may be useful. Color duplex Doppler ultrasonography cannot image the SVC and proximal segment of the brachiocephalic veins [16, 23].

References 1 Otten TR, Stein PD, Patel KC, Mustafa S, Silbergleit A. Thromboembolic disease involving the superior vena cava and brachiocephalic veins. Chest 2003; 123: 809–812.

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VTE involving SVC and brachiocephalic veins

17 Gooding GA, Hightower DR, Moore EH et al. Obstruction of the superior vena cava or subclavian veins: sonographic diagnosis. Radiology 1986; 159: 663–665. 18 Schwartz EE, Goodman LR, Haskin ME. Role of CT scanning in the superior vena cava syndrome. Am J Clin Oncol 1986; 9: 71–78. 19 Hartnell GG, Hughes LA, Finn JP et al. Magnetic resonance angiography of the central chest veins. A new gold standard? Chest 1995; 107: 1053–1057. 20 Finn JP, Zisk JHS, Edelman RR et al. Central venous occlusion: MR angiography. Radiology 1993; 187: 245–251.

43

21 Qanadli SD, EL Hajjam M, Bruckert F et al. Helical CT phlebography of the superior vena cava: diagnosis and evaluation of venous obstruction. Am J Roentgenol 1999; 172: 1327–1333. 22 Kroencke TJ, Taupitz M, Arnold R et al. Threedimensional gadolinium-enhanced magnetic resonance venography in suspected thrombo-occlusive disease of the central chest veins. Chest 2001; 120: 1570–1576. 23 Falk RL, Smith DF. Thrombosis of upper extremity thoracic inlet veins: diagnosis with duplex Doppler sonography. Am J Roentgenol 1987; 149: 677–682.


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CHAPTER 9

Venous thromboembolic disease in the four seasons

Introduction

26

30

11.0

11.8

12.1

10

12.0

20

O ct −D ec

ep −S ly Ju

un e Ap r− J

Ja

n−

M ar

0

44

There is no meaningful seasonal variation of mortality from PE [13]. From 1980 to 1998, quarterly mortality rates throughout the entire United States, based on data from the United States National Center for Health Statistics, ranged from 0.93 to 1.05 PE deaths/quarter/100,000 population [13] (Table 9.1). Quarterly mortality rates from PE in four regions of the United States (Northeast, South, Midwest, and West) were evaluated separately [13] (Table 9.2). All were within 1 PE death/quarter/100,000 population [13]. Small differences were statistically significant due to the large number of patients evaluated (184,201 death certificates indicating PE as the cause of death). Recognizing that the death certificate diagnosis of fatal or large PE is accurate in only 32–35% of patients [14, 15] we assumed that whatever inaccuracy exists in the death certificates was constant throughout the seasons [13]. Differing observations had been reported previously on seasonal differences of mortality from acute PE. Several investigators reported peak mortality rates

.2

.7 27

28

.0 28

40 Rate per 100,000

.1

An absence of seasonal variation was shown in all regions of the United States, including the Southern region where winters are mild, and the Northeastern and Midwestern regions where seasons are sharply defined [1] (Figure 9.1). These observations were based on 21 years of data from the National Hospital Discharge Survey [1]. The results were based on data in 2,457,000 hospitalized patients with pulmonary embolism (PE) and 5,767,000 hospitalized patients with deep venous thrombosis (DVT). The data apply to patients with broad differences of ethnic, social, and racial backgrounds and to regions with wide differences in climate. This absence of seasonal variation was concordant with results of others who found no seasonal variations in PE [2] or DVT [3–5]. Seasonal variability of thromboembolic disease has been suggested to be present since 1939 [6]. Some showed a peak incidence in winter months for PE [2–8], fatal PE [7], DVT [8, 9], and thromboembolic disease [10]. Others showed a decreased incidence of PE in the winter, or a peak in spring and autumn [11] or peaks in both summer and winter [12].

Mortality from acute PE according to season

DVT PE

Figure 9.1 Rates of diagnosis in hospitalized patients/100,000 population for pulmonary embolism (PE), deep venous thrombosis (DVT), and venous thromboembolism (VTE) according to quarter of year. Data are averaged from 1979 to 1999. (Reprinted from Stein et al. [1], with permission from Elsevier.)


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Venous thromboembolic disease in the four seasons

Table 9.1 Average quarterly rate of deaths from pulmonary embolism: 1980–1998 (PE deaths/100,000 population). Jan–Mar

Apr–Jun

Jul–Sep

Oct–Dec

All seasons

Northeast

1.11

0.98

0.97

1.03

1.02

Midwest

1.14

1.00

0.99

1.06

1.05

South

1.22

1.06

1.09

1.16

1.13

West

0.65

0.59

0.60

0.65

0.62

All regions

1.03

0.91

0.91

0.98

0.96

Differences between regions: South > Northeast, Midwest, West (P < 0.05); Northeast, Midwest > West (P < 0.05). Differences between seasons: Jan–Mar > Apr–Jun, Jul–Sep, Oct–Dec (P < 0.05); Oct–Dec > Apr–Jun, Jul–Sep (P < 0.05). PE, pulmonary embolism. Reprinted with permission from Stein et al. [13].

in the first quarter of the year [16–20], sometimes with overlap in the last quarter [21] and sometimes with second peaks in the third quarter [16, 17]. Others reported peak mortality rates in the second quarter [22–24], sometimes with second peaks in the third and fourth quarter [22], or fourth quarter alone [23]. Some reported peaks only in the third and fourth quarter [25]. Some reported more frequent fatal PE during “fine weather phases” of the year and “at the beginning of fine weather” [26]. Some reported no quarterly varia-

tion [27, 28]. Many of these investigations were based on observations in less than 200 patients [16–18, 20, 21]. The largest investigation included less than 1500 patients [26]. The absence of meaningful seasonal variation of the rate of diagnosis in hospitalized patients [1] and mortality from PE [13] based on data from several thousands of patients indicate that PE is not affected by the season, contrary to reports based on smaller investigations.

Table 9.2 Regions of United States defined according to states and district of Columbia. West

Midwest

South

Northeast

Alaska

Illinois

Delaware

Maine

Arizona

Indiana

Maryland

New Hampshire

California

Iowa

District of Columbia

Vermont

Colorado

Kansas

Virginia

Massachusetts

Hawaii

Michigan

West Virginia

Connecticut

Idaho

Minnesota

North Carolina

Rhode Island

Montana

Missouri

South Carolina

New York

Nevada

Nebraska

Georgia

New Jersey

New Mexico

North Dakota

Florida

Pennsylvania

Oregon

Ohio

Kentucky

Utah

South Dakota

Tennessee

Washington

Wisconsin

Wyoming

Alabama Mississippi Arkansas Louisiana Oklahoma Texas

Reprinted from Stein et al. [1], with permission from Elsevier.


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References

15 Attems J, Arbes S, Bohm G, Bohmer F, Lintner F. The clinical diagnostic accuracy rate regarding the immediate cause of death in a hospitalized geriatric population; an autopsy study of 1594 patients. Wien Med Wochenschr 2004; 154: 159–162. 16 Chau KY, Yuen ST, Wong MP. Seasonal variation in the necropsy incidence of pulmonary thromboembolism in Hong Kong. J Clin Pathol 1995; 48: 578–579. 17 Colantonio D, Casale R, Natali G, Pisqualetti P. Seasonal periodicity in fatal pulmonary thromboembolism. Lancet 1990; 335: 56–57. 18 Gallerani M, Manfredini R, Ricci L et al. Sudden death from pulmonary thromboembolism: chronobiological aspects. Eur Heart J 1992; 13: 661–665. 19 Mobius C, Gunther U, Klinker L, Putzke HP. [Meteoropathologic effects on the development of fatal lung embolism]. Z Gesamte Hyg 1989; 35: 391–392. 20 Manfredini R, Gallerani M, Salmi R, Zamboni P, Fersini C. Fatal pulmonary embolism in hospitalized patients: evidence for a winter peak. J Int Med Res 1994; 22: 85– 89. 21 Wroblewski BM, Siney PD, White R. Fatal pulmonary embolism after total hip arthroplasty. Seasonal variation. Clin Orthop Relat Res 1992; 276: 222–224. 22 Green J, Edwards C. Seasonal variation in the necropsy incidence of massive pulmonary embolism. J Clin Pathol 1994; 47: 58–60. 23 Hackl H. [Environmental effects and pulmonary embolism]. Dtsch Med J 1968; 19: 475–477. 24 Montes Santiago J, Rey Garcia G, Mediero Dominguez A. [Seasonal changes in morbimortality caused by pulmonary thromboembolism in Galicia]. An Med Interna 2003; 20: 457–460. 25 Steiner I, Matejek T. [Pulmonary embolism–temporal aspects]. Cesk Patol 2003; 39: 185–188. 26 Putzke HP, Mobius C, Gunther U, Bargenda M, Dobberphul J. [The incidence of fatal lung emboli with special reference to the underlying disease and the effect of weather]. Z Gesamte Inn Med 1989; 44: 106–110. 27 Coon WW, Coller FA. Some epidemiologic considerations of thromboembolism. Surg Gynecol Obstet 1959; 109: 487–501. 28 Golin V, Sprovieri SR, Bedrikow R, Salles MJ. Pulmonary thromboembolism: retrospective study of necropsies performed over 24 years in a university hospital in Brazil. Sao Paulo Med J 2002; 120: 105–108.

1 Stein PD, Kayali F, Olson RE. Analysis of occurrence of venous thromboembolic disease in the four seasons. Am J Cardiol 2004; 93: 511–513. 2 Galle C, Wautrecht JC, Motte S et al. The role of season in the incidence of deep vein thrombosis. J Mal Vasc 1998; 23: 99–101. 3 Bounameaux H, Hicklin L, Desmarais S. Seasonal variation in deep vein thrombosis. BMJ 1996; 312: 284–285. 4 Luthi H, Gruber UF. Is there a seasonal fluctuation in the appearance of deep venous thrombosis? Anasth Intensivther Notfallmed 1982; 17(3): 158–160. 5 National Hospital Discharge Survey Multi-year Data File 1979–1999. CD-ROM Series 13, No. 19A. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics, Hyattsville, MD, reissued March 2001. http://www.cdc.gov/nchs/about/major/hdasd/nhds.htm. 6 Oschner A, DeBakey M. Thrombophlebitis and phlebothrombosis. South Surg 1939; 8: 269–290. 7 Lawrence JC, Xabregas A, Gray L, Ham JM. Seasonal variation in the incidence of deep vein thrombosis. Br J Surg 1977; 64: 777–780. 8 Boulay F, Berthier F, Schoukroun G, Raybaut C, Gendreike Y, Blaive B. Seasonal variations in hospital admission for deep vein thrombosis and pulmonary embolism: analysis of discharge data. BMJ 2001; 323: 601–602. 9 Ferrari E, Baudouy M, Cerboni P et al. Clinical epidemiology of venous thromboembolic disease. Results of a French multicentre registry. Eur Heart J 1997; 18: 685– 691. 10 Green J, Edwards C. Seasonal variation in the necropsy incidence of massive pulmonary embolism. J Clin Pathol 1994; 47: 58–60. 11 Bilora F, Manfredini R, Petrobelli F, Vettore G, Boccioletti V, Pomerri F. Chronobiology of non fatal pulmonary thromboembolism. Panminerva Med 2001; 43: 7–10. 12 Coon WW. The spectrum of pulmonary embolism: twenty years later. Arch Surg 1976; 111: 398–402. 13 Stein PD, Kayali F, Beemath A et al. Mortality from acute pulmonary embolism according to season. Chest 2005; 128: 3156–3158. 14 Dismuke SE, VanderZwaag R. Accuracy and epidemiological implications of the death certificate diagnosis of pulmonary embolism. J Chronic Dis 1984; 37: 67–73.

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CHAPTER 10

Regional differences in the United States of rates of diagnosis of pulmonary embolism and deep venous thrombosis and mortality from pulmonary embolism

Regional rates of diagnosis of pulmonary embolism and deep venous thrombosis The Western region of the United States from 1979 to 2001 showed lower rates of diagnosis of deep venous thrombosis (DVT) and venous thromboembolism (VTE) in hospitalized patients than any other region [1] (Table 10.1, Figure 10.1). The rates of diagnosis of DVT and VTE were lower in the Western region than in other regions from 1979 to 1989 and remained lower from 1990 to 2001 (Table 10.1). Rate ratios of the rates of the diagnosis of DVT, PE, and VTE comparing the Western region to other regions ranged from 0.65 to 0.87 [1] (Table 10.2). Rates of diagnosis were based on data from The National Hospital Discharge Survey [2]. Population estimates were from the United States Bureau of the Census [3]. Regions of the United States were defined by the National Hospital Discharge Survey (see Table 10.2, Chapter 9). In Caucasians, from 1979 to 2001, the rates of diagnosis of DVT and VTE were lower in the Western region than all other regions and the rate of diagnosis of PE was lower in the West than other regions except the Midwest [1]. In African Americans, the rates of diagnosis of PE, DVT, and VTE were lower in the West than in the Midwest (Table 10.3). In both men and women, the rates of diagnosis of DVT and VTE were lower in the West than any other region [1] (Table 10.4). Within each region, the rates of diagnosis of DVT and VTE in men were lower than in women [1] (Table 10.4).

In patients ≥65 years, rates of diagnosis of DVT and VTE were lower in the Western region than other regions, but there was only a trend toward a lower rate of PE in the Western region [1]. In the Western region, rates of DVT in men and women ≥65 years were comparable, although in the Midwestern and Southern regions, rates of DVT were higher in women ≥65 years than in men ≥65 years. Caucasians ≥65 years of age and <65 years of age, from 1979 to 2001, had lower rates of diagnosis of DVT and VTE in the Western region than in other regions (P < 0.01 to P < 0.001). African Americans ≥65 years showed no regional differences in rates of diagnosis. Younger African Americans (aged <65 years) showed lower rates of DVT, PE, and VTE in the West than the Midwest [1]. Relatively low rates of diagnosis of PE and DVT were observed on the Pacific and Atlantic coasts of the United States from 1986 to 1989 in patients ≥65 years, based on a sample of Medicare enrollees [4].

Regional mortality rates from PE The PE mortality rate from 1979 to 1998 was lower in the Western region than any other region [1] (Figure 10.2). It was lower in the Western region in both men and women and in African Americans and Caucasians (all P < 0.001). Rate ratios for rates of mortality comparing the Western region to other regions ranged from 0.55 to 0.60. In patients ≥65 years and patients <65 years, the mortality rates were lower in the Western region in both Caucasians and African

47


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Prevalence, risks, and prognosis of PE and DVT

Table 10.1 Rate of diagnosis of deep venous thrombosis, pulmonary embolism, and venous thromboembolism according to region. Year

West

Midwest

South

Northeast

Deep venous thrombosis/100,000/yr 1979–1989

88

116

101

114

1990–2001

78

131

120

138

1979–2001

83

124

112

127

Pulmonary embolism/100,000/yr 1979–1989

48

59

51

55

1990–2001

34

46

41

50

1979–2001

40

52

46

53

Venous thromboembolism/100,000/yr 1979–1989

128

164

145

160

1990–2001

102

163

150

173

1979–2001

113

163

147

167

16 7

VTE DVT

53

40

50

46

100

52

83

112

124

150

127

11 3

200

PE

or

th

ea

st

So ut h N

M

id

w

es

es t

t

0 W

DX/100,000/yr

14 7

16 3

Deep venous thrombosis: 1979–1989: West < Northeast, Midwest (P < 0.001); West < South (P < 0.01) 1990–2001: West < Northeast, Midwest, and South (all P < 0.001) 1979–2001: West < Northeast, Midwest, and South (all P < 0.001) 1979–1989: South < Northeast, Midwest (P < 0.01) 1990–2001: South < Northeast (P < 0.05) 1979–2001: South < Northeast, Midwest (P < 0.01). Pulmonary embolism: 1990–2001: West < Northeast, Midwest (P < 0.001); West < South (P < 0.05) 1979–2001: West < Northeast, Midwest (P < 0.001) 1990–2001: South < Northeast (P < 0.05). Venous thromboembolism: 1979–1989: West < Northeast, Midwest (P < 0.001); West < South (P < 0.05) 1990–2001: West < Northeast, Midwest, and South (all P < 0.001) 1979–2001: West < Northeast, Midwest, and South (all P < 0.001) 1979–1989: South < Northeast, Midwest (P < 0.05) 1990–2001: South < Northeast (P < 0.01) 1979–2001: South < Northeast, Midwest (P < 0.01). Comparisons with probabilities of P > 0.05 were excluded. Reprinted from Stein et al. [1], with permission from Elsevier.

Figure 10.1 Rates of diagnosis (Dx)/100,000 population/year of pulmonary embolism (PE), deep venous thrombosis (DVT), and venous thromboembolism (VTE) according to region from 1979 to 2001. (Reprinted from Stein et al. [1], with permission from Elsevier.)


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Americans (P < 0.01 to P < 0.001). The mortality rate in women was higher than in men within all regions (P = 0.04 to P = 0.004). The rate ratios of mortality of women to men within each region ranged from 1.09 to 1.16. Death from PE was obtained from the United States Bureau of the Census records. The Western region, from 1990 to 2001, had a higher percentage of Asian Americans-Pacific Islanders (8.2%) than the Northeastern (3.2%), Midwestern (1.6%), or Southern (1.7%) regions [1]. Racial categories for Asian-Pacific Islanders did not exist in census data before 1990 [5]. Data were insufficient to make regional comparisons with Asian-Pacific Islanders. Men ≥65 years constituted 9.5% of the population in the Western region and 10.6–11.5% in other regions. Women ≥65 years constituted 12.1% of the population in the Western region and 13.8–15.4% in other regions. The rate ratio of women to men aged ≥65 years (1.3) was the same in all regions.

Table 10.2 Rate ratios of rates of diagnosis of deep venous thrombosis, pulmonary embolism, and venous thromboembolism according to region. Year

49

Regional differences of VTE in the United States

West/Northeast

West/Midwest

West/South

Deep venous thrombosis/100,000/yr 1979–1989

0.77

0.76

0.87

1990–2001

0.57

0.60

0.65

1979–2001

0.65

0.66

0.74

Pulmonary embolism/100,000/yr 1979–1989

0.87

0.82

0.94

1990–2001

0.67

0.74

0.82

1979–2001

0.76

0.77

0.87

Venous thromboembolism/100,000/yr 1979–1989

0.80

0.78

0.88

1990–2001

0.59

0.63

0.68

1979–2001

0.68

0.69

0.77

Reprinted from Stein et al. [1], with permission from Elsevier.

Table 10.3 Rates of diagnosis of deep venous thrombosis, pulmonary embolism, and venous thromboembolism according to region and race (1979–2001). Race

West

Midwest

South

Northeast

Deep venous thrombosis/100,000/yr White patients

68

95

109

122

Black patients

75

113

96

96

Pulmonary embolism/100,000/yr White patients

32

39

44

52

Black patients

38

50

39

40

Venous thromboembolism/100,000/yr White patients

92

125

143

162

Black patients

106

150

128

126

Deep venous thrombosis: Black patients: West < Midwest (P < 0.001) White patients: West < Midwest, South, Northeast (P < 0.001); Midwest < Northeast (P < 0.001); Midwest < South (P < 0.01); South < Northeast (P < 0.01). Pulmonary embolism: Black patients: West < Midwest (P < 0.05) White patients: West < Northeast (P < 0.001); West < South (P < 0.01); Midwest < Northeast (P < 0.01); South < Northeast (P < 0.05). Venous thromboembolism: Black patients: West < Midwest (P < 0.001); South, Northeast < Midwest (P < 0.05) White patients: West < Midwest, South, Northeast (P < 0.001); Midwest < Northeast (P < 0.001); Midwest < South (P < 0.01); South < Northeast (P < 0.01). Comparisons with probabilities of P > 0.05 were excluded. Reprinted from Stein et al. [1], with permission from Elsevier.


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Prevalence, risks, and prognosis of PE and DVT

Table 10.4 Rates of diagnosis of deep venous thrombosis, pulmonary embolism, and venous thromboembolism according to region and sex (1979–2001). Sex

West

Midwest

South

Northeast

Deep venous thrombosis/100,000/yr Men

76

107

90

114

Women

90

143

134

141

Pulmonary embolism/100,000/yr Men

37

48

41

48

Women

43

56

50

57

Venous thromboembolism/100,000/yr Men

104

143

121

148

Women

123

185

174

185

Deep venous thrombosis: Men: West < Midwest, Northeast (P < 0.001); West < South (P < 0.05); South < Northeast (P < 0.001); South < Midwest (P < 0.01) Women: West < Midwest, South, Northeast (P < 0.001). Pulmonary embolism: Men: West < Midwest, Northeast (P < 0.05) Women: West < Midwest, Northeast (P < 0.001); West < South (P < 0.05). Venous thromboembolism: Men: West < Midwest, Northeast (P < 0.001); West < South (P < 0.01); South < Northeast, Midwest (P < 0.001) Women: West < Midwest, South, Northeast (P < 0.001). Comparisons with probabilities of P > 0.05 were excluded. Reprinted from Stein et al. [1], with permission from Elsevier.

PE deaths/100,000/yr

Kniffin and associates, in a population of patients ≥65 years of age, showed lower age adjusted rates of diagnosis of PE in women than men and a tendency toward higher rates of DVT in women than men [4]. We showed comparable rates of diagnosis of PE in men and women ≥65 years of age in each of the regions and comparable rates of DVT in the Western and

10 8 6 4

4.2

4.5

4.1

Midwest

South

Northeast

2.5

2 0 West

Figure 10.2 Mortality rates from PE (deaths from PE/100,000 population/year) from 1979 to 1998. The mortality rate in the Western region was lower than the mortality rate in all other regions (P < 0.001). (Reprinted from Stein et al. [1], with permission from Elsevier.)

Northeastern regions, but higher rates of DVT in elderly women than elderly men in the Midwestern and Southern regions [1]. Throughout the United States for patients of all ages, the rate of diagnosis of DVT was higher in women than men [6], but in elderly patients the rates of DVT and PE were comparable in men and women [7]. A somewhat younger population would have contributed to the lower rates of DVT and VTE and the lower mortality rate in the Western region [7]. However, such lower rates were observed in patients ≥65 years as well. A higher percentage of Asian Americans and/or Pacific Islanders in the Western region than in other regions would also have contributed to the lower rates of diagnosis and lower mortality rate in the Western region, because the incidences of PE and of DVT are lower in Asian Americans than in African Americans or Caucasians [8–10]. However, lower rates of diagnosis of DVT, PE, and VTE were shown in Caucasians in the Western region and lower mortality rates from PE were shown in Caucasians and African Americans in the Western region. The observed difference


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Regional differences of VTE in the United States

in regional rates of diagnosis of DVT and VTE are unlikely to be related to differences in climate. We observed no seasonal variation in the rate of diagnosis of DVT, PE, or VTE in any of the regions, including the Southern region, where winters are mild, and the Northeastern and Midwestern regions, where seasons are sharply defined [5] (see Chapter 9). Lilienfeld and Godbold, based on data from 1980 to 1984, showed lower mortality rates from PE in the Pacific and Mountain regions than other parts of the country [11].

References 1 Stein PD, Kayali F, Olson RE. Regional differences in rates of diagnosis and mortality of pulmonary thomboembolism. Am J Cardiol 2004; 93: 1194–1197. 2 National Hospital Discharge Survey 1979–2001 Multiyear Public-use data file documentation. US Department of Health and Human Services, Public Health Service, National Center for Health Statistics. http://www.cdc.gov/ nchs/about/major/hdasd/nhds.htm. 3 Bureau of the Census, Department Of Commerce, United States Department of Health and Human Services (US DHHS) Centers for Disease Control and Prevention (CDC), CDC WONDER On-line Database. http:// wonder.cdc.gov/census.shtml.

51

4 Kniffin WD, Jr, Baron JA, Barrett J, Birkmeyer JD, Anderson FA, Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994; 154: 861–866. 5 Stein PD, Kayali F, Olson RE. Analysis of venous thromboembolic disease in the four seasons. Am J Cardiol 2004; 93: 511–513. 6 Stein PD, Hull RD, Patel KC et al. Venous thromboembolic disease: comparison of the diagnostic process in men and women. Arch Intern Med 2003; 163: 1689–1694. 7 Stein PD, Hull RD, Kayali F, Ghali WA, Alshab AK, Olson RE. Venous thromboembolism according to age: the impact of an aging population. Arch Intern Med 2004; 164: 2260–2265. 8 Klatsky AL, Armstrong MA, Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in AsianAmericans. Am J Cardiol 2000; 85: 1334–1337. 9 White RH, Zhou H, Romano PS. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann Intern Med 1998; 128: 737–740. 10 Stein PD, Kayali F, Olson RE, Milford, CE. Pulmonary thromboembolism in Asian-Pacific Islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med 2004; 116: 435–442. 11 Lilienfeld DE, Godbold JH. Geographic distribution of pulmonary embolism mortality rates in the United States, 1980 to 1984. Am Heart J 1992; 124: 1068–1072.


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CHAPTER 11

Venous thromboembolism in the elderly patients than in younger patients (20–69 years). The 21-year trends for the diagnosis of DVT according to age are shown in Figure 11.1b [1]. The elderly population showed the greatest increase in the 1990s. The diagnosis of pulmonary embolism (PE) in patients 70 years or older was 6.2 than the rate in younger patients (Figure 11.2a) [1]. Contrary to DVT, the rate of diagnosis of PE decreased from 370 PE/100,000 population in 1979 to 254 PE/100,000 population in 1990 (Figure 11.2a) and then remained constant.

Rates of diagnosis and trends in the diagnosis of deep venous thrombosis and pulmonary embolism in the elderly Deep venous thrombosis (DVT) in elderly patients (70 years or older) increased 44% from 454 DVT/100,000 population in 1990 to 655 DVT/100,000 population in 1999 (Figure 11.1a) [1]. Deep venous thrombosis was diagnosed 4.7 times more frequently in elderly (a) DVT DVT/100,000 population

800

Age >70

600 400 Age 20−69

200 0

1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

Year

(b) DVT: age distribution

DVT/100,000 population

1000 800

70−89

600 400

60−69 50−59 40−49 20−39

200 0 1999

1997

1995

1993

52

1991

1989

1987

1985

1983

1981

1979

Year

Figure 11.1 (a) Among elderly patients (70 years or older), trends over 21 years in the rate of diagnosis of deep venous thrombosis (DVT) was constant from 1979 to 1990 and increased from 1990 to 1999. In younger patients (20–69 years), there was a slight but significant decline in the rate of diagnosis of DVT between 1979 and 1990. The rate then increased somewhat between 1990 and 1999. (b) From 1979 to 1990, the rate of diagnosis of DVT was constant in patients aged 60–69 and 70–89 years. During this time interval, the rate decreased in younger age groups. From 1990 to 1999, the rate of diagnosis of DVT increased in all age groups. (Reproduced from Stein et al. [1], with permission from American Medical Association. All rights reserved.)


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53

Venous thromboembolism in the elderly (a) PE

200 100

Age 20−69

0 1999

1997

1995

1993

1991

1989

1987

1985

1983

PE/100,000 population

500

PE: age distribution

400 300

70−89

200 60−69 50−59 40−49 20−39

100 0 1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

Year

DVT/100,000 population/yr

Smaller changes were observed in patients aged 20– 69 years from 67 PE/100,000 population in 1979 to 30 PE/100,000 population in 1990 (Figure 11.2b). The rate increased somewhat between 1990 and 1999. The rates of diagnosis of DVT or PE in elderly men and women, and elderly black and white patients were comparable [1].

Figure 11.3 Deep venous thrombosis (DVT)/100,000 population/year, diagnosed at hospital discharge, shown according to age for the year 1999. (Data from Stein et al. [1, 2].)

1981

Year

(b)

1979

Figure 11.2 (a) Among elderly patients (70 years or older), trends over 21 years in the rate of diagnosis of pulmonary embolism (PE) decreased from 1979 to 1990 and then remained constant from 1990 to 1999. In younger patients there was a slight but significant decline in the rate of diagnosis of PE between 1979 and 1990. The rate then increased somewhat between 1990 and 1999. (b) Trends over 21 years in the rate of diagnosis of PE in patients as shown by age group. In all age groups, the rate of diagnosis of PE significantly decreased from 1979 to 1990. From 1990 to 1999, the rate of diagnosis of PE remained constant in all age groups except age 20–39, which showed a slight increase. (Reproduced from Stein et al. [1], with permission from American Medical Association. All rights reserved.)

Age >70

300

1979

PE/100,000 population

400

Deep venous thrombosis, based on hospital discharges, was diagnosed in 700 patients/100,000 population/year aged 70–89 years, 300/100,000 population/year aged 60–69 years, and lower proportions of the population of younger people [1, 2] (Figure 11.3). Comparing the rate of DVT at each decade of age with the rate at age 20–29, the rate ratio increased 700

700 600 500 400

300

300 200

200 100 0

<5

10

30

60

100

0−14 15−19 20−29 30−39 40−49 50−59 60−69 70−89

Age groups (years)


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54

PART I

40

DVT 1980−1999

Prevalence, risks, and prognosis of PE and DVT

PE 1980−1999

40

.7

11

1

Rate ratio

Rate ratio

.7

20

1

6.

2.

6

10

7 7

90−99

80−89

70−79

60−69

250

50−59

300

300

40−49

exponentially up to age 89 (Figure 11.4) [1]. In patients aged 70–79 years and 80–89 years, the rate ratios for DVT were 12.7 and 17.7, respectively. Pulmonary embolism, based on hospital discharges, was diagnosed in 300 patients/100,000 population/year aged 70–89 years, 100/100,000 population/year aged 60–69 years, and lower proportions of the population of younger people [1, 2] (Figure 11.5). Comparing the rate of PE at each decade of age with the rate at age 20–29, the rate ratio increased exponentially up to age 89 (Figure 11.6) [1]. In patients aged 70–79 years and 80–89 years, the rate ratios for

30−39

Figure 11.4 Rate ratios for the rate of diagnosis of deep venous thrombosis (DVT), comparing each decade of age with the rate at age 20–29 years. Rate ratios were averaged over 21 years. Between ages 20–29 and 80–89 years, the rate ratios for the diagnosis of DVT increased exponentially. (Reproduced from Stein et al. [1], with permission from American Medical Association. All rights reserved.)

0 20−29

90−99

80−89

70−79

60−69

50−59

40−49

30−39

20−29

Age groups (years)

PE/100,000 population/yr

1

1.

7

3.

1. 0

Age groups (years) Figure 11.6 Rate ratios for the rate of diagnosis of pulmonary embolism (PE), comparing each decade of age with the rate at age 20–29 years. Rate ratios were averaged over 21 years. Between ages 20–29 and 80–89 years, the rate ratios for the diagnosis of PE increased exponentially. (Reproduced from Stein et al. [1], with permission from American Medical Association. All rights reserved.)

PE were 20.6 and 27.9, respectively. There was no step change of rate of diagnosis of PE or DVT at any age. The recommended approach to the diagnosis of PE is applicable to elderly patients [3]. An abundance of literature documents that the risk of venous thromboembolism increases with age [1, 4–19].

Case fatality rate From 1989 to 1998, the estimated case fatality rate from PE in the United States was 7.7 PE deaths/100 cases of PE [20]. The estimated case fatality rate from PE is strongly age-dependent, and increased exponentially with age from 3.6% in patients aged 25–34 years to 17.4% in patients aged >85 years [20] (see Chapter 3).

Antithrombotic prophylaxis and age

200 150

100

100

80

50 0

.3

.9 .6

12 8. 4.

10

20

.7

20

27

.9

17

17

30

27

30

<1 0−14

4

10

20

20

15−19 20−29 30−39 40−49 50−59 60−69 70−89

Age groups (years)

Figure 11.5 Pulmonary embolism (PE)/100,000 population/ year, diagnosed at hospital discharge, shown according to age for the year 1999. (Data from Stein et al. [1, 2].)

Recommendations for antithrombotic prophylaxis in patients undergoing surgical procedures are partially based on the age of the patient [21]. Patients less than 40 years have been considered at low-risk for venous thromboembolism for specific in-hospital surgical groups, such as general surgical patients, and age as a risk factor has become more important at 40 years or older with regard to thromboprophylaxis [21]. This led to the general belief that age as a risk factor has a


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Venous thromboembolism in the elderly

55

break point at the age of 40 years. For patients aged 30–39 years, there is almost a 2-fold increase in the risk of DVT or PE compared with younger patients [1]. The concept that the elderly are at the greatest need for thromboprophylaxis is emphasized by these data which show an 18–28-fold increase in the risk of DVT or PE for patients ≥70 years compared with those 20–29 years of age [1].

the PE in 44% [25]. Comparable percentages of patients in the younger age groups were immobilized or underwent surgery before the PE. Malignancy was more frequent among patients ≥70 years (26%) than among the patients <40 years old (2%), but patients 40–69 years had malignancy nearly as frequently as did patients ≥70 years old (24%). Estrogen use was infrequent among female patients ≥70 years old. Its use among female patients <40 years of age preceded PE in 35% and childbirth in women <40 years of age preceded PE in 25% [25].

CHAPTER 11

Diagnosis of acute PE The diagnosis of PE among elderly patients has been thought to be particularly difficult because the expected signs and symptoms may be absent or ignored [22–24]. This did not seem to be the case in the experience of the Prospective Investigation of the Pulmonary Embolism Diagnosis (PIOPED I) [25] and, in general, not in the experience of PIOPED II [26]. In PIOPED II, however, dyspnea and tachypnea were less frequent in patients ≥70 years old than in patients <40 years old [26]. The typical signs and symptoms known to occur among younger patients were common among elderly patients [25, 26]. In the absence of these signs and symptoms, unexplained radiographic abnormalities were important diagnostic clues [25]. When the diagnosis of PE is uncertain, computed tomographic (CT) angiography can be performed safely in elderly patients, providing renal function is adequate [3]. Renal failure was a problem among elderly patients who underwent conventional angiography [25].

Predisposing factors according to age Among 72 patients ≥70 years old in PIOPED I, 67% were immobilized before the PE, and surgery preceded

Syndromes of PE according to age The usual syndromes of PE, among all patients, irrespective of prior cardiopulmonary disease, characterized by (1) hemoptysis or pleuritic pain, (2) isolated dyspnea, or (3) circulatory collapse were observed in PIOPED I among elderly patients [25]. However, 11% of patients ≥70 years of age in PIOPED I and 15% in PIOPED II did not show these syndromes [25, 26]. In PIOPED I they were identified on the basis of unexpected radiographic abnormalities, which may have been accompanied by tachypnea or a history of thrombophlebitis [25]. Unexplained radiographic abnormalities may be an important clue to the diagnosis of PE, particularly among elderly patients in whom the expected signs and symptoms are absent, as has been previously observed [22]. Among all patients with PE in PIOPED II, the syndrome of hemoptysis or pleuritic pain was less frequent in patients ≥70 years than in patients <40 years (P < 0.025) and isolated dyspnea was more frequent (P < 0.05) (Table 11.1). In PIOPED II, among patients with no prior cardiopulmonary disease, the prevalence of the various syndromes was similar among all age groups (Table 11.2).

Table 11.1 Syndromes of acute PE according to age: all patients with pulmonary embolism: PIOPED II. Syndromes Hypotension, LOC

≥70 yr (n = 55) [n (%)]

40–69 yr (n = 106) [n (%)]

<40 yr (n = 31) [n (%)]

2 (4)

10 (9)

3 (10)

Hemoptysis or pleuritic pain

15 (27)

43 (41)

16 (52)

Isolated dyspnea

30 (55)

39 (37)

10 (32)

8 (15)

14 (13)

2 (6)

No syndrome

The syndrome of hemoptysis or pleuritic pain was less frequent in patients ≥70 years than in patients <40 years (P <0.025) and isolated dyspnea was more frequent (P <0.05). PE, pulmonary embolism; LOC, loss of consciousness. Data from Stein et al. [26].


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Prevalence, risks, and prognosis of PE and DVT

Table 11.2 Syndromes of acute PE according to age: patients with no prior cardiopulmonary disease: PIOPED II. ≥70 yr (n = 35) [n (%)]

Syndromes Hypotension, LOC

40–69 yr (n = 76) [n (%)]

<40 yr (n = 22) [n (%)]

2 (6)

7 (9)

2 (9)

Hemoptysis or pleuritic pain

11 (31)

30 (39)

10 (45)

Isolated dyspnea

17 (49)

29 (38)

8 (36)

6 (17)

11 (14)

2 (9)

No syndrome

Differences comparing age groups not significant. PE, pulmonary embolism; LOC, loss of consciousness. Data from Stein et al. [26].

Symptoms according to age Dyspnea was the most frequent symptom in all patients with PE, occurring in 78 and 75% of ≥70 years old in PIOPED I and PIOPED II [25, 26] (Tables 11.3) and in 66% of patients ≥70 years old with no prior cardiopulmonary disease (Table 11.4). Pleuritic pain occurred in 51 and 33% of all patients with PE in PIOPED I and PIOPED II. Pleuritic pain occurred more frequently than hemoptysis in all age groups. In gen-

eral, all symptoms occurred with equal frequency in the different age groups, but there were occasional exceptions, as noted in Tables 11.3–11.4

Signs according to age Tachypnea (respiratory rate ≥20/min) was the most frequent sign in all age groups with PE [25, 26] (Table 11.5) and in those with no prior cardiopulmonary disease (Table 11.6). All signs, occurred with

Table 11.3 Symptoms in all patients with acute pulmonary embolism according to age: PIOPED I and PIOPED II. ≥70 yr

Dyspnea

<40 yr

40–69 yr

PIOPED I

PIOPED II

PIOPED I

PIOPED II

PIOPED I

(n = 72)

(n = 53–55)

(n = 144)

(n = 100–106)

(n = 44)

PIOPED II (n = 30–31)

(%)

(%)

(%)

(%)

(%)

(%) 87

78

75

78

79

82

Dyspnea (rest or exertion)

75

79

87

Dyspnea (at rest)

60

59

71

Dyspnea (exertion only)

13

19

13

Orthopnea (>2-pillow)

31

40

32

51

33

58

53

70

53

Cough

35

44

42

46

45

35

Purulent

11

10

6

Clear

9

11

6

Nonproductive

20

21

23

Leg swelling

35

26

33

50

14

33

Leg pain

31

28

26

45

20

48

Palpitation

13

15

9

Wheezing

10

25

12

32

16

35

Angina-like pain

10

13

13

18

7

23

8

4

4

6

32*

10

Pleuritic pain

Hemoptysis

*P <0.01, ≥70 years vs. <40 years; P <0.001, 40–69 years vs. <40 years among patients in PIOPED I. Data from Stein et al. [25, 26].


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Table 11.4 Symptoms in patients with PE and no preexisting cardiac or pulmonary disease according to age: PIOPED II.

Syndromes

≥70 yr

40–69 yr

<40 yr

(n = 30–35)

(n = 72–76)

(n = 21–22)

(%)

(%)

(%)

Dyspnea Dyspnea (rest or exertion)

66

75

82

Dyspnea (at rest)

49

55

68

Dyspnea (exertion only)

14

19

9

Orthopnea (≥2-pillow)

23

33

18

Pleuritic pain

35

46

45

Chest pain (not pleuritic)

18

20

23

Cough

29

36

36

Hemoptysis

3

5

9

Purulent

6

5

5

Clear Nonproductive Wheezing

6

5

5

11

21

27

9

24

27

Calf swelling

26

49*

24

Thigh swelling

11

5

9

0

0

5

Calf pain

26

47

41

Thigh pain

11

24

19

0

3

5

Thigh swelling, no calf swelling

Thigh pain, no calf pain

*P = 0.025, age ≥70 years vs. age 40–69 years, P = 0.048, age 40–69 years vs. age <40 years. All other differences between age groups not significant. Data from Stein et al. [26].

Table 11.5 Signs in all patients with acute pulmonary embolism according to age: PIOPED I and PIOPED II. ≥70 yr

<40 yr

40–69 yr

PIOPED I

PIOPED II

PIOPED I

PIOPED II

PIOPED I

PIOPED II

(n = 72)

(n = 52–55)

(n = 144)

(n = 101–106)

(n = 44)

(n = 29–31)

(%)

(%)

(%)

(%)

(%)

(%)

Tachypnea (>20/min)

74

51

69

58

82

60

Rales

65

26

61

17

41

26

Tachycardia (>100/min)

29

21

26

24

32

43

Increased P2

15

7

20

19

34

18

Deep venous thrombosis

15

47

17

49

9

42

Diaphoresis

8

2

10

7

18

0

Wheezes

8

4

10

2

5

6

Temperature >38.5◦ C

7

0

5

2

14

3

Third heart sound

7

6

5

Right ventricular lift

4

7

0

Jugular venous distention

19

12

10

Rhonchi

6

6

0

Decreased breath sounds

29

19

13

Pleural friction rub

6

2

5

1

0

0

Homans’ sign

4

2

2

Cyanosis

3

0

3

1

2

0

Differences between age groups in both PIOPED I and PIOPED II were not significant. Data from Stein et al. [25, 26].

57


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Prevalence, risks, and prognosis of PE and DVT

Table 11.6 Signs in patients with PE and no preexisting cardiac or pulmonary disease according to age: PIOPED II. ≥70 yr

40–69 yr

<40 yr

(n = 30–35)

(n = 71–76)

(n = 20–22)

(%)

(%)

(%)

Tachypnea (≥20/min)

47

59

52

Tachycardia (>100/min)

23

21

38

Diaphoresis

3

3

0

Cyanosis

0

0

0

Signs General

Temperature >38.5◦ C (>101.3◦ F)

0

3

5

Cardiac examination (any)

23

22

14

Increased P2*

12

15

19

0

6

0

Jugular venous distension

20

14

5

Lung examination (any)

43

22

27

Rales (crackles)

Right ventricular lift†

26

14

19

Wheezes

3

1

0

Rhonchi

0

3

0

23

14

18

0

0

0

Decreased breath sounds Pleural friction rub DVT Calf or thigh

51

48

36

Calf only

34

31

32

Calf and thigh

14

16

5

3

1

0

Thigh only

All differences comparing age groups not significant. * Data in 26 patients ≥70 years, 61 patients 40–69 years, 16 patients ≤40 years. † Data in 30 patients ≥70 years, 64 patients 40–69 years, 16 patients <40 years. P2, pulmonary component of second heart sound; DVT, deep venous thrombosis. Data from Stein et al. [26].

similar frequency among all age groups (Tables 11.5 and 11.6).

Chest radiograph The chest radiograph among all patients with PE in PIOPED I was normal in 4% ≥70 years old [25]. Atelectasis or pulmonary parenchymal abnormalities were the most frequent radiographic abnormalities among all age groups. All radiographic abnormalities occurred with a comparable frequency among all age groups (Table 11. 7).

Combinations of symptoms and signs and radiographic abnormalities Even among patients ≥70 years old, a combination of nonspecific symptoms and signs that typically occur

with PE was present in the great majority of patients with PE [25, 26]. Dyspnea or tachypnea among all patients with PE occurred in 92% of patients ≥70 years of age in PIOPED I, but in only 77% in PIOPED II (Table 11.8) and in 70% with no prior cardiopulmonary disease in PIOPED II (Table 11.9). Among all patients with PE, dyspnea or tachypnea or pleuritic pain occurred in 94% of patients ≥70 years old in PIOPED I and in 87% in PIOPED II [25, 26]. If signs of DVT were added, 94% of patients ≥70 years in PIOPED I and 96% in PIOPED II had 1 or more of these findings (Tables 11.8). Combinations of signs and symptoms occurred with similar frequency in all age groups, except dyspnea or tachypnea among patients with PE and no prior cardiopulmonary disease were less frequent in patients 70 years than in patients <40 years [26] (Tables 11.8 and 11.9).


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Table 11.7 Chest radiograph in all patients with acute pulmonary embolism according to age: PIOPED I. ≥70 yr

40–69 yr

<40 yr

(n = 72) (%)

(n = 144) (%)

(n = 44) (%)

4

8

Atelectasis or pulmonary parenchymal abnormality

Normal

71

69

14 64

Pleural effusion

57

46

45

Pleural-based opacity

42

34

43

Prominent central pulmonary artery

29

20

11

Elevated diaphragm

28

27

18

Cardiomegaly

22

17

14

Decreased pulmonary vascularity

19

22

20

Pulmonary edema

13

12

7

Westermark’s sign

7

8

0

Differences among age groups were not significant. Westermark’s sign = prominent central pulmonary artery and decreased pulmonary vascularity. Reprinted from Stein et al. [25], with permission from the American College of Cardiology Foundation.

The electrocardiogram according to age Nonspecific ST segment or T wave changes were the most frequent electrocardiographic abnormalities in all patients with PE, either or both occurring in 56% of patients ≥70 years old and with nearly the same

frequency in younger patients [25]. With the exception of left anterior hemiblock (left axis deviation) among patients ≥70 years of age, other electrocardiographic abnormalities occurred in 12% or fewer patients in all age groups in PIOPED I. No differences in the frequency of occurrence of any ECG abnormalities

Table 11.8 Combinations of signs and symptoms in all patients with acute pulmonary embolism according to age: PIOPED I and PIOPED II. ≥70 yr

<40 yr

40–69 yr

PIOPED I

PIOPED II

PIOPED I

PIOPED II

PIOPED I

PIOPED II

(n = 72)

(n = 52)

(n = 144)

(n = 104)

(n = 44)

(n = 30)

(%)

(%)

(%)

(%)

(%)

(%)

Dyspnea or tachypnea

92

77

90

88

95

Dyspnea or tachypnea or hemoptysis

92

91

98

93 —

Dyspnea or tachypnea or pleuritic pain*

94

87

98

93

100

Dyspnea or tachypnea or signs of deep

92

91

98

97

94

96

99

96

100

100

97

98

100

99

100

venous thrombosis Dyspnea or tachypnea or pleuritic pain or

100

signs of deep venous thrombosis* Dyspnea or tachypnea or radiographic atelectasis or parenchymal abnormality Dyspnea or tachypnea or pleuritic pain or radiographic atelectasis or parenchymal abnormality* *The addition of hemoptysis did not improve the sensitivity of the combination for the detection of pulmonary embolism. Tachypnea = respiratory rate ≥20/min. Differences among age groups in PIOPED I and PIOPED II were not significant. Data from Stein et al. [25, 26].


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Prevalence, risks, and prognosis of PE and DVT

Table 11.9 Combinations of signs and symptoms in patients with acute pulmonary embolism and no prior cardiopulmonary disease according to age: PIOPED II. ≥70 yr (n = 33) (%)

40–69 yr (n = 75) (%)

<40 yr (n = 21) (%)

Dyspnea or tachypnea (≥20/min)

70*

88

90

Dyspnea or tachypnea (≥20/min) or

85

93

95

97

97

100

pleuritic pain Dyspnea or tachypnea (≥20/min) or pleuritic pain or signs of DVT Tachypnea = respiratory rate ≥20/min. P = 0.025, age ≥70 years vs. age <40 years. Other differences among age groups were not significant. Data from Stein et al. [26].

were apparent between patients ≥70 years of age and younger patients, although incomplete right bundle branch block was less frequent among patients 40–69 years than among patients less than 40 years of age (Table 11.10).

Blood gases according to age The partial pressure of oxygen in arterial blood (PaO2 ) was lower among patients ≥70 years than among those <40 years of age based on data in PIOPED I among all patients with PE [25]. Among patients 40–69 years, the PaO2 was lower than in patients <40 years, but not significantly lower than in patients ≥70 years of age [25]. The PaO2 among patients with PE ≥70 years of age, 40–69 years of age, and <40 years of age was 61 ± 12,

67 ± 15, and 75 ± 18 mm Hg, respectively (mean ± standard deviation). In PIOPED II, the PaO2 in all patients with PE who were 70 years old was 91 ± 72 mm Hg and did not differ significantly from values in patients 40–69 years (83 ± 31 mm Hg) (unpublished data from [26]). In those with PE and no prior cardiopulmonary disease, the PaO2 in patients 70 years old was 88 ± 45 mm Hg and it also did not differ significantly from values in patients 40–69 years (84 �� 27 mm Hg) (unpublished data from [26]). The alveolar–arterial oxygen difference (gradient) among patients with PE ≥70 years of age was 47 ± 14 mm Hg, which was higher than among patients 40–69 years old (40 ± 17 mm Hg) and it was higher than in patients <40 years old (31 ± 17 mm Hg). The alveolar–arterial oxygen difference in normal adults increases with age [27–30].

Table 11.10 Electrocardiographic findings in all patients with acute pulmonary embolism according to age: PIOPED I. ≥70 yr (n = 72) (%)

40–69 yr (n = 113) (%)

<40 yr (n = 36) (%)

Normal

21

27

22

ST segment or T wave changes

56

51

56

Left axis deviation

18

11

8

Left ventricular hypertrophy

12

7

11

Acute myocardial infarction pattern

12

4

6

Low voltage QRS

9

5

0

Complete right bundle branch block

7

4

3

Right ventricular hypertrophy

4

3

3

Right axis deviation

2

3

8

P-pulmonale

2

2

0

Incomplete right bundle branch block

2

0

11*

*P < 0.01, age 40–69 years vs. age <40 years. Reprinted from Stein et al. [25], with permission from the American College of Cardiology Foundation.


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Clinical assessment according to age The accuracy of clinical assessment was comparable among patients in all age groups [25]. When physicians were 80–100% confident that PE was present on the basis of clinical judgment and laboratory tests with the exception of ventilation–perfusion scans, they were correct in 90% of 10 patients ≥70 years old. When they believed that there was less than 20% likelihood of PE, it was present in 19% of 69 patients. In most patients physicians were uncertain of the diagnosis, believing that there was a 20–79% chance of PE.

Ventilation–perfusion lung scan according to age Among patients ≥70 years of age the positive predictive value of a high-probability interpretation of the ventilation–perfusion lung scan (94%) was higher than in patients <40 years of age (69%) [25] (Table 11.11). The positive predictive value of other interpretations was comparable in all age groups. The sensitivity of ventilation–perfusion lung scans indicating a high probability of PE among patients ≥70 years of age (47%) did not differ significantly from the sensitivity of such scans among younger age groups [25].

CT angiography according to age Among 773 patients with an adequate CT pulmonary angiography and 737 patients with an adequate CT pulmonary angiography/CT venography, the sensitivity and specificity for PE for age groups 18–59, 60–79, and 80–99 years did not differ to a statistically significant extent [31]. Multidetector CT pulmonary an-

giography and CT pulmonary angiography/CT venography may be used with various diagnostic strategies in adults of all ages.

Acute hemorrhage/infarction syndrome in the elderly The syndrome of hemoptysis or pleuritic pain, in addition to signs and symptoms, was investigated in detail in elderly patients [32]. The electrocardiogram was normal in 62% of such patients [32]. If abnormal, the most frequent abnormalities were nonspecific ST segment or T wave changes (38%). The chest radiograph showed atelectasis or a pulmonary parenchymal abnormality in 82% of elderly patients with the hemoptysis/pleuritic pain syndrome. The central pulmonary artery dilated in 29% of such elderly patients. A normal chest radiograph was uncommon, occurring in only 6% of elderly patients. The ventilation–perfusion lung scan was interpreted as high probability for PE in 41% of elderly patients with the hemoptysis/pleuritic pain syndrome. Elderly patients with the hemoptysis/pleuritic pain syndrome had a higher pulmonary artery mean pressure (25 ± 9 versus 17 ± 7 mm Hg) and lower PaO2 (64 ± 10 versus 81 ± 14 mm Hg) than patients <40 years of age, and elderly patients tended to have more mismatched segmental perfusion defects on the ventilation–perfusion lung scan than patients <40 years of age [32].

Use of diagnostic tests in the elderly Diagnostic approaches to DVT and PE have changed markedly over the past two decades in temporal

Table 11.11 Results of ventilation–perfusion lung scans in all patients with acute pulmonary embolism according to age: PIOPED I. ≥70 yr V–Q scan probability High Intermediate Low Near normal/normal

PE/n

≤40 yr

40–69 yr (%)

PE/n

(%)

PE/n

(%)

34/36

(94)*

60/68

(88)

11/16

(69)

27/100

(27)

59/199

(30)

22/52

(42)

10/71

(14)

24/172

(14)

8/57

(14)

1/8

(13)

1/55

(2)

3/68

(4)

*P ≤ 0.025 ≤70 years vs ≤40, all other differences among age groups were not significant. n, number of patients with the scan result shown in column; PE, pulmonary embolism. Reprinted from Stein et al. [25], with permission from the American College of Cardiology Foundation.


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Venograms/100,000 population

PART I

Prevalence, risks, and prognosis of PE and DVT

200 150 Age >70

100 Age 20−69

50 0

1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

Year

harmony with the evolving literature [3, 33]. Changes in the use of diagnostic tests in the elderly parallel the changes in the general population. The use of diagnostic tests in elderly black and white patients was comparable [1]. During the 1980s and early 1990s, the use of contrast venography of the lower extremities was strikingly higher in elderly patients than in younger patients

Figure 11.7 Trends over 21 years in the use of contrast venography of the lower extremities in elderly patients compared with younger patients. The use of contrast venography peaked in 1986 and began to decline sharply in 1989 and thereafter in patients aged 70 or older. The use of contrast venography was higher in elderly patients than in younger patients. (Reproduced from Stein et al. [1], with permission from American Medical Association. All rights reserved.)

(Figure 11.7) [1]. The use of contrast venography sharply declined as the use of ultrasonography increased. Doppler ultrasonography has supplanted ascending contrast venography as the preferred diagnostic approach for DVT [33]. Between 1989 and 1999, the elderly population utilized 5.7 times far more venous ultrasound tests of the lower extremities than the younger population (20–69 years) (Figure 11.8a) [1].

(a) Ultrasound/100,000 population

Ultrasound 300

Age >70 200 100

Age 20−69 0 1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

Year

(b) Ultrasound 1989−1999

30

25.3

Rate ratio

20.4

20

14.6 8.4

10 1.4

2.5

30−39

40−49

4.8

0 90−99

80−89

70−79

60−69

50−59

20−29

Age groups (years)

Figure 11.8 (a) The use of Doppler ultrasonography in the elderly markedly increased after 1982 and stabilized in the 1990s. (b) Rate ratios comparing the rate of use of venous ultrasound at age 20–29 to older decades for the interval of 1989 to 1999. Between ages 20–29 and age 80–89, the rate ratios increased exponentially with age. The 95% confidence intervals were too narrow to illustrate. (Reproduced from Stein et al. [1], with permission from American Medical Association. All rights reserved.)


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Venous thromboembolism in the elderly

80−89

400

70−79

300 200

60−69 50−59

100

40−49 20−39

0 1999

1997

1995

1993

1991

1989

1987

1985

Year

427 patients 40–69 years, and in 0.7% of 135 patients <40 years of age. Renal failure, either major or minor, was the most frequent complication of conventional pulmonary angiography among elderly patients [25]. It occurred in 3% of 200 patients ≥70 years of age, compared with 0.7% of 562 patients ≤69 years of age. Among the 10 patients who developed renal failure, 3 required dialysis. “Minor” complications of renal failure were important complications, although dialysis was not required. Patients with these complications showed either an elevation of the serum creatinine from previously normal levels to ≥2.1 mg/100 mL (range 2.1–3.5 mg/100 mL) or an increase in a previously abnormal serum creatinine level ≥2 mg/100 mL.

40 30 Age >70

20

AGE 20−69

10 0

9 −9 97 19 6 −9 94 19 3 −9 91 19 0 −9 88 19 7 −8 85 19 4 −8 82 19 1 −8 79

19

The rate ratio of use of ultrasound, comparing each decade of age with the rate at age 20–29, based on average values from 1989 to 1999, was the highest in the elderly (Figure 11.8b). The use of lung scans over 21 years of observation was highest in elderly patients (Figure 11.9a) [1]. In all age groups, the use of lung scans has decreased since mid-1980s (Figure 11.9a). The utility of ventilation– perfusion lung scans among patients ≥70 years old was comparable with that in younger patients [25]. The positive predictive value of all probabilities of ventilation–perfusion lung scans using original PIOPED criteria [34] were comparable in all age groups (Table 11.11) [25]. However, a higher proportion of patients ≥70 years of age had nondiagnostic (intermediate or low probability) V–Q scans, (80%), than patients ≤40 years of age (56%) (Table 11.11). Among patients ≥70 years of age with ventilation–perfusion lung scans indicating a high probability of PE, 94% had PE (Table 11.11). The rate of use of pulmonary angiograms over a 21-year period of observation was higher in elderly patients than in younger patients (Figure 11.10) [1]. Both for elderly patients and for younger patients the use of pulmonary angiograms increased from 1979 to 1999. Pulmonary angiography was not more hazardous among the elderly, although renal failure was a more frequent sequela among patients ≥70 years of age than among younger patients [25]. Major complications occurred in 1.0% of 200 patients ≥70 years, in 1.2% of

1983

1981

1979

Figure 11.9 Trends over 21 years in the use of radioisotopic lung scans in elderly patients (70 years or older) showed a higher utilization compared with younger patients. The use of lung scans in elderly patients began to increase sharply in 1983, peaked in 1986, and showed a progressive decline in 1987. (Reproduced from Stein et al. [1], with permission from American Medical Association. All rights reserved.)

500

Angios/100,000 population

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Lung scans/100,000 population

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Year Figure 11.10 Trends over 21 years in the use of pulmonary angiograms in elderly patients compared with younger patients. The rate of use of pulmonary angiograms was higher in elderly patients than in younger patients. (Reproduced from Stein et al. [1], with permission from American Medical Association. All rights reserved.)


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References 1 Stein PD, Hull RD, Kayali F, Ghali WA, Alshab AK, Olson RE. Venous thromboembolism according to age: the impact of an aging population. Arch Intern Med 2004; 164: 2260–2265. 2 Stein PD, Kayali F, Olson RE. Incidence of venous thromboembolism in infants and children: data from the National Hospital Discharge Survey. J Pediatr 2004; 145: 563–565. 3 Stein PD, Woodard PK, Weg JG et al. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II Investigators. Am J Med 2006; 119: 1048–1055. 4 Anderson FA, Jr, Wheeler HB, Goldberg RJ et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT study. Arch Intern Med 1991; 151: 933–938. 5 Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ, III. Trends in the incidence of deep vein thrombosis and pulmonary embolism. A 25year population based study. Arch Intern Med 1998; 158: 585–593. 6 Gillum RF. Pulmonary embolism and thrombophlebitis in the United States, 1970–1985. Am Heart J 1987; 114: 1262–1264. 7 Giuntini C, Ricco GD, Marini C, Mellilo E, Palla A. Pulmonary embolism: epidemiology. Chest 1995; 107 (suppl): 3S–9S. 8 Nordstrom M, Linblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Int Med Res 1992; 232: 155–160. 9 Coon WW, Willis PW, III, Keller JB. Venous thromboembolism and other venous disease in the Tecumseh Community Health Study. Circulation 1973; 48: 839–846. 10 Kniffin WD, Jr, Baron JA, Barrett J, Birkmeyer JD, Anderson FA, Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994; 154: 861–866. 11 Coon WW, Coller FA. Some epidemiologic considerations of thromboembolism. Surg Gynecol Obstet 1959; 109: 487–501. 12 Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353: 1386–1389. 13 Ferrari E, Baudouy M, Cerboni P et al. Clinical epidemiology of venous thromboembolic disease. Results of a French Multicentre Registry. Eur Heart J 1997; 18: 685– 691. 14 Hansson P-O, Welin L, Tibblin G, Eriksson H. Deep vein thrombosis and pulmonary embolism in the general pop-

15

16

17 18

19

20

21 22

23 24 25

26

27

28

29

30

31

Prevalence, risks, and prognosis of PE and DVT

ulation. The study of men born in 1913. Arch Intern Med 1997; 157: 1665–1670. Hume M, Sevitt S, Thomas DP. Venous Thrombosis and Pulmonary Embolism. A Commonwealth Fund Book. Harvard University Press, Cambridge, MA, 1970. Nicolaides AN, Irving D. Clinical factors and the risk of deep venous thrombosis. Thromboembolism. In: Nicolaides AN, ed. Etiology, Advances in Prevention and Management. University Park Press, Baltimore, 1975: 199–204. Stein PD, Patel KC, Kalra NK et al. Deep venous thrombosis in a general hospital. Chest 2002; 122: 960–962. Stein PD, Huang H-L, Afzal A, Noor H. Incidence of acute pulmonary embolism in a general hospital: relation to age, sex, and race. Chest 1999; 116: 909–913. Stein PD, Patel KC, Kalra NK et al. Estimated incidence of acute pulmonary embolism in a community/teaching general hospital. Chest 2002; 121: 802–805. Stein PD, Kayali F, Olson RE. Estimated case fatality rate from pulmonary embolism, 1979–1998. Am J Cardiol 2004; 93: 1197–1199. Geerts WH, Heit JA, Clagett GP et al. Prevention of venous thromboembolism. Chest 2001; 119(suppl): 132S–175S. Taubman LB, Silverstone FA. Autopsy proven pulmonary embolism among the institutionalized elderly. J Am Geriatr Soc 1986: 34: 752–756. Morrell MT. The incidence of pulmonary embolism in the elderly. Geriatrics 1970; 25: 138–153. Busby W, Bayer A, Pathy J. Pulmonary embolism in the elderly. Age Ageing 1988; 17: 205–209. Stein PD, Gottschalk A, Saltzman HA, Terrin ML. Diagnosis of acute pulmonary embolism in the elderly. J Am Coll Cardiol 1991; 18: 1452–1457. Stein PD, Beemath A, Matta F et al. Clinical Characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med 2007 (In press). Mellemgaard K. The alveolar–arterial oxygen difference: its size and components in normal man. Acta Physiol Scand 1966; 67: 10–20. Harris EA, Kenyon AM, Nisbet HD, Seelye ER, Whitlock RML. The normal alveolar–arterial oxygen-tension gradient in man. Clin Sci (Colch) 1974; 46: 89–104. Filley GF, Gregoire F, Wright GW. Alveolar and arterial oxygen tensions and the significance of the alveolar– arterial oxygen tension difference in normal men. J Clin Invest 1954; 33: 517–529. Kanber GJ, King FW, Eshchar YR, Sharp JT. The alveolar– arterial oxygen gradient in young and elderly men during air and oxygen breathing. Am Rev Respir Dis 1968; 97: 376–381. Stein PD, Beemath A, Quinn DA et al. Usefulness of multidetector spiral computed tomography according to age and sex for diagnosis of acute pulmonary embolism. Am J Cardiol (In press).


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32 Stein PD, Henry JW. Acute pulmonary embolism presenting as pulmonary hemorrhage/infarction syndrome in the elderly. Am J Geriatr Cardiol 1998; 7: 36– 42. 33 Stein PD, Hull RD, Ghali WA et al. Tracking the uptake of evidence: two decades of hospital practice trends for diag-

nosing deep vein thrombosis and pulmonary embolism. Arch Intern Med 2003; 163: 1213–1219. 34 The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA 1990; 263: 2753–2759.

CHAPTER 11


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CHAPTER 12

Pulmonary thromboembolism in infants and children

Twenty-three years of data were analyzed in children discharged from hospitals in the United States were based on the database of the National Hospital Discharge Survey (NHDS) [1]. Venous thromboembolic disease was coded at discharge from short-stay hospitals with sufficient frequency to indicate that it should be considered in the diagnosis of children with appropriate clinical findings [1]. Infants, teenage girls, and black children had the highest rates of diagnosis [1]. From 1979 to 2001, pulmonary embolism (PE) was diagnosed at discharge from short-stay non-Federal hospitals throughout the United States in 13,000 infants and children ≤17 years of age, deep venous thrombosis (DVT) in 64,000, and venous thromboembolism (VTE) in 75,000 [1]. Rates of diagnosis were 0.9 PE/100,000 children/year, 4.2 DVT/100,000 children/year, and 4.9 VTE/100,000 children/year (Figure 12.1) [1]. The rates of diagnosis of DVT and of VTE did not change from the triennial periods 1979–1982 to 1999–2001. Rates of diagnosis of PE, DVT, and VTE were higher in infants than children aged 2–14 years (Figures 12.2– 12.4) [1]. The rates were also higher in teenagers aged 15–17 years than in children aged 2–14 years, but the rates in teenagers were comparable to the rates in infants.

In teenagers aged 15–17 years, the rate of diagnosis of DVT was 2.1 times higher in girls than boys. Teenage girls with DVT had an associated pregnancy in 27%. The rate of DVT in nonpregnant teenage girls was 10 DVT/100,000 teenage girls/year, and the rate of pregnancy-associated DVT was 109 DVT/100,000 teenage girls/year. The rate of DVT in nonpregnant teenage girls did not differ significantly from the rate for teenage boys. The rate of diagnosis of PE in black children, 1.6/100,000/year, was 2.4 times higher than in white children, 0.7/100,000/year. The rate of DVT in black children, 5.7/100,000/year, was 1.7 times the rate in white children, 3.3/100,000/year. The rate of VTE in black children was 1.8 times the rate in white children. A double-peaked curve was shown for DVT [1, 2] and PE [1] with the highest rates of diagnosis in infants less than 1-year-old and a second peak in teenagers. Teenage girls had twice the rates of DVT and VTE as teenage boys, although in younger children the frequencies were comparable. Bernstein and associates, among adolescents, observed PE in twice as many girls as boys [3]. Pregnancy-related DVT accounted for the difference in rates between teenage boys and teenage girls.

6 5 4 3 2 1 0

4.9 4.2

0.9

3 2.2

1

0.4 0−1

PE

2.0

2

0

DVT

VTE

Figure 12.1 Thromboembolic disease in children ≤17 years of age. (Data from Stein et al. [1].)

66

PE/100,000/yr

PE, DVT, VTE/100,000 children/yr

4

2−14

15−17

Age (years) Figure 12.2 Pulmonary embolism (PE) in children. (Data from Stein et al. [1].)


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CHAPTER 12

DVT/100,000/yr

10

15:10

67

Pulmonary thromboembolism in infants and children 9.9 8.7

8 6 4 2.1

2

12 VTE/100,000/yr

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11.4

10.5

10 8 6 4

2.4

2 0

0 0−1

2−14

15−17

0−1

Age (years) Figure 12.3 Deep venous thrombosis (DVT) in children. (Data from Stein et al [1].)

Abortion and/or contraceptives were shown to be risk factors in 75% of female adolescents who had PE [3]. Teenage users of oral contraceptives did not appear to be at an increased risk of VTE compared to older users [4]. Indwelling catheter use was the most common predisposing factor for PE or DVT in children and adolescents, followed by surgery and trauma [5]. Neonatal thrombosis, with the exception of spontaneous renal vein thrombosis was almost always associated with indwelling catheters (86 of 97 cases, 89%) [6]. Lower extremity DVT in children, when unrelated to venous catheterization or surgery, appeared to be related to local infection of the involved extremity, trauma or immobilization [7]. One or more coagulopathies were reported in 26 of 40 (65%) children with venous thrombosis who had an evaluation for a deficiency of protein C, protein S, or antithrombin III and assessment for a lupus anticoagulant [8]. In the Canadian registry, 9% of children with VTE had a coagulopathy, but the majority did not receive coagulation testing [2, 9]. Among patients with heart disease at autopsy, the prevalence of PE as a cause of death was particularly high in children <10 years old [10]. Among medical patients with heart disease <10 years old, PE as a cause of death was found at autopsy in 14.5% and in postoperative children with heart disease at autopsy PE caused death in 8.0% [10]. Prior to 1962, under 50 cases of PE in children had been reported in the world literature [11]. Only 36 children with DVT and 10 with PE were identified among all Scottish hospital inpatients from 1968 to 1971 [12]. From 1975 to 1991, 308 children with DVT or PE were reported in the English and French literature [5]. A

2−14 Age (years)

15−17

Figure 12.4 Venous thromboembolism (VTE) in children. (Data from Stein et al. [1].)

Canadian registry of 15 hospitals from July 1990 to December 1992 identified 137 children aged 1 month to 17 years old who had DVT [2].

References 1 Stein PD, Kayali F, Olson RE. Incidence of venous thromboembolism in infants and children: data from the National Hospital Discharge Survey. J Pediatr 2004; 145: 563–565. 2 Andrew M, David M, Adams M et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994; 83: 1251–1257. 3 Bernstein D, Coupey S, Schonberg SK. Pulmonary embolism in adolescents. Am J Dis Child 1986; 140: 667–671. 4 Royal College of General Practitioners’ Oral Contraception Study. Oral contraceptives, venous thrombosis, and varicose veins. J R Coll Gen Pract 1978; 28: 393–399. 5 David M, Andrew M. Venous thromboembolic complications in children. J Pediatr 1993; 123: 337–346. 6 Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 96: 939–943. 7 Wise RC, Todd JK. Spontaneous, lower-extremity venous thrombosis in children. Am J Dis Child 1973; 126: 766– 769. 8 Nuss R, Hays T, Manco-Johnson M. Childhood thrombosis. Pediatrics 1995; 96: 291–294. 9 Manco-Johnson MJ. Disorders of hemostasis in childhood: risk factors for venous thromboembolism. Thromb Haemost 1997; 78: 710–714. 10 Pulido T, Aranda A, Zevallos MA et al. Pulmonary embolism as a cause of death in patients with heart disease. An autopsy study. Chest 2006; 129: 1282–1287. 11 Emery JL. Pulmonary embolism in children. Arch Dis Child 1962; 37: 591–595. 12 Jones DR, Macintyre IM. Venous thromboembolism in infancy and childhood. Arch Dis Child 1975; 50: 153–155.


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CHAPTER 13

Venous thromboembolism in men and women The Tecumseh Community Health Study showed 4.5 PE/10,000 women/year compared with 1.75 PE/10,000 men/year [4]. The largest investigation was based on data from the National Hospital Discharge Survey [7]. From 1979 to 1999, 2,448,000 patients were discharged

(a)

(b)

80 Women

60 40 Men

20

80

Age-adjusted PE/100,000

PE/100,000 population

Pulmonary embolism (PE) has been reported to occur more frequently in women than in men due to estrogen use, childbearing, and a higher frequency of deep venous thrombosis (DVT) [1â&#x20AC;&#x201C;5]. A postmortem study showed PE in 11% of women and 7% of men [6].

Women

60

40

Men

20

(d) Women

160

120 Men

80

40

Men

100

50 1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

Figure 13.1 (a) Unadjusted rates of diagnosis of pulmonary embolism (PE) per 100,000 population over a 21-year period. The unadjusted rate of diagnosis was higher in women than men. (b) Age-adjusted rates of diagnosis of PE per 100,000 population over a 21-year period. The age-adjusted rates of diagnosis were comparable in men and women. (c) Unadjusted rates of diagnosis of deep venous thrombosis (DVT) per 100,000

Women

150

1979

1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

Year

Age-adjusted DVT/100,000

DVT/100,000 population

1999

1997

1995

1993

1991

Year

(c)

68

1989

1987

1985

1983

1981

1979

1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

Year

Year

population over a 21-year period. The unadjusted rate of diagnosis of DVT was higher in women than in men. (d) Age-adjusted rates of diagnosis of DVT per 100,000 population over a 21-year period. The age-adjusted rate of diagnosis was higher in women. (Reproduced from Stein et al. [7], with permission from American Medical Association. All rights reserved.)


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1999

1997

1995

1993

1991

1989

(b) 60 45

Women

30

Men

15 0 1999

1997

1995

1993

1991

1989

1987

1985

Figure 13.2 Rates of use per 100,000 population of ventilation–perfusion (V–Q) lung scans. The rates were higher among women than in men. (Reproduced from Stein et al. [7], with permission from American Medical Association. All rights reserved.)

1987

1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

Year

Year

1983

Men

0

Men

0 1985

20

Women

1981

Women

15

1983

40

30

1981

60

45

1979

80

(a)

1979

from short-stay non-Federal hospitals with PE and 5,691,000 were discharged with DVT. Either PE or DVT was listed as the discharge diagnosis in 7,589,000 patients [7]. Given that PE and DVT are conditions that increase in incidence with age, age-adjusted rates of diagnosis as well as crude (unadjusted) rates were calculated [7]. In 1999, 139,000 patients were discharged from nonFederal short-stay hospitals with a diagnosis of PE. The rate of diagnosis not adjusted for age was 42 PE/100,000 men/year and 60 PE/100,000 women/year (Figure 13.1a) [7]. The age-adjusted rate of diagnosis of PE/100,000 population/year in men and women was comparable (Figure 13.1b) [7]. This was concordant with some prior investigations of PE [8–11], but PE has also been reported more frequently in men [12– 15] and older men [16]. Both the unadjusted rate of diagnosis of DVT/ 100,000 population/year and the age-adjusted rates of diagnosis of DVT/100,000 population/year were higher in women (Figures 13.1c and 13.1d) [7]. This is concordant with most prior literature [8, 16, 17], but the prior literature is not uniform. Objectively diagnosed DVT had also been reported to be more frequent in men [9]. In 1999, the unadjusted rate of diagnosis was 115 DVT/100,000 men/year and 154 DVT/100,000 women/year [7]. In 1999, 369,000 patients were discharged from non-Federal short-stay hospitals with a diagnosis of DVT. The rates of use/100,000 population/year of ventilation–perfusion lung scans (Figure 13.2) and

V−Q scans/100,000 population

69

Venous thromboembolism in men and women

Venograms/100,000 population

CHAPTER 13

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Ultrasonography/100,000 population

BLUK077-Stein

Year Figure 13.3 (a) Rates of venography per 100,000 population over a 21-year period. The rates of use among men and women were comparable. (b) Rates of venous ultrasonography of the lower extremities per 100,000 population over a 21-year period. The rate of use was higher among women. (Reproduced from Stein et al. [7], with permission from American Medical Association. All rights reserved.)

venous ultrasound examinations of the lower extremities were higher among women (Figure 13.3b) [7]. In 1999, the rate of use of ventilation–perfusion lung scans was 18/100,000 men/year and 24/100,000 women/year. During the same year the rate of use of venous ultrasound examinations of the lower extremities was 31/100,000 men/year and 38/100,000 women/year. A more frequent use of venous ultrasonography for the diagnosis of DVT had been observed previously in women [18]. The rates of use/100,000 population/year of contrast venography among men and women were comparable (Figure 13.3a). The durations of hospitalization among patients with a primary discharge diagnosis of PE and of DVT were comparable among men and women (Figure 13.4a) [7].


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70

PART I

(a)

Table 13.1 Signs and symptoms of acute pulmonary embolism in women and men.

Prevalence, risks, and prognosis of PE and DVT

PE hospitalization days

16 12 Women

8 Men

4 0 1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

Year

DVT hospitalization days

8

Women

Men

4

1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

0

(n = 132)

percent

percent

80

78

Pleuritic pain

60

57

Cough

41

40

Leg swelling

24

36†

Leg pain

23

30

Hemoptysis

10

21‡

Rales (crackles)

60

57

2

7*

* P < 0.05. † P < 0.04. ‡ P < 0.02, women vs. men. Data are from Quinn et al. [19].

16 12

Men

(n = 119)

Dyspnea

Pleural friction rub

(b)

Women

Year Figure 13.4 (a) Duration of hospitalization for men and women with a primary discharge diagnosis of pulmonary embolism (PE). Duration was comparable among genders. (b) Duration of hospitalization for men and women with a primary discharge diagnosis of deep venous thrombosis (DVT). The duration of hospitalization was comparable among genders. (Reproduced from Stein et al. [7], with permission from American Medical Association. All rights reserved.)

Regarding the signs and symptoms of acute PE, women recruited in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) less frequently had hemoptysis (10% versus 21%), leg swelling (24% versus 36%), and pleural friction rub (2% versus 7%) (Table 13.1). Except for minor differences of heart rate, the prevalence of other signs and symptoms of acute PE did not differ significantly between women and men [19]. The sensitivity and specificity of the ventilation– perfusion scan, using original PIOPED criteria [20], were the same in women and men. The positive predic-

tive values of a high-probability ventilation–perfusion scan were similar between women (86%) and men (90%) and the negative predictive values of normal or nearly normal ventilation–perfusion scans were also similar, 93% in women and 88% in men [19]. There was no difference between women and men during 1-year follow-up in the recurrence of PE [19].

References 1 Palevsky HI. Pulmonary hypertension and thromboembolic disease in women. Cardiovasc Clin 1989; 19: 267– 283. 2 Bernstein D, Goupey S, Schonberg SK. Pulmonary embolism in adolescents. AJDC 1986; 140: 667–671. 3 Coon W. Epidemiology of venous thromboembolism. Ann Surg 1977; 186: 149–164. 4 Coon WW, Willis PW, III, Keller JB. Venous thromboembolism and other venous disease in the Tecumseh Community Health Study. Circulation 1973; 48: 839–846. 5 Breckenridge RT, Ratnoff OD. Pulmonary embolism and unexpected death in supposedly normal persons. N Engl J Med 1964; 270: 298–299. 6 Karwinski B, Svendsen E. Comparison of clinical and postmortem diagnosis of pulmonary embolism. J Clin Pathol 1989; 42: 135–139. 7 Stein PD, Hull RD, Patel KC et al. Venous thromboembolic disease: comparison of the diagnostic process in men and women. Arch Intern Med 2003; 163: 1689–1694. 8 Ferrari E, Baudouy M, Cerboni P et al. Clinical epidemiology of venous thromboembolic disease. Results of a


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9

10

11

12

13

14

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Venous thromboembolism in men and women

French multicentre registry. Eur Heart J 1997; 18: 685– 691. Anderson FA, Jr, Wheeler HB, Goldberg RJ et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933–938. Stein PD, Huang H-L, Afzal A, Noor H. Incidence of acute pulmonary embolism in a general hospital: relation to age, sex, and race. Chest 1999; 116: 909–913. Stein PD, Patel KC, Kalra NK et al. Estimated incidence of acute pulmonary embolism in a community/teaching general hospital. Chest 2002; 121: 802–805. Lilienfeld DE, Godbold JH, Burke GL, Sprafka JM, Pham DL, Baxter J. Hospitalization and case fatality for pulmonary embolism in the twin cities: 1979–1984. Am Heart J 1990; 120: 392–395. Janke RM, McGovern PG, Folsom AR. Mortality, hospital discharges, and case fatality for pulmonary embolism in the twin cities 1980–1995. J Clin Epidemiol 2000; 53: 103– 109. Silverstein MD, Heit JA, Mohr DN et al. Trends in the incidence of deep vein thrombosis and pulmonary

15

16

17 18

19

20

71

embolism. A 25-year population-based study. Arch Intern Med 1998; 158: 585–593. Giuntini C, Di Ricco G, Marini C, Melillo E, Palla A. Pulmonary embolism: epidemiology. Chest 1995; 107(suppl): 3S–9S. Kniffin WD, Jr, Baron JA, Barrett J, Birkmeyer JD, Anderson FA, Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994; 154: 861–866. Stein PD, Patel KC, Kalra NK et al. Deep venous thrombosis in a general hospital. Chest 2002; 122: 960–962. Beebe HG, Scissons RP, Salles-Cunha SX et al. Gender bias in use of venous ultrasonography for diagnosis of deep vein thrombosis. J Vasc Surg 1995; 22: 538– 542. Quinn DA, Thompson BT, Terrin ML et al. A prospective investigation of pulmonary embolism in women and men. JAMA 1992; 268: 1689–1696. A Collaborative Study by the PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA 1990; 263: 2753–2759.


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CHAPTER 14

Comparison of the diagnostic process in black and white patients

Introduction The death rate among patients with pulmonary embolism (PE) in the United States is higher among black patients than among white patients [1]. Recognizing that there is a racial disparity in the use of some health services [2â&#x20AC;&#x201C;10], one could speculate that such a disparity could contribute to the higher death rate among black patients with PE. However, nothing was found to suggest that diagnostic tests were being withheld in black patients [11]. Also, there was no evidence of a failure to reach a diagnosis in black patients with thromboembolic disease [11]. Caution has been recommended in the use of race as a variable [12]. It is necessary to account for distinctions between race and socioeconomic status [12]. An emphasis on ethnic groups rather than on race implies an appreciation of cultural and behavioral attitudes, beliefs, lifestyle patterns, diet, environmental living conditions, and other factors [13]. Disparities in health care may be due to a lack of appropriate health care messages, limited access to care and services, lack of trust of health care providers, and racial bias among medical care providers [12]. Data on trends over 21 years and relative differences among races in the prevalence of PE and DVT (deep venous thrombosis) and the use of diagnostic tests were obtained from the National Hospital Discharge Survey from 1979 to 1999 [11]. During these 21 years, 2,448,000 patients were discharged from short-stay non-Federal hospitals with PE, 5,691,000 patients were discharged with DVT and 7,589,000 patients were discharged with either PE or DVT. The rate of diagnosis of PE/100,000 population/year not adjusted for age, was comparable among black and white patients (Figure 14.1a) [11]. In 1999, the rate of diagnosis among black patients was 41 PE/100,000

72

population/year and among white patients it was 42 PE/100,000 population/year. Despite some year-toyear fluctuation, the rate of diagnosis of PE among black patients did not change appreciably over the 21year period studied. White patients, however, showed a decreasing rate of PE in the population over the period of survey [11]. Adjustment for age caused the rate of diagnosis of PE among black patients to separate from white patients after the mid-1980s (Figure 14.1b) [11]. The age-adjusted rates indicate the hospitalization rates for black and white patients assuming identical age distributions for both populations. The age-adjusted rate of diagnosis of PE/100,000 population/year was higher in black patients than in white patients (Figure 14.1b). From 1979 to 1992, there was a decline in the rate of diagnosis both among black patients and among white patients. From 1992 to 1999, the rate of diagnosis was constant in black patients, but the rate of diagnosis increased somewhat in white patients. The rate of diagnosis of DVT/100,000 population/ year, not adjusted for age, was comparable among black and white patients (Figure 14.1c) [11]. In 1999, the rate of diagnosis among black patients was 110 DVT/100,000 population/year and among white patients it was 115 DVT/100,000 population/year. The rate of diagnosis increased over the 21-year period of survey in black patients. Among white patients, the rate of diagnosis remained unchanged during the period of survey. The age-adjusted rate of diagnosis of DVT/100,000 population/year was higher in black patients than in white patients (Figure 14.1d). From 1979 to 1992, the age-adjusted rate of diagnosis was constant in black patients, whereas white patients showed a gradual decrease in the rate. From 1992 to 1999, the rate of diagnosis increased sharply in black patients; the rate increased more gradually in white patients.


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73

VTE in black and white patients

60

Black patients

40 White patients

20

Black patients

60 40

White patients

20 0

Year

150

Black patients

100 White patients

50 0

200

Black patients

150 100 White patients

50 0

1999

1997

1995

60 45

Black patients

30 15

White patients

0 1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

V−Q scans/100,000 population

diagnosis over a 21-year period of deep venous thrombosis (DVT) per 100,000 population according to race. The rate of diagnosis was comparable among black and white patients. (d) Age-adjusted rates of diagnosis of DVT per 100,000 population according to race. The rate was higher in black patients than in white patients. (Reproduced from Stein et al. [11], with permission from American Medical Association. All rights reserved.)

1979

The use of pulmonary angiograms/100,000 population/year was low among both black and white patients. The frequency of use of angiograms among black patients was too low to calculate rates. However, inspection of the data showed no suggestion of a disparity of use between black and white patients. Rates of use of ventilation–perfusion lung scans among black and white patients from 1979 to 1999 were comparable (Figure 14.2). The use of ventilation– perfusion lung scans in both groups increased sharply between 1979 and 1986. The use then declined in black as well as white patients.

1993

Use of diagnostic tests for PE and deep vein thrombosis

1991

Year

Year Figure 14.1 (a) Unadjusted (crude) rates of diagnosis over a 21-year period of pulmonary embolism (PE) per 100,000 population according to race. The rates of diagnosis were comparable among black and white patients. (b) Ageadjusted rates of diagnosis of PE per 100,000 population according to race. There was no change in the rate of diagnosis among black patients over the 21-year period. White patients, however, showed a decreasing rate of PE over the period of survey. (c) Unadjusted (crude) rates of

1989

1987

1985

1983

1981

1979

1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

Age-adjusted DVT/100,000

(d)

(c) DVT/100,000 population

1999

1997

1995

1993

1991

Year

1989

1987

1985

1983

1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

1981

0

80

1979

PE/100,000 population

80

Age-adjusted PE/100,000

(b)

(a)

Year Figure 14.2 Rates of use per 100,000 population of ventilation–perfusion (V–Q) lung scans among black and white patients. The rates were comparable. (Reproduced from Stein et al. [11], with permission from American Medical Association. All rights reserved.)


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PART I

Prevalence, risks, and prognosis of PE and DVT

Venography/100,000 population

(a) 50

25

White patients Black patients

0 1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

Year

60 Black patients 40 White patients

20

0 1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

Ultrasonography/100,000 population

(b)

Year

Figure 14.3 (a) Rates of use per 100,000 population of contrast venography among black and white patients. The rates were comparable. (b) Rates of use per 100,000 population of venous ultrasound of the lower extremities among black and white patients. The rates were comparable. (Reproduced from Stein et al. [11], with permission from American Medical Association. All rights reserved.)

(a)

PE, days

18

12 Black patients White patients 1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

6

Year

(b)

DVT, days

15 10 Black patients 5

White patients

0 1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

Year

Figure 14.4 (a) Duration of hospitalization for black and white patients with a primary discharge diagnosis of pulmonary embolism (PE). The durations were comparable among races. (b) Duration of hospitalization for black and white patients with a primary discharge diagnosis of deep venous thrombosis (DVT). The durations were comparable among races. (Reproduced from Stein et al. [11], with permission from American Medical Association. All rights reserved.)


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VTE in black and white patients

The rates of use of contrast venography among black and white patients from 1979 to 1999 were comparable (Figure 14.3a) [11]. The rates of use of venograms in black and white patients peaked in the late 1980s. The rates of use of venous ultrasound of the lower extremities among black and white patients from 1979 to 1999 were comparable (Figure 14.3b). Between 1988 and 1999, the ratio of use of ultrasounds in black to white patients ranged from 1.2 to 1.8. The rate of use of venous ultrasounds increased in both until 1991.

Use of medical facilities for treatment of PE and deep vein thrombosis The duration of hospitalization for black and white patients with a primary discharge diagnosis of PE was comparable (Figure 14.4a) [11]. The duration of hospitalization decreased over time in both groups. The duration of hospitalization for black and white patients with a primary discharge diagnosis of DVT was also comparable (Figure 14.4b). As with PE, the duration of hospitalization decreased over time in both. This reflects the use of protocols for a rapid attainment of therapeutic levels of heparin, a shorter duration of therapy with heparin, and use of low-molecular heparin [14]. These data were obtained entirely from hospitalized patients [11]. Information related to care after hospitalization was not available. Some have reported a shorter duration of anticoagulant therapy in black patients [15].

References 1 Lilienfeld DE. Decreasing mortality from pulmonary embolism in the United States, 1979–1996. Int J Epidemiol 2000; 29: 465–469. 2 Freeman HP, Payne R. Racial injustice in health care. N Engl J Med 2000; 342: 1045–1047.

75

3 Schneider EC, Zaslavsky AM, Epstein AM. Racial disparities in the quality of care for enrollees in Medicare managed care. JAMA 2002; 287: 1288–1294. 4 Ayanian JZ, Udvarhelyi S, Gatsonis CA et al. Racial differences in the use of revascularization procedures after coronary angiography. JAMA 1993; 269: 2642–2646. 5 Gornick ME, Eggers PW, Reilly TW et al. Effects of race and income on mortality and use of services among Medicare beneficiaries. N Engl J Med 1996; 335: 791–799. 6 Roetzheim RG, Pal N, Tennant C, et al. Effect of health insurance and race on early detection of cancer. J Natl Cancer Inst 1999; 91: 1409–1415. 7 Kasiske BL, Neylan JF, III, Riogio RR et al. The effect of race on access and outcome in transplantation. N Engl J Med 1991; 324: 302–307. 8 Bach PB, Cramer LD, Warren JL, Begg CB. Racial differences in the treatment of early stage of lung cancer. N Engl J Med 1999; 341: 1198–1205. 9 Brawley OW, Freeman HP. Race and outcomes: is this the end of the beginning for minority health research? J Natl Cancer Inst 1999; 91: 1908–1909. 10 Roach M, III, Cirrincione C, Budman D et al. Race and survival from breast cancer based on Cancer and Leukemia Group B Trial 8541. Cancer J Sci Am 1997; 3: 107–112. 11 Stein PD, Hull RD, Patel KC et al. Venous thromboembolic disease: comparison of the diagnostic process in blacks and whites. Arch Intern Med 2003; 163: 1843–1848. 12 Thomas SB. The color line: race matters in the elimination of health disparities. Am J Public Health 2001; 91: 1046– 1048. 13 Haynes MA, Smedley BD (eds.) The Unequal Burden of Cancer: An Assessment of NIH Research and Programs for Ethnic Minorities and the Medically Underserved. National Academy Press, Washington, DC, 1999: 19. 14 Hyers TM, Agnelli G, Hull RD et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001; 119(suppl): 176S–193S. 15 Ganz DA, Glynn RJ, Mogun H et al. Adherence to guidelines for oral anticoagulation after venous thrombosis and pulmonary embolism. J Gen Intern Med 2000; 15: 776– 781.


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CHAPTER 15

Pulmonary thromboembolism in Asians/Pacific Islanders

Introduction Most investigations of pulmonary embolism (PE), deep venous thrombosis (DVT), and venous thromboembolism (VTE) in countries in Asia suggest that the rate of diagnosis is lower in Asians [1–13] than in persons from North America or Europe [14–18], although some did not describe differences [19–22]. Data from the National Hospital Discharge Survey combined with data from the Bureau of the Census show that in the United States the rate of diagnosis of DVT, PE, and VTE; the incidence in hospitalized patients; and mortality rate from PE were all lower in Asians/Pacific Islanders than in whites and African Americans [23].

Unadjusted population-based rates of diagnosis From 1990 to 1999, rates of diagnosis of PE in Asian/Pacific/Islanders were 5/100,000 population/ year, compared with 34/100,000/year in whites and 39/100,000/year African Americans [23] (Table 15.1, Figure 15.1). Regarding DVT, rates of diagnosis in Asian/Pacific Islanders were 20/100,000 population/year compared with 98/100,000/year in whites and 105/100,000/ year in African Americans. Rates for VTE were 23/ 100,000 population/year in Asian/Pacific Islanders, 122/100,000/year in whites and 134/100,000/year in African Americans [23]. Others too, reported VTE among Asian Americans to be lower than in whites and African Americans in two investigations [12, 13]. Klatsky et al. [12] studied the rate of a primary diagnosis of VTE among hospitalized patients in California from 1978 to 1985, and reported rates of 2/100,000 population/year in Asian Americans, 21/100,000 population/year in whites, and 22/100,000 population/year in African Americans.

76

Klatsky et al. [12] reported even lower rates of diagnosis of venous thromboembolic disease among Asian Americans, whites, and African Americans in California than we observed throughout the United States [23]. The likely reason is that they required a primary diagnosis of PE or DVT, whereas we included all patients with PE or DVT [23]. White et al. [13] investigated idiopathic DVT in hospitalized patients in California between 1991 and 1994, and reported rates of 6/100,000 population/year in Asian Americans, 23/100,000 population/year in whites, and 29/100,000 population/year in African Americans. White et al. [13] also reported lower rates of DVT among Asian Americans, whites, and African Americans in California, which would seem to relate to the study requirement of idiopathic DVT and the exclusion of patients with cancer and those with temporary risk factors such as surgery and trauma. We included all patients with DVT [23].

Age-adjusted population-based rates of diagnosis Age-adjusted rates of diagnosis of PE were also lower in Asians/Pacific Islanders than in African Americans and whites (Table 15.1, Figure 15.1). Considering VTE (DVT and/or PE) [23], age-adjusted rates for the 10year period were also lower among Asians/Pacific Islanders than in African Americans and whites [23] (Table 15.1, Figure 15.1). Among Asians/Pacific Islanders, the age-adjusted rates of DVT were similar in men and women (19/100,000/year versus 24/100,000/year), as were the rates for PE (5/100,000/year versus 8/100,000/year), and VTE (22/100,000/year versus 30/100,000/year) [23].

Incidence in hospitals There was a disproportionately low rate of hospitalizations among Asians/Pacific Islanders (5000


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77

Pulmonary thromboembolism in Asians

Figure 15.1 Age-adjusted rates (diagnoses/100,000 population/year) of pulmonary embolism (PE), deep venous thrombosis (DVT), and venous thromboembolism (VTE) in hospitalized patients from 1990 to 1999. (Reprinted from Stein et al. [23], with permission from Elsevier.)

Age-adjusted rates/100,000/year

BLUK077-Stein

200 138

130 150 107

104

100

26 50

VTE

22 36

40

7

0 Whites

hospitalizations/100,000 population/year) compared with whites (9000 hospitalizations/100,000 population/year) and African Americans (11,000 hospitalizations/100,000 population/year) [23]. The incidence of DVT among hospitalized Asians/Pacific Islanders aged ≥20 years (0.4/100 hospitalizations) was lower than among African Americans (1.1/100 hospitalizations) and whites (1.1/100 hospitalizations) (Table 15.2) [23]. In patients ≥20 years, the incidence of PE in hospitalized patients was also lower among Asians/Pacific Islanders (0.1/100 hospitalizations) than among whites (0.4/100 hospitalizations) and African Americans (0.4/100 hospitalizations) [23]. Similarly, in patients aged ≥20 years, the incidence of VTE in hospitalized patients was lower in Asians/Pacific Islanders (0.5/100 hospitalizations) than in whites (1.4/100 hospitalizations) and African Americans (1.4/100 hospitalizations) [23].

Population mortality rates Age-adjusted mortality from 1990 to 1998 for PE was lower in “others” (1.0 deaths/100,000 population/year) than in whites (3.4 deaths/100,000 population/year) and African Americans (6.9 deaths/100,000 population/year) (Table 15.3) [23]. Mortality from PE among Asians/Pacific Islanders was included in mortality rates described in “others.” Lower rates of fatal PE in Asians were reported at autopsy in Singapore [1] but not in Chinese in Hong Kong [21]. The low rate of diagnosis was related partly to the low rate of all hospitalizations in Asians/Pacific Islanders. The lower incidence of thromboembolic disease in hospitalized patients was independent of effects of a disproportionately low rate of all-cause hospitalization

African Americans

DVT PE

Asian/Pacific Islanders

among Asians/Pacific Islanders. The lower mortality among Asians/Pacific Islanders was also independent of the lower rate of all-cause hospitalizations. A lower rate of VTE in Asians than whites has been observed in several Asian ethnicities, as well as in many different clinical settings, including autopsy, where possible ethnic customs related to outpatient therapy would hardly have affected the results (Table 15.4). In the study by Klatsky et al. on Asians in northern California, 42.2% were Chinese, 11.9% were Japanese, 29.5% were Filipinos, 5.0% were South Asians, and 11.2% were other Asians [13]. Lower rates of thromboembolic disease have been shown in investigations in China [1, 5, 8–11], Japan [2], Thailand [3, 4], and Malaysia [6, 7]. Some of these investigations included patients from other Asian regions, including India [1, 5, 6]. A lower rate of PE was found at autopsy among Indians from Vellore, South India, than among patients in Boston and Los Angeles [2]. A lower prevalence of genetically induced abnormalities predisposing to VTE, such as factor V Leiden, has been speculated to contribute to the lower incidence of VTE in Asians [24]. Factor V Leiden, an abnormal factor V protein that is relatively resistant to degradation by protein C [25], is the most common genetic mutation predisposing to VTE [25, 26]. Factor V Leiden has been found in 4–5% of whites in North America and Europe [27, 28], 0.9–1.2% of African Americans, and in only 0–0.5% of Asians [27–29]. Differences in coagulation factors may also contribute to the low rate of VTE in Asians. Plasma fibrinogen levels are lower in Japanese than in whites, irrespective of whether they live in a rural or urban area of Japan or whether they are Japanese Americans [30]. Blood levels of factor VIIc and factor VIIIc were


78 18,000

5,000

127,000

736,000

embolism

21,000

440,000

2,641,000

embolism

P < 0.0005 Asian-Pacific Islanders vs. Caucasians and African American. Reprinted from Stein et al. [23], with permission from Elsevier.

* 10 year sum of census estimates.

Asian-Pacific Islander

344,000

2,128,000

Caucasian

African American

thrombosis

thrombo-

Race

Venous

venous

Pulmonary

Deep

Number of patients (1990–1999)

92,179,599

328,136,068

2,170,606,118

Population*

39 5†

20†

34

embolism

Pulmonary

105

98

thrombosis

venous

Deep

23†

134

122

embolism

thrombo-

Venous

(Diagnoses/100,000 population/year)

Crude rate

22†

107

104

thrombosis

venous

Deep

7†

40

36

embolism

Pulmonary

26†

138

130

embolism

thrombo-

Venous

(Diagnoses/100,000 population/year)

Age-adjusted rate

March 12, 2007

Table 15.1 Deep venous thrombosis, pulmonary embolism, and venous thromboembolism according to race (1990–1999).

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Pulmonary thromboembolism in Asians

Table 15.2 Deep venous thrombosis and venous thromboembolic disease in hospitalized patients according to race and age groups (1990–1999). Number of patients

Diagnoses/100

(1990–1999)

hospitalizations

Deep

Venous

Age

venous

thrombo-

All discharges

Deep venous

Venous thrombo-

(years)

thrombosis

embolism

(1990–1999)

thrombosis

embolism

Caucasians 0–19

25,000

29,000

20,222,000

0.1

0.1

20–49

419,000

503,000

67,389,000

0.6

0.7

50–69

705,000

869,000

48,630,000

1.5

1.8

≥70

979,000

1,240,000

67,112,000

1.5

1.8

2,128,000

2,641,000

203,352,000

1.0

1.3

All ages African Americans 0–19 20–49

9,000

12,000

6,620,000

0.1

0.2

130,000

166,000

16,553,000

0.8

1.0

50–69

104,000

133,000

7,683,000

1.4

1.7

≥70

101,000

129,000

6,429,000

1.6

2.0

All ages

344,000

440,000

37,285,000

0.9

1.2

Asian-Pacific Islanders 0–19

—*

—*

20–49

6,000

8,000

592,000

—*

—*

2,110,000

0.3

0.4

50–69

7,000

8,000

892,000

0.8

0.9

≥70

4,000

5,000

936,000

0.4

0.5

18,000†

21,000

4,530,000

0.4

0.5

All ages * Insufficient data. †

Represents the sum of all age groups before rounding. Reprinted from Stein et al. [23], with permission from Elsevier.

lower in rural and urban Japanese than in whites and Japanese Americans [30]. Some differences of coagulation factors between Asians and whites are attributable to environmental factors, especially diet and smoking, as well as genetic differences [26, 30]. In some venographic studies of patients recovering from total hip replacement, the incidence of asymp-

tomatic DVT in Asians was reported to be comparable with rates observed in the general population in North America [19, 20]. This may suggest that Asians have a more efficient inactivation of coagulation by activated protein C or more fibrinolytic activity [24], thereby lowering the rate of PE and the rate of symptomatic DVT.

Table 15.3 Mortality from pulmonary embolism (1990–1998). Crude mortality rate Death count Race

(1990–1998)

Population*

Age-adjusted mortality rate

(deaths/100,000

deaths/100,000

population/year)

(population/year)

Caucasian

66,879

1,946,786,446

3.4

3.4

African American

14,033

293,437,621

4.8

6.9

Other

584

100,803,416

0.6

1.0

* Sum of census estimates 1990–1998. Reprinted from Stein et al. [23], with permission from Elsevier.


Clinical/laboratory Clinical/laboratory

Major gynecological surgery Hospitalized patients

Deep venous thrombosis

Deep venous thrombosis

Venogram

80 Hospital Hospital idiopathic

Primary venous thromboembolism

Deep venous thrombosis

Discharge codes

Discharge codes and chart review

Clinical/laboratory autopsy

Autopsy

Venogram

Venogram

Venogram

Venogram

Fibrinogen uptake test

Fibrinogen uptake test/venogram

Clinical/laboratory

Reprinted from Stein et al. [23], with permission from Elsevier.

* Diagnosis of deep venous thrombosis was made by venous ultrasound or venography only [16].

Autopsy Hospital

Femoral fracture

Deep venous thrombosis

Fatal pulmonary embolism

Femoral fracture

Deep venous thrombosis

Venous thromboembolism

Total hip replacement

Gynecological surgery

Deep venous thrombosis Total knee replacement

Stroke

Deep venous thrombosis

Fibrinogen uptake test

General surgery

Deep venous thrombosis

Deep venous thrombosis

Deep venous thrombosis

Fibrinogen uptake test

General surgery General surgery

Deep venous thrombosis

Deep venous thrombosis

Laboratory

Pregnancy Pregnancy

Deep venous thrombosis

Venous thromboembolism

Fibrinogen uptake test

Fibrinogen uptake test

Total hip replacement

Autopsy

Autopsy

Hysterectomy

Autopsy

Pulmonary embolism

Deep venous thrombosis

Autopsy

Pulmonary embolism

Method

6/100,000/ year

2/100,000/year

0.013

3.6

53

50

77

64

2.6

17

2.6

12

0.02

0.2

0.04

0.08

3.8

1.7

4

1.4

0.16

Asia (%)

13â&#x20AC;&#x201C;19/100,000/year

21â&#x20AC;&#x201C;22/100,000/year

0.27

4.2

48

48

64

54

16

55

25

25

25

0.1

0.1

0.8

35

16

54

14.0, 14.7

14

European (%)

North American/

California

California

China

China

China

Malaysia

Malaysia

Malaysia

China

China

China

Malaysia

Malaysia

China

Malaysia

Singapore

Thailand

Thailand

Thailand

Japan

Singapore

location

Asian

13

12

11, 18

21

15, 20

15, 19

15, 19

15, 19

10, 15

9, 15

8, 15

7, 15

15

17, 22

6, 17

5, 16*

4

4

3, 15

2

1, 14

References

March 12, 2007

Deep venous thrombosis

Group

Venous thromboembolism

Rate of diagnosis

Table 15.4 Comparison of rates of venous thromboembolism, pulmonary embolism, and deep venous thrombosis in Asians versus North Americans/Europeans.

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Pulmonary thromboembolism in Asians

81

Asians appear to be more sensitive to warfarin than whites [31]. The target range of the International Normalized Ratio (INR) for patients with nonvalvular atrial fibrillation, 1.5–2.1 in Japanese [32], and for mechanical prosthetic heart valves, 1.5–2.5 in Japanese [33], is lower than the target range of 2.0–3.0 for most indications in patients from North America and Europe [34, 35]. Clinical problems with toxicity and dosage adjustment of warfarin have been found in patients with a genetic polymorphism to CYP2C9 [36, 37], but this polymorphism does not appear to be more frequent in Asians than whites, nor does it explain the observed greater sensitivity to warfarin [38]. Differences in the activity of CYP2C9 between Asians and whites may relate to differences in the pharmacokenetics of warfarin [38].

bolism in the Chinese in Hong Kong. Int J Cardiol 1988; 20: 373–380. Klatsky AL, Armstrong MA, Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in AsianAmericans. Am J Cardiol 2000; 85: 1334–1337. White RH, Zhou H, Romano PS. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann Intern Med 1998; 128: 737–740. Coon WW, Coller FA. Some epidemiologic considerations of thromboembolism. Surg Gynecol Obstet 1959; 109: 487–501. Geerts WW, Heit JA, Clagett GP et al. Prevention of venous thromboembolism. Chest 2001; 119(suppl): 132S– 175S. Stein PD, Patel KC, Kalra NK et al. Deep venous thrombosis in a general hospital. Chest 2002; 122: 960–962. Andersen BS, Steffensen FH, Sorensen HT, Nielsen GL, Olsen J. The cumulative incidence of venous thromboembolism during pregnancy and puerperium—an 11 year Danish population-based study of 63,300 pregnancies. Acta Obstet Gynecol Scand 1998; 77: 170–173. Stein PD, Patel KC, Kalra NK et al. Estimated incidence of acute pulmonary embolism in a community/teaching general hospital. Chest 2002; 121: 802–805. Dhillon KS, Askander A, Doraisamy S. Postoperative deep-vein thrombosis in Asian patients is not a rarity: a prospective study of 88 patients with no prophylaxis. J Bone Joint Surg 1996; 78B: 427–430. Mok CK, Hoaglund FT, Rogoff SM, Chow SP, Ma A, Yau AC. The incidence of deep vein thrombosis in Hong Kong Chinese after hip surgery for fracture of the proximal femur. Br J Surg 1979; 66: 640–642. Dickens P, Knight BH, Ip P, Fung WS. Fatal pulmonary embolism: a comparative study of autopsy incidence in Hong Kong and Cardiff, Wales. Forensic Sci Int 1997; 90: 171–174. Chan LY, Tam WH, Lau TK. Venous thromboembolism in pregnant Chinese women. Obstet Gynecol 2001; 98: 471–475. Stein PD, Kayali F, Olson RE, Milford, CE. Pulmonary thromboembolism in Asian-Pacific Islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med 2004; 116: 435–442. White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107: I4–I8. Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517–522. Franco RF, Reitsma PH. Genetic risk factors of venous thrombosis. Hum Genet 2001; 109: 369–384.

CHAPTER 15

12

13

14

15

16 17

References 1 Hwang WS. The rarity of pulmonary thromboembolism in Asians. Singapore Med J 1968; 9: 276–279. 2 Hirst AE, Gore I, Tanaka K, Samuel I, Krishtmukti I. Myocardial infarction and pulmonary embolism. Arch Pathol 1965; 80: 365–370. 3 Atichartakarn V, Pathepchotiwong K, Keorochana S, Eurvilaichit C. Deep vein thrombosis after hip surgery among Thai. Arch Intern Med 1988; 148: 1349–1353. 4 Chumnijarakij T, Poshyachinda V. Postoperative thrombosis in Thai women. Lancet 1975; 1: 1357–1358. 5 Kueh YK, Wang TL, Teo CP, Tan YO. Acute deep vein thrombosis in hospital practice. Ann Acad Med Singapore 1992; 21: 345–348. 6 Liam CK, Ng SC. A review of patients with deep vein thrombosis diagnosed at university hospital, Kuala Lumpur. Ann Acad Med 1990; 19: 837–840. 7 Cunningham IGE, Yong NK. The incidence of postoperative deep vein thrombosis in Malaysia. Br J Surg 1974; 61: 482–483. 8 Nandi P, Wong KP, Wei WI, Ngan H, Ong GB. Incidence of postoperative deep vein thrombosis in Hong Kong Chinese. Br J Surg 1980; 67: 251–253. 9 Tso SC. Deep vein thrombosis after strokes in Chinese. Aust N Z J Med 1980; 10: 513–514. 10 Tso SC, Wong V, Chan V, Chan TK, Ma HK, Todd D. Deep vein thrombosis and changes in coagulation and fibrinolysis after gynaecological operations in Chinese: the effect of oral contraceptives and malignant disease. Br J Haematol 1980; 46: 603–612. 11 Woo KS, Tse LK, Tse CY, Metreweli C, Vallance-Owen J. The prevalence and pattern of pulmonary thromboem-

18

19

20

21

22

23

24 25

26


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27 Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA 1997; 277: 1305–1307. 28 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133–1134. 29 Gregg JP, Yamane AJ, Grody WW. Prevalence of the factor V-Leiden mutation in four distinct American ethnic populations. Am J Med Genet 1997; 73: 334–336. 30 Iso H, Folsom AR, Wu KK et al. Hemostatic variables in Japanese and Caucasian men. Plasma fibrinogen, factor VIIc, factor VIIIc, and von Willebrand factor and their relations to cardiovascular disease risk factors. Am J Epidemiol 1989; 130: 925–934. 31 Takahashi H, Echizen H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J 2003; 3: 202–214. 32 Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial. Stroke 2000; 31: 817–821.

33 Matsuyama K, Matsumoto M, Sugita T et al. Anticoagulant therapy in Japanese patients with mechanical mitral valves. Circulation 2002; 66: 668–670. 34 Hirsh J, Dalen JE, Anderson DR et al. Managing oral anticoagulant therapy. Chest 2001; 119(suppl): 3S–7S. 35 Stein PD, Alpert JS, Bussey HI, Dalen JE, Turpie AG. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 2001; 119(suppl): 220S–227S. 36 Tabrizi AR, Zehnbauer BA, Borecki IB, McGrath SD, Buchman TG, Freeman BD. The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J Am Coll Surg 2002; 194: 267–273. 37 Aithal GP, Day CP, Kesteven PJL, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717–719. 38 Takahashi H, Wilkinson GR, Caraco Y et al. Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese. Clin Pharmacol Ther 2003; 73: 253–263.

Prevalence, risks, and prognosis of PE and DVT


January 5, 2007

CHAPTER 16

Pulmonary thromboembolism in American Indians and Alaskan Natives 155 131 150

71

100 126

107

50

55

VTE DVT

A Afr m ic er a ic n an A s A me la ri sk ca an n N Ind at ia iv n es s

ca

si

an

s

0

au

Rates of diagnosis of deep venous thrombosis (DVT), pulmonary embolism (PE), and venous thromboembolism (VTE) are lower in American Indians and Alaskan Natives than rates in African Americans or Caucasians [1, 2]. From 1996 to 2001, the rate of diagnosis of VTE (PE and/or DVT) in American Indians/Alaskan Natives, based on combined data from the National Hospital Discharge Survey and the Indian Health Service, was 71/100,000/year, compared with 155/100,000/year in African Americans and 131/100,000 in Caucasians (Figure 16.1) [1]. Rates of diagnosis of DVT according to race are shown in Figure 16.1 [1]. The number of PEs in American Indians/Alaskan Natives was too low to give an accurate estimate of the rate of diagnosis. Only 1 patient with PE was hospitalized in Indian Health Service hospitals between 1996 and 2001. During this interval, an estimated 420,000 patients were hospitalized [1]. The rate of diagnosis of VTE among patients discharged from Indian Health Service hospital care from 1980 to 1996 was reported as 33/100,000/year in American Indians/Alaskan Natives [2]. The relatively low incidence of VTE in American Indians/Alaskan Natives would seem to be due to as yet undetermined genetic factors. A lower prevalence of Factor V Leiden in American Indians/Alaskan Natives populations (1.25%) compared with Caucasians (5.3%) perhaps contributes to the lower incidence of VTE in American Indians/Alaskan Natives [3]. The concept that racial groups can differ genetically and the differences can have medical importance has recently been discussed [4]. The possibility that American Indians/Alaskan Natives have different diets or lifestyles

DX/100,000/yr

16

18:14

C

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Figure 16.1 Rates of diagnosis of deep venous thrombosis (DVT) and venous thromboembolic disease (VTE) in American Indians/Alaskan Natives, Caucasians, and African Americans from 1996 to 2001 based on combined data from the National Hospital Discharge Survey and the Indian Health Service. Rates of diagnosis of DVT and of VTE were lower in Indians/Alaskan Natives than Caucasians or African Americans (all differences P < 0.001). The rates of diagnosis in Caucasians and African Americans were comparable. (Reproduced from Stein et al. [1], with permission from American Medical Association. All rights reserved.)

that affect the rate of diagnosis of VTE cannot be excluded [5].

References 1 Stein PD, Kayali F, Olson RE, Milford, CE. Pulmonary thromboembolism in American Indians and Alaskan Natives. Arch Intern Med 2004; 164: 1804â&#x20AC;&#x201C;1806. 2 Hooper WC, Holman RC, Heit, JA, Cobb N. Venous thromboembolism hospitalizations among American Indians and Alaska Natives. Thrombosis Res 2003; 108: 273â&#x20AC;&#x201C; 278.

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3 Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of Factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA 1997; 277: 1305– 1307.

PART I

Prevalence, risks, and prognosis of PE and DVT

4 Burchard EG, Ziv E, Coyle N et al. The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med 2003; 348: 1170–1175. 5 Cooper RS, Kaufman JS, Ward R. Race and genomics. N Engl J Med 2003; 348: 1166–1170.


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CHAPTER 17

Venous thromboembolism in patients with cancer

Introduction Venous thromboembolism (VTE) is one of the most common complications in patients with cancer [1, 2]. The association of venous thrombosis with gastric carcinoma was described in 1865 [3]. A fourfold

increased risk of VTE has been found among patients with malignant neoplasm [4, 5]. Among patients insured through the Medicare program (patients aged 65 years or older), 0.6% of patients admitted with malignancy also had VTE [5]. A higher rate was reported by others [6]. Among patients hospitalized with solid

Table 17.1 Venous thromboembolism, pulmonary embolism, and deep venous thrombosis in patients with cancer as well as no cancer. All ages 1979â&#x20AC;&#x201C;1999 Diagnoses/ 100 hospitalizations

Number of patients Cancers Pancreas Brain Myeloproliferative, other lymphatic/ hematopoeitic Stomach Lymphoma, lymphosarcoma, reticulosarcoma Uterus Trachea, bronchus, and lung Esophagus Prostate Rectum, rectosigmoid junction, anus Kidney Colon Ovary Liver, gallbladder, intra- and extrahepatic ducts Leukemia Breast (female) Cervix Bladder Lip, oral cavity, pharynx Average incidences No cancer

VTE

PE

DVT

All discharges

VTE

PE

DVT

51,000 27,000 15,000

14,000 8,000 *

41,000 22,000 13,000

1,176,000 772,000 521,000

4.3 3.5 2.9

1.2 1.0 *

3.5 2.8 2.5

24,000 79,000

7,000 20,000

20,000 63,000

887,000 3,182,000

2.7 2.5

0.7 0.6

2.3 2.0

26,000 170,000 12,000 95,000 30,000

6,000 56,000 *

1,180,000 8,120,000 603,000 4,643,000 1,457,000

2.2 2.1 2.0 2.0 2.1

0.5 0.6 *

30,000 11,000

21,000 129,000 8,000 72,000 21,000

0.6 0.7

1.8 1.6 1.3 1.6 1.4

19,000 69,000 31,000 13,000

5,000 24,000 8,000 6,000

15,000 49,000 27,000 8,000

939,000 3,614,000 1,669,000 703,000

2.0 1.9 1.9 1.8

0.5 0.6 0.5 0.9

1.6 1.4 1.6 1.1

45,000 82,000 14,000 21,000 <5,000

10,000 22,000 *

2,655,000 4,932,000 875,000 2,011,000 849,000

1.7 1.7 1.6 1.0 <0.6

0.4 0.4 *

5,000 *

38,000 64,000 12,000 17,000 *

0.3 *

1.4 1.3 1.4 0.8 *

823,000 6,854,000

232,000 2,212,000

640,000 5,124,000

40,788,000 662,309,000

2.0 1.0

0.6 0.3

1.6 0.8

* Insufficient data. VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep venous thrombosis. Reprinted from Stein et al. [15], with permission from Elsevier.

85


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tumors, 7.8% also had VTE and 1.1% had PE (pulmonary embolism) [7]. The risk of VTE varies according to the type of cancer [5â&#x20AC;&#x201C;8]. Carcinoma of the pancreas has been associated with the greatest risk of VTE [9]. High rates of VTE have been reported among patients with solid neoplasms originating at several sites including the lung, ovary, brain, pancreas, stomach, kidney, colon [5â&#x20AC;&#x201C;7]. Patients with lymphoma, leukemia, and myeloproliferative syndromes also often have associated VTE [5, 6]. However, cancers originating at some sites, including head and neck and bladder, did not have a high incidence of associated VTE [5, 6]. A review of cancer patients who underwent surgery showed that they had twice the risk of postoperative deep venous thrombosis (DVT) as noncancer patients who underwent similar procedures [10].

Several mechanisms may be involved in the pathogenesis of thromboembolic events in patients with cancer [11]. These include (1) tumor cell procoagulants and/or cytokines, (2) tumor associated inflammatory cell procoagulants and/or cytokines, and (3) mediators of platelet adhesion or aggregation generated by tumor cells and/or tumor-associated inflammatory cells [11]. Stasis and endothelial damage may also be involved in the pathogenesis of thromboembolic events in patients with cancer [11]. The extent of cancer influences the risk of VTE [12]. Chemotherapy and radiation increase the risk of VTE [10, 12]. Risk factors may interact [10]. The risk of VTE increases with age [13] and age is also associated with malignancy. Among cancer patients undergoing surgery, advanced age, debility, prolonged and difficult surgery, and a lengthy and

(a)

4 3.5 3 2.5 2 1.5 1 0.5 0

Prevalence, risks, and prognosis of PE and DVT

Cancer patients

Noncancer patients 99

97

95

93

91

89

87

85

83

81

79

VTE in hospitalized cancer and noncancer patients (%)

86

(b)

2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0

Cancer patients

Noncancer patients 99

97

95

93

91

89

87

85

83

81

79

PE in hospitalized cancer and noncancer patients (%)

Year

(c)

4 Cancer patients

3.5 3 2.5 2 1.5 1

Noncancer patients

0.5 0

99

97

95

93

Year

91

89

87

85

83

81

79

DVT in hospitalized cancer and noncancer patients (%)

Year

Figure 17.1 (a) Incidence of venous thromboembolism (VTE) in patients hospitalized with cancer and those without cancer. From 1989 to 1999, there was a prominent increase in the incidence of VTE in patients discharged with cancer. The incidence of VTE in patients without cancer also increased but the slope was lower. (b) Incidence of pulmonary embolism (PE) in patients hospitalized with cancer and those without cancer. From 1989 to 1999, the incidence of PE in patients discharged with cancer increased. The incidence of PE in patients without cancer increased a little. (c) Incidence of deep venous thrombosis (DVT) in patients hospitalized with cancer and those without cancer. From 1989 to 1999, there was a prominent increase in the incidence of DVT in patients discharged with cancer. The incidence of DVT in patients without cancer also increased but the slope was lower. (Reprinted from Stein et al. [15], with permission from Elsevier.)


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Venous thromboembolism in cancer patients

twice the incidence of VTE in hospitalized patients who did not have any of these malignancies, 6,854,000 of 662,309,000 (1.0%) [15]. The highest incidence of VTE was in patients with carcinoma of the pancreas (4.3%) (Table 17.1). The lowest incidence of VTE was

complicated postoperative course add to the risk of DVT [14]. Among patients hospitalized from 1979 to 1999, with any of the malignancies listed in Table 17.1, 827,000 of 40,787,000 (2.0%) had VTE [15]. This was

(a)

4 3.5 3 2.5 2 1.5 1 0.5

Pancreas Brain Myeloprol Stomach Lymphoma Uterus Lung Esophagus Prostate Rectal Kidney Colon Ovary Liver Leukemia Breast Cervix Bladder

Relative risk of VTE in cancer patients

4.5

4.5 4 3.5 3 2.5 2 1.5 1 0.5 Pancreas Brain Myeloprol Stomach Lymphoma Uterus Lung Esophagus Prostate Rectal Kidney Colon Ovary Liver Leukemia Breast Cervix Bladder

Relative risk of PE in cancer patients

(b)

(c) 5 4 3 2 1 Cervix

Bladder

Breast

Liver

Leukemia

Colon

Ovary

Rectal

Kidney

Prostate

Lung

Esophagus

Uterus

Stomach

Lymphoma

Myeloprol

Brain

0 Pancreas

Relative risk of DVT in cancer patients

Figure 17.2 (a) Relative risks of venous thromboembolism (VTE) in patients hospitalized with cancer compared to those without cancer. The relative risk of VTE ranged from 1.02 to 4.34. (b) Relative risks of pulmonary embolism (PE) in patients hospitalized with cancer compared to those without cancer. The relative risk of PE ranged from 0.77 to 3.66. (c) Relative risks of deep venous thrombosis (DVT) in patients hospitalized with cancer compared to those without cancer. The relative risk of DVT ranged from 1.07 to 4.65. (Reprinted from Stein et al. [15], with permission from Elsevier.)


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in patients with carcinoma of the bladder (1.0%) (Table 17.1). The incidence of VTE in patients with carcinoma of the lip, oral cavity or pharynx was lower, but data were insufficient to calculate the incidence. Pulmonary embolism among patients hospitalized with carcinoma of the pancreas occurred in 1.2% and in patients with carcinoma of the bladder in 0.3% [15] (Table 17.1). Patients hospitalized with malignancies, on average, had twice the incidence of PE as in those who did not have malignancies (0.6% versus 0.3%) (Table 17.1).

The incidence of DVT associated with patients hospitalized with various neoplasms are shown in Table 17.1. As in patients with VTE and PE, patients hospitalized with cancer had twice the incidence of DVT as those who did not have cancer (1.6% versus 0.8%) (Table 17.1). The incidence of VTE in hospitalized patients with malignant neoplasms began to sharply increase in 1989 [15] (Figure 17.1a). The incidence of VTE in hospitalized patients who did not have cancer also showed an increasing incidence beginning in 1989, but

Prevalence, risks, and prognosis of PE and DVT

Table 17.2 Venous thromboembolism, pulmonary embolism, and deep venous thrombosis in patients with cancer as well as no cancer. Age group 40â&#x20AC;&#x201C;59, 1979â&#x20AC;&#x201C;1999 Diagnoses/ Number of patients Cancers

VTE

PE

100 hospitalizations DVT

All discharges

VTE

PE

DVT

Pancreas

10,000

*

10,000

217,000

4.6

*

4.6

Brain

11,000 *

*

9,000 *

206,000

5.3 *

*

4.4 *

Myeloproliferative, other

*

49,000

*

lymphatic/ hematopoeitic Stomach Lymphoma, lymphosarcoma,

5,000

*

5,000

171,000

2.9

*

2.9

18,000

5,000

16,000

738,000

2.4

0.6

2.2

reticulosarcoma 6,000

*

5,000

318,000

1.9

*

1.6

52,000 *

13,000 *

43,000 *

2,057,000 157,000

2.5 *

0.6 *

2.1 *

Prostate

5,000

*

*

332,000

1.5

*

*

Rectum, rectosigmoid

5,000

*

*

291,000

1.7

*

*

Uterus Trachea, bronchus, and lung Esophagus

junction, anus *

*

*

232,000

*

*

*

Colon

11,000

*

8,000

612,000

1.8

*

1.3

Ovary

9,000 *

*

8,000 *

572,000

1.6 *

*

1.4 *

8,000

5,000

7,000

358,000

2.2

1.4

2.0

26,000

6,000 *

21,000

1,734,000

1.5

1.2

347,000

*

5,000 *

247,000

1.4 *

0.3 *

*

*

293,000

Kidney

Liver, gallbladder, intra- and

*

149,000

*

extrahepatic ducts Leukemia Breast (female) Cervix Bladder Lip, oral cavity, pharynx Average incidences No cancer

5,000 * *

*

1.4 *

*

*

*

171,000

29,000

137,000

9,080,000

1.9

0.3

1.5

1,693,000

504,000

1,295,000

131,893,000

1.3

0.4

1.0

* Insufficient data. VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep venous thrombosis. Reprinted from Stein et al. [15], with permission from Elsevier.


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Venous thromboembolism in cancer patients

the increasing incidence was not as high. The incidence of PE among patients with cancer increased in the 1990s (Figure 17.1b), but the increasing incidence was not as high as with DVT (Figure 17.1c) or VTE (Figure 17.1a). The relative risk of VTE, PE, and DVT among hospitalized patients with various malignancies, compared to patients who did not have any of these malignancies, is shown in Figures 17.2a–17.2c [15]. The highest relative risk of VTE, 4.3, was among hospitalized patients with carcinoma of the pancreas. The lowest relative risk, 1.0, was among patients with carcinoma

of the bladder. The relative risks of PE and DVT paralleled the relative risks of VTE (Figures 17.2b and 17.2c). Among patients aged 40–59 years who were hospitalized with cancer, average incidence of VTE and DVT were 46 to 50% higher than in patients who did not have these types of cancer but the incidence of PE was not higher [15] (Table 17.2). Among patients aged 60–79 years who were hospitalized with cancer, average incidence of VTE and DVT were only 29 to 42% higher than in patients who did not have these cancers (Table 17.3).

Table 17.3 Venous thromboembolism, pulmonary embolism and deep venous thrombosis in patients with cancer as well as no cancer. Age group 60–79, 1979–1999 Diagnoses/ Number of patients Cancers

VTE

PE

100 hospitalizations DVT

All discharges

VTE

PE

DVT

Pancreas

37,000

724,000

5.1

9,000

245,000

4.9

1.7 *

3.9

12,000

12,000 *

28,000

Brain

9,000

*

8,000

263,000

3.4

*

3.0

Myeloproliferative, other

3.7

lymphatic/ hematopoeitic Stomach

13,000

*

11,000

494,000

2.6

*

2.2

Lymphoma, lymphosarcoma,

43,000

12,000

33,000

1,432,000

3.0

0.8

2.3

16,000

5,000

13,000

697,000

2.3

0.7

1.9

105,000

76,000 *

5,159,000

2.0

7,000

38,000 *

359,000

1.9

0.7 *

1.5 *

Prostate

66,000

21,000

51,000

2,992,000

2.2

0.7

1.7

Rectum, rectosigmoid

19,000

7,000

13,000

846,000

2.2

0.8

1.5

reticulosarcoma Uterus Trachea, bronchus, and lung Esophagus

junction, anus Kidney

12,000

*

9,000

507,000

2.4

*

1.8

Colon

44,000

32,000

2,087,000

2.1

17,000

15,000

842,000

2.0

0.8 *

1.5

Ovary

16,000 *

6,000

*

4,000

383,000

1.6

*

1.0

Liver, gallbladder, intra- and

1.8

extrahepatic ducts Leukemia

25,000

5,000

21,000

1,060,000

2.4

0.5

2.0

Breast (female)

42,000

13,000 *

32,000

2,300,000

1.8

1.4

4,000

263,000

1.9

0.6 *

*

11,000 *

1,217,000

*

425,000

1.2 *

*

0.9 *

Cervix Bladder Lip, oral cavity, pharynx Average incidences No cancer

5,000 14,000 *

*

1.5

492,000

129,000

370,000

22,033,704

2.2

0.6

1.7

3,018,000

1,038,000

2,151,000

174,352,000

1.7

0.6

1.2

* Insufficient data. VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep venous thrombosis. Reprinted from Stein et al. [15], with permission from Elsevier.


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Prevalence, risks, and prognosis of PE and DVT

Table 17.4 Venous thromboembolism, pulmonary embolism, and deep venous thrombosis according to sex in patients with cancer as well as no cancer. Incidence (%) VTE

PE

DVT

Cancers

Male

Female

Male

Female

Male

Female

Pancreas

4.4

4.3 3.0

1.3 *

3.5

3.9

1.2 *

3.5

Brain

3.4

2.2

Myeloproliferative, other lymphatic/hematopoeitic

2.8

3.1

*

*

2.3

2.6

Stomach

3.0

2.1

*

*

2.4

1.8

Lymphoma, lymphosarcoma, reticulosarcoma

2.4

2.6

0.8

0.5

1.8

2.2

Trachea, bronchus, and lung

2.1 2.2

2.1 *

0.7 *

0.7 *

1.5

Esophagus

1.6

1.7 *

Rectum, rectosigmoid junction, anus

1.9

2.2 2.2

0.7 *

1.5

1.9

0.7 *

1.4

Renal

1.5

1.7

Colon

2.0 2.6

0.7 *

0.7

Liver/gallbladder/extrahepatic duct

1.7 *

1.2 *

1.5

Leukemia

1.3

2.2

*

Bladder

1.1 *

*

0.5 *

Lip, oral cavity, pharynx

1.1 *

*

*

0.8 *

Average incidences

2.1

2.1

0.3

0.4

1.6

1.6

No cancer

1.1

1.0

0.4

0.3

0.8

0.8

1.4

1.0

1.5 1.9 * *

* Insufficient data. VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep venous thrombosis. Reprinted from Stein et al. [15], with permission from Elsevier.

On average, the incidences of VTE, PE, and DVT in patients with cancer were similar in men and women, but differences were shown with various malignancies [15] (Table 17.4). The incidence of VTE, PE, and DVT according to race, on average, were similar in African Americans and whites (Table 17.5). Differences were observed with various malignancies. The rates we reported [15] were the same order of magnitude as reported by Levitan et al. [6]. In patients with carcinoma of pancreas, the relative risk of VTE was 4.3 times that of noncancer patients. The rates of VTE, PE, and DVT showed an increase starting in the late 1980s. The incidences of DVT and PE increase exponentially with age [13]. However, the relative risk of VTE among patients aged 40–59 years was paradoxically higher than in older patients. This reflected a disproportionately higher incidence of VTE in the older noncancer patients. Cancer age did not greatly increase the incidence of VTE in older patients.

The cancers that we evaluated were shown by others to have a higher incidence of VTE than in patients without cancer [5–7]. The extent of malignancy, invasion, metastasis, chemotherapy, radiotherapy, and surgery, which may increase the incidence of associated VTE, was not available on discharge codes.

Pulmonary embolism as a cause of death in patients who died with cancer Among 506 autopsies of patients in whom 96% had “some sort of neoplasm,” 35 (7%) died from PE [16]. Numerous other investigations describe the association of PE with cancer, but do not describe the frequency of fatal PE in patients who died with cancer. Among patients who died from PE, 22.9% had cancer [17]. Among patients with cancer who died from 1980 to 1998, the estimated average frequency of PE as the cause of death, after adjustment for the


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Table 17.5 Venous thromboembolism, pulmonary embolism, and deep venous thrombosis according to race in patients with cancer as well as no cancer. Incidence (%) VTE

PE

DVT

Cancers

White

Black

White

Black

White

Black 2.9

Pancreas

4.4

4.2

1.2

1.7

3.5

Brain

3.8

5.1

1.0

3.2

3.2

2.0

Myeloproliferative, other lymphatic/hematopoeitic

3.0

3.7

0.7

0.4

2.6

3.3

Stomach

2.9

2.6

0.9

0.6

2.4

2.1

Lymphoma, lymphosarcoma, reticulosarcoma

2.5 2.2

0.6 *

0.5 *

2.1

Uterus

2.3 *

2.1 *

Trachea, bronchus, and lung

2.1

Esophagus

2.2

1.8 *

0.7 *

0.7 *

1.9 1.6

1.3 *

1.5

Prostate

2.2

1.6

0.6

0.6

1.7

1.3

Rectum, rectosigmoid junction, anus

1.9

3.3

0.7

1.2

1.3

2.1

Kidney

1.9

1.7

0.5

0.5

1.5

1.3

Colon

1.8

2.3

0.6

0.7

1.3

1.7

Ovary

1.9 1.8

0.5 *

0.5 *

1.6

Liver, gallbladder, intra- and extrahepatic ducts

2.0 *

1.6 *

1.2

Leukemia

1.8

1.8

0.4

0.6

1.6

1.2

Breast (female)

1.7 1.8

0.4 *

0.4 *

1.3

Cervix

1.7 *

1.2 *

Bladder

*

*

*

*

*

*

0.8 *

*

Lip, oral cavity, pharynx

1.0 *

Average incidences

2.2

1.8

0.5

0.6

1.7

1.3

No cancer

1.1

0.9

0.4

0.3

0.8

0.7

1.6

*

* Insufficient data. VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep venous thrombosis. Reprinted from Stein et al. [15], with permission from Elsevier.

myeloproliferative disease and lowest in patients who died with cancer of the liver, gallbladder, intra- and extrahepatic ducts. The rate of fatal PE among patients who died with cancer decreased from 1980 to 1998 (Figure 17.3). This

0.6 0.5 0.4 0.3 0.2 0.1 0 98

96

94

92

Year

90

88

86

84

82

80

Figure 17.3 Frequency of fatal pulmonary embolism (PE) among patients who died with cancer from 1980 to 1998. The frequency declined over the 19-year period of study. (Reprinted from Stein et al. [18], with permission from Elsevier.)

Deaths from PE in patients who died with cancer (%)

inaccuracy of death certificates, was between 0.60 and 1.05% [18]. However, these values appear low compared to the prevalence of large or fatal PE in all patients at autopsy, about 4% (Chapter 1). The incidence of fatal PE was highest among those who died with


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presumably reflects an improvement in achieving an early diagnosis and more vigorous prophylaxis over these 19 years.

8 Thodiyil PA, Kakkar AK. Variation in relative risk of venous thromboembolism in different cancers. Thomb Haemost 2002; 87: 1076–1077. 9 Rickles FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau’s syndrome revisited. Blood 1983; 62: 14–31. 10 Bergqvist D. Venous thromboembolism and cancer: prevention of VTE. Thromb Res 2001; 102: V209–V213. 11 Rickles FR, Levine M, Edwards RL. Hemostatic alterations in cancer patients. Cancer Metast Rev 1992; 11: 237–248. 12 Lee AYY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003; 107: I-17–I-21. 13 Stein PD, Hull RD, Kayali F, Ghali WA, Alshab AK, Olson RE. Venous thromboembolism according to age: the impact of an aging population. Arch Intern Med 2004; 164: 2260–2265. 14 Gallus AS. Prevention of post-operative deep leg vein thrombosis in patients with cancer. Thromb Haemost 1997; 78: 126–132. 15 Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 2006; 119: 60–68. 16 Ambrus JL, Ambrus CM, Mink IB, Pickren JW. Causes of death in cancer patients. J Med 1975; 6: 61–64. 17 Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979–1998: an analysis using multiple-cause mortality data. Arch Intern Med 2003; 163: 1711–1717. 18 Stein PD, Beemath A, Meyers FA, Kayali F, Skaf E, Olson RE. Pulmonary embolism as a cause of death in patients who died with cancer. Am J Med 2006; 119: 163–165.

References 1 Arklel YS. Thrombosis and cancer. Semin Oncol 2000; 27: 362–374. 2 Donati MB. Cancer and thrombosis. Haemostatis 1994; 24: 128–131. 3 Trousseau A. Phlegmassia alba dolens. In: Clinique Medicale de l’Hotel-Dieu de Paris, Vol. 3. New Sydenham Society, London, 1865: 94. Quoted by Rickles and Edwards in Reference [9]. 4 Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ, III. Risk factors for deep vein thrombosis and pulmonary embolism. A populationbased case–control study. Arch Intern Med 2000; 160: 809– 815. 5 Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 715–722. 6 Levitan N, Dowlati A, Remick SC et al. Rates of initial and recurrent thromboembolic diseases among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine 1999; 78: 285–291. 7 Sallah S, Wan JY, Nguyen NP. Venous thrombosis in patients with solid tumors: determination of frequency characteristics. Thromb Haemost 2002; 87: 575–579.

Prevalence, risks, and prognosis of PE and DVT


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CHAPTER 18

Venous thromboembolism in patients with heart disease

Patients with heart failure Heart failure (HF) is considered a major risk factor for venous thromboembolism (VTE), defined as pulmonary embolism (PE) and/or deep venous thrombosis (DVT) [1–6]. In patients with advanced HF, thrombophlebitis of the pelvic or leg veins is a common complication and this may also be a source of PE [7]. Based on data from the National Hospital Discharge Survey (NHDS) [8], among hospitalized patients with HF, PE was diagnosed in 0.73%, DVT in 1.03%, and

VTE in 1.63% [9] (Table 18.1). Among hospitalized patients who were not diagnosed with HF, PE was diagnosed in 0.34%, DVT was diagnosed in 0.85%, and VTE in 1.11%. The prevalence of PE in HF was similar to findings reported in smaller investigations that used defined criteria for HF [10, 11]. Others showed that HF patients with lower ejection fractions had a higher risk of thromboembolic events [10, 12]. The reported frequency of PE in patients with HF has ranged widely from 0.9 to 39% of patients [3, 7, 10, 12–15]. At autopsy the incidence of PE in patients with HF ranged

Table 18.1 Prevalence and relative risk of pulmonary embolism, deep venous thrombosis, and venous thromboembolism in hospitalized patients according to age groups. n/N (%)* Age groups (yrs)

HF

No HF

HF vs. No HF(95% CI)

<40

13,000/1,129,000 (1.15)

333,000/339,063,000 (0.10)

11.72 (11.52–11.93)

40–59

65,000/6,410,000 (1.01)

655,000/164,010,000 (0.40)

2.54 (2.52–2.56)

60–79

236,000/28,745,000 (0.82)

1,229,000/205,140,000 (0.60)

1.37 (1.36–1.38)

>80

157,000/22,590,000 (0.69)

404,000/74,491,000 (0.54)

1.28 (1.27–1.29)

All ages

431,000/58,873,000 (0.73)

2,662,000/782,704,000 (0.34)

2.15 (2.15–2.16)

<40

19,000/1,129,000 (1.68)

1,045,000/339,063,000 (0.31)

5.46 (5.38–5.54)

40–59

85,000/6,410,000 (1.33)

1,762,000/164,010,000 (1.07)

1.23 (1.23–1.24)

60–79

317,000/28,745,000 (1.10)

2,833,000/205,140,000 (1.38)

0.80 (0.80–0.80)

>80

281,000/22,590,000 (1.24)

948,000/74,491,000 (1.27)

0.98 (0.97–0.98)

All ages

607,000/58,873,000 (1.03)

6,683,000/782,704,000 (0.85)

1.21 (1.20–1.21)

<40

30,000/1,129,000 (2.66)

1,304,000/339,063,000 (0.38)

6.91 (9.83–6.99)

40–59

139,000/6,410,000 (2.17)

2,227,000/164,010,000 (1.36)

1.60 (1.59–1.61)

60–79

509,000/28,745,000 (1.77)

3,749,000/205,140,000 (1.83)

0.97 (0.97–0.97)

>80

405,000/22,590,000 (1.79)

1,256,000/74,491,000 (1.69)

1.06 (1.06–1.07)

All ages

960,000/58,873,000 (1.63)

8,660,000/782,704,000 (1.11)

1.47 (1.47–1.48)

Pulmonary embolism

Deep venous thrombosis

Venous thromboembolism

* 95% confidence intervals are all ≤0.04%. HF, heart failure; yrs, years; CI, confidence interval. Reproduced from Beemath et al. [9], with permission from Elsevier.

93


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Prevalence, risks, and prognosis of PE and DVT

Table 18.2 Prevalence and relative risks of pulmonary embolism and deep venous thrombosis in hospitalized patients according to sex and race. Pulmonary embolism Prevalence (%)* HF

No HF

Deep venous thrombosis Prevalence (%)*

Relative risk HF vs. No HF

HF

No HF

Relative risk HF vs. No HF

Sex Male

0.69

0.38

1.80 (1.79–1.80)

0.89

0.90

0.98 (0.98–0.99)

Female

0.77

0.31

2.45 (2.44–2.46)

1.14

0.82

1.39 (1.39–1.40)

Race White

0.75

0.36

2.10 (2.09–2.11)

1.03

0.89

1.15 (1.15–1.15)

African American

0.85

0.30

2.82 (2.79–2.84)

1.13

0.79

1.44 (1.43–1.45)

* 95% confidence intervals are all ≤0.02%. HF, heart failure. Reproduced from Beemath et al. [9], with permission from Elsevier.

DVT and PE in patients hospitalized with heart failure (%)

from 28 to 48% [14, 16, 17]. The reported frequency of DVT in patients with HF also ranged widely from 10 to 59% [2, 3, 5]. The relative risk of PE in patients with HF was highest in patients <40 years of age (relative risk 11.72) and the relative risk for DVT was 5.46 [9] (Table 18.1). In patients aged 40–59 years, the relative risk for PE was 2.54 and for DVT 1.23. With older age groups the relative risks for both PE and DVT decreased (Table 18.1). With increasing age and its accompanying risk factors for PE and DVT, other risk factors balance or outweigh the risk of HF alone. In older patients therefore, the higher relative risk for PE or DVT is thereby reduced or eliminated. The high relative risk of PE and DVT in younger adults is readily explained, but the somewhat higher rates of PE and DVT in younger adults are not explained. This observation is not in accordance with

previous findings of an increased risk of PE and DVT with age [18]. The relative risk of PE was higher in patients with HF compared to those patients with no HF among both women and men and African Americans and whites [9] (Table 18.2). The relative risk of DVT was higher in patients with HF compared with no HF among women but not in men. Both African Americans and whites with HF had higher relative risks for DVT compared with those who did not have HF (Table 18.2). The rate of PE among patients hospitalized with HF decreased from 1.38% in 1979–1981 to 0.61% in 2000– 2003 [9] (Figure 18.1). The rate of diagnosis of DVT in patients hospitalized with HF decreased from 0.89% in 1979–1981 to 0.71% in 1988–1990 and then increased to 1.35% in 2000–2003 (Figure 18.1).

1.6 1.4

DVT

1.2 1 0.8 0.6

PE

0.4 '79−81 '82−84 '85−87 '88−90 '91−93 '94−96 '97−99 '00−03 Years

Figure 18.1 Rates of pulmonary embolism (PE) and deep venous thrombosis (DVT) in hospitalized patients with heart failure (HF). Data were averaged over 3-year periods from 1979 to 1999 and over the 4-year period 2000–2003. The rate of PE decreased from 1979–1981 to 2000–2003. The rate of DVT decreased from 1979–1981 to 1988–1990. The rate of DVT then increased from 1988–1990 to 2000–2003. (Reproduced from Beemath et al. [9], with permission from Elsevier.)


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VTE in patients with heart failure

Figure 18.2 Frequency of fatal pulmonary embolism (PE) among adults who died with heart failure (HF) from 1980 to 1998. The frequency declined over the 19-year period of study. (Reproduced from Beemath et al. [27], with permission from Elsevier.)

Deaths from PE in adults who died with heart failure (%)

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Figure 18.3 Frequency of fatal pulmonary embolism (PE) among adults who died with heart failure (HF) among the different age groups. (Reproduced from Beemath et al. [23], with permission from Elsevier.)

Deaths from PE in adults who died with heart failure (%)

Heart failure appears to be a stronger risk factor in woman. Dries et al. [10] reported a significant difference between the sexes in the distribution of thromboembolic events in patients with HF. Among women with HF, 24% had PE whereas among men with HF 14% had PE [10]. African Americans with HF also had a somewhat higher risk for PE and DVT than whites. In 2004, it was recommended that patients hospitalized with HF should receive antithrombotic prophylaxis [19]. Roberts et al. reported PE as the cause of death in 12 of 139 (9%) autopsied patients who died with HF [15]. Goldhaber et al. reported PE as the cause of death at autopsy in 13 of 41 (32%) patients with HF [16]. In other studies, PE was found in the wide range of 0.4–50% of autopsied patients who died with HF, but whether PE caused or contributed to these deaths was not stated [11, 14, 20–22]. We investigated the rate of death from PE in patients who died with HF from 1980 to 1998 based on data from death certificates, as listed by the United States Bureau of the Census [23].

Among adults with HF who died over a 19-year period of study, PE was the listed cause of death in 20,387 of 755,807 (2.7%) [23]. Assuming a sensitivity of 26.7% for the death certificate diagnosis of fatal PE [24], the frequency of fatal PE among patients who died with HF over the 19-year period of study would be 10.1%. The frequency of death from PE in patients who died with HF decreased from 5.0% in 1980 to 1.6% in 1998 (Figure 18.2). These rates were not adjusted for the 26.7% sensitivity of PE diagnoses on death certificates. We assume that whatever inaccuracy exists in the death certificates was constant throughout the 19-year period of study. The trend of a decreasing rate of death from PE in adults who died with HF, therefore, would appear to be accurate. The decreasing rate of fatal PE among patients who died with HF during the 19-year period of study presumably reflects an improvement in achieving an early diagnosis and more vigorous prophylaxis. The risk of PE in patients with HF is twice the risk of PE observed in patients who do not have

12 10 8 6 4 2 0

20−34

35−44 45−54

55−64

65−74

Age group (years)

75−84

85−99


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HF [9]. Antithrombotic prophylaxis is recommended in such patients [19]. The rate of fatal PE in adults who died with HF decreased with age with the highest rate in the age group 20–34 years (10.6%) (Figure 18.3). The reason for this is not clear.

PART I

9

10

Patients with any heart disease Among 1032 autopsies of patients with heart disease, 231 patients (24.4%) had PE and 100 (9.7%) had massive PE, considered to be the cause of death [25]. Strikingly, the prevalence of PE as a cause of death was particularly high in young patients (<10 years old) with heart disease [25]. Among 59 patients who died from PE and in whom the cardiac pathology was described, 34 (58%) had right ventricular dilatation, and 8 (14%) biventricular dilatation [25]. An antemortem suspicion of PE was raised in only 18% of patients with heart disease who died from PE [25].

References 1 Shively BK. Deep venous thrombosis prophylaxis in patients with heart disease. Curr Cardiol Rep 2001; 3(1): 56–62. 2 Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160(22): 3415–3420. 3 Anderson FA, Jr, Wheeler HB, Goldberg RJ et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151(5): 933–938. 4 Isnard R, Komajda M. Thromboembolism in heart failure, old ideas and new challenges. Eur J Heart Fail 2001; 3(3): 265–269. 5 Cogo A, Bernardi E, Prandoni P et al. Acquired risk factors for deep-vein thrombosis in symptomatic outpatients. Arch Intern Med 1994; 154(2): 164–168. 6 Jafri SM, Ozawa T, Mammen E, Levine TB, Johnson C, Goldstein S. Platelet function, thrombin and fibrinolytic activity in patients with heart failure. Eur Heart J 1993; 14(2): 205–212. 7 Segal JP, Harvey WP, Gurel T. Diagnosis and treatment of primary myocardial disease. Circulation 1965; 32: 837– 844. 8 US Department of Health and Human Services, Public Health Service, National Center for Health Statistics

11

12

13

14 15

16

17 18

19

20

21

22

Prevalence, risks, and prognosis of PE and DVT

National Hospital Discharge Survey 1979–1999 Multiyear Public-Use Data File Documentation. Available at: http://www.cdc.gov/nchs/about/major/hdasd/nhds.htm. Last accessed Jan/ 20/, 2006. Beemath A, Stein PD, Skaf E, Al Sibae MR et al. Risk of venous thromboembolism in patients hospitalized with heart failure. Am J Cardiol. 2006; 98(6): 793–795. Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. J Am Coll Cardiol 1997; 29(5): 1074–1080. Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Warfarin anticoagulation and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 1998; 31(4): 749–753. Kyrle PA, Korninger C, Gossinger H et al. Prevention of arterial and pulmonary embolism by oral anticoagulants in patients with dilated cardiomyopathy. Thromb Haemost 1985; 54(2): 521–523. Dunkman WB, Johnson GR, Carson PE, Bhat G, Farrell L, Cohn JN, for The V-HeFT VA Cooperative Studies Group. Incidence of thromboembolic events in congestive heart failure. Circulation 1993; 87(6 suppl): VI94– VI101. Kinsey D, White P. Fever in congestive heart failure. Arch Intern Med 1940; 65: 163–170. Roberts WC, Siegel RJ, McManus BM. Idiopathic dilated cardiomyopathy: analysis of 152 necropsy patients. Am J Cardiol 1987; 60: 1340–1355. Goldhaber SZ, Savage DD, Garrison RJ et al. Risk factors for pulmonary embolism. The Framingham Study. Am J Med 1983; 74(6): 1023–1028. Greenstein J. Thrombosis and pulmonary embolism. South African Med J 1945; 19: 350–377. Stein PD, Hull RD, Kayali F, Ghali WA, Alshab AK, Olson RE. Venous thromboembolism according to age: the impact of an aging population. Arch Intern Med 2004; 164(20): 2260–2265. Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 suppl): 338S–400S. Harvey WP, Finch CA. Dicumarol prophylaxis of thromboembolic disease in congestive heart failure. N Engl J Med 1950; 242: 208–211. Anderson GM, Hull E. The effect of dicumarol upon the mortality and incidence of thromboembolic complications in congestive heart failure. Am Heart J 1950; 39: 697–702. Spodick DH, Littmann D. Idiopathic myocardial hypertrophy. Am J Cardiol 1958; 1: 610–623.


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VTE in patients with heart failure

23 Beemath A, Skaf E, Stein PD. Pulmonary embolism as a cause of death in patients who died with heart failure. Am J Cardiol 2006; 98: 1073–1075. 24 Attems J, Arbes S, Bohm G, Bohmer F, Lintner F. The clinical diagnostic accuracy rate regarding the immediate cause of death in a hospitalized geriatric population; an

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autopsy study of 1594 patients. Wien Med Wochenschr 2004; 154: 159–162. 25 Pulido T, Aranda A, Zevallos MA et al. Pulmonary embolism as a cause of death in patients with heart disease. An autopsy study. Chest 2006; 129: 1282– 1287.


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CHAPTER 19

Venous thromboembolism in patients with ischemic and hemorrhagic stroke

Patients with stroke are at particular risk of developing deep venous thrombosis (DVT) and pulmonary embolism (PE) because of limb paralysis, prolonged bed rest, and increased prothrombotic activity [1]. Deep venous thrombosis in the paralyzed legs of patients with stroke was reported as early as 1810 by Ferriar and again by Lobstein in 1833 [2]. Among 14,109,000 patients hospitalized with ischemic stroke, PE occurred in 72,000 (0.51%), DVT occurred in 104,000 (0.74%), and VTE (venous thromboembolism) occurred in 165,000 (1.17%) [3] (Figure 19.1). Among 1,606,000 patients hospitalized with hemorrhagic stroke, rates were higher. Pulmonary embolism occurred in 11,000 (0.68%), DVT occurred in 22,000 (1.37%), and VTE occurred in 31,000 (1.93%)

[3] (Figure 19.1). The rate of VTE in hospitalized patients with ischemic stroke and with hemorrhagic stroke did not change significantly over the 25-year period of observation [3] (Figure 19.2). The higher rate of PE, DVT, and VTE among patients with hemorrhagic stroke compared with patients with ischemic stroke may represent more frequent use of antithrombotic prophylaxis in patients with ischemic stroke although treatment was not known [3]. Since 1980, with the use of modern diagnostic techniques and general awareness of the importance of antithrombotic prophylaxis, only a few previous case series have been reported, the largest of which had 607 patients [4â&#x20AC;&#x201C;10]. In most, antithrombotic prophylaxis was either not given or not described [4â&#x20AC;&#x201C;7, 9].

2 1.93

1.8 1.6 1.4 PE, DVT or VTE 1.2 (%) 1 0.8 0.6 0.4 0.2 0

1.37

0.68 0.51

1.17 0.74 Hemorrhagic stroke Ischemic stroke

PE DVT VTE Figure 19.1 Rates of pulmonary embolism (PE), deep venous thrombosis (DVT), and venous thromboembolism (VTE) in hospitalized patients with ischemic and

98

hemorrhagic stroke. Data were averaged from 1979 to 2003. (Reprinted from Skaf et al. [3], with permission from Elsevier.)


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VTE in patients with stroke

Figure 19.2 Trends in the rates of venous thromboembolism (VTE) in hospitalized patients with ischemic and hemorrhagic stroke. Data were pooled in 5-year intervals. The rate of VTE in patients with ischemic stroke and in patients with hemorrhagic stroke did not change over the 25-year period of observation. (Reprinted from Skaf et al. [3], with permission from Elsevier.)

2.8 2.4

Hemorrhagic stroke

2 1.6 1.2 Ischemic stroke 0.8 1979−84

The prevalence of PE in these patients with stroke ranged from 0 to 4%. The prevalence of PE was 0.8% among 245 patients who received antithrombotic prophylaxis [8]. The International Stroke Trial Collaboration Group showed that among patients with ischemic stroke who received low-dose heparin (5000 IU twice daily), the rate of PE within 14 days was 33 of 4860 (0.7%) and among those who received medium-dose heparin (12,500 IU twice daily), the rate of PE within 14 days was 20 of 4856 (0.4%) [11]. Some received aspirin 300 mg/day in addition. Among all patients treated with aspirin, heparin, both, or neither, the rate of PE ranged from 0.5 to 0.8% [11]. Most investigations of antithrombotic therapy for stroke [11] or to prevent DVT among stroke patients [10, 12] excluded patients with hemorrhagic stroke. Clinically apparent DVT was reported in 1.7–5.0% of patients with stroke [4–8]. Subclinical DVT occurred in 28–73% of patients with stroke, usually in the paralyzed limb [10, 12, 13]. A high proportion of patients with DVT also have subclinical PE [14]. Although deaths within a few days of stroke are usually due to the direct consequence of brain damage, those occurring over the following weeks are mainly due to potentially preventable problems including PE [4]. In the experience of some, PE is the leading cause of death during the 2–4 weeks after onset of stroke [15, 16], yet PE is one of the preventable causes of death after stroke [16–18]. Prior to the general use of antithrombotic prophylaxis (1941–1952), 26% of immediate survivors of stroke who subsequently died, died of PE [19]. More recently, among patients with stroke who died and had autopsies, PE was the cause of death

1985−89

1990−94

1995−99

2000−03

Year

in 8–16% [15, 17, 18, 20]. Others, who described the rate of PE as the cause of death in patients who died with stroke, based on death certificates and autopsy between 1961 and 1984, reported rates of 1.3–5.9% [16, 21–25]. In 1997, the International Stroke Trial Collaborative Group showed PE as a cause of death in 75 of 1781 (4.2%) of patients with ischemic stroke who died [11]. Among patients with ischemic stroke who died from 1980 to 1998, PE was the listed cause of death on death certificates in 11,101 of 2,000,963 (0.55%) [26]. Adjusted rates of fatal PE in stroke, based on an assumed sensitivity for fatal PE on death certificates of 26.7– 37.2%, were 1.5–2.1% [26]. Death rates from PE among patients who died with ischemic stroke decreased from 1980 to 1998 (Figure 19.3) [26]. The uncorrected death rate from PE

Fatal PE among stroke deaths (%)

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VTE in hospitalized patients with ischemic or hemorrhagic stroke (%)

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0.7 0.6 0.5 0.4 '80 '82 '84 '86 '88 '90 '92 '94 '96 '98 Year

Figure 19.3 Proportion of deaths from pulmonary embolism (PE) in patients who died with ischemic stroke. The proportion of deaths from PE with ischemic stroke decreased over the 19-year period of observation. (Reprinted from Skaf et al. [26], with permission from Elsevier.)


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among patients with ischemic stroke, 0.55%, was similar to the average uncorrected death certificate rate from PE in the general population (0.45%) [27]. The decreasing proportion of deaths from PE among patients with ischemic stroke who died suggests an increased and effective use of antithrombotic prophylaxis in these patients.

13 Warlow C, Ogston D, Douglas AS. Deep venous thrombosis of the legs after strokes. BMJ 1976; 1: 1178– 1181. 14 Moser KM, Fedullo PF, LittleJohn JK, Crawford R. Frequent asymptomatic pulmonary embolism in patients with deep venous thrombosis. JAMA 1994; 271: 223– 225. 15 Viitanen M, Winblad B, Asplund K. Autopsy-verified causes of death after stroke. Acta Med Scand 1987; 222: 401–408. 16 Silver FL, Norris JW, Lewis AJ, Hachinski VC. Early mortality following stroke: a prospective review. Stroke 1984; 15: 492–496. 17 Brown M, Glassenberg M. Mortality factors in patients with acute stroke. JAMA 1973; 224: 1493–1495. 18 Bounds JV, Wiebers DO, Whisnant JP, Okazaki H. Mechanisms and timing of deaths from cerebral infarction. Stroke 1981; 12: 474–477. 19 Marquardsen J. The natural history of acute cerebrovascular disease: a retrospective study of 769 patients. Acta Neurol Scand 1969; 45: 9–88. 20 Ulbrich J. Woran sterben die apoplektiker. Ther Umsch 1981; 38: 703–708. 21 Marshall J, Kaeser AC. Survival after non-haemorrhagic cerebrovascular accidents. A prospective study. BMJ 1961; 2: 73–77. 22 Baker RN, Schwartz WS, Ramseyer JC. Prognosis among survivors of ischemic stroke. Neurology 1968; 18: 933– 941. 23 Marquardsen J. The natural history of acute cerebrovascular disease. Acta Neurol Scand 1969; 45: 131–137. 24 Matsumoto N, Whisnant JP, Kurland LT, Okazaki H. Natural history of stroke in Rochester, Minnesota, 1955 through 1969: an extension of a previous study, 1945 through 1954. Stroke 1973; 4: 20–29. 25 Miah K, von Arbin M, Britton M, de Faire U, Helmers C, Maasing R. Prognosis in acute stroke with special reference to some cardiac factors. J Chronic Dis 1983; 36(3): 279–288. 26 Skaf E, Stein PD, Beemath A, Sanchez J, Olson RE. Fatal pulmonary embolism and stroke. Am J Cardiol 2006; 97: 1776–1777. 27 Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979–1998. An analysis using multiple-cause mortality data. Arch Intern Med 2003; 163: 1711–1717.

References 1 Harvey RL. Prevention of venous thromboembolism after stroke. Topics Stroke Rehab 2003; 10: 61–69. 2 Lobstein JF. Traite d’ Anatomie Pathologique, Vol 2. Levranle FG, Paris, 1833: 610. Quoted by Warlow et al. in Reference [13]. 3 Skaf E, Stein PD, Beemath A, Sanchez J, Bustamante MA, Olson RE. Venous thromboembolism in patients with ischemic and hemorrhagic stroke. Am J Cardiol 2005; 96: 1731–1733. 4 Davenport RJ, Dennis MS, Wellwood I, Warlow CP. Complications after acute stroke. Stroke 1996; 27: 415–420. 5 Dromerick A, Reding M. Medical and neurological complications during inpatient stroke rehabilitation. Stroke 1994; 25: 358–361. 6 Dobkin BH. Neuromedical complications in stroke patients transferred for rehabilitation before and after diagnostic related groups. J Neurol Rehab 1987; 1: 3–7. 7 McClatchie G. Survey of the rehabilitation outcomes of stroke. Med J Aust 1980; 1: 649–651. 8 Kalra L, Yu G, Wilson K, Roots P. Medical complications during stroke rehabilitation. Stroke 1995; 26: 990–994. 9 Subbararao BJ, Smith J. Pulmonary embolism during stroke rehabilitation. Illinois Med J 1984; 165: 328–332. 10 Turpie AGG, Levine MN, Hirsh J et al. Double-blind randomized trial of org 10172 low-molecular-weight heparinoid in prevention of deep-vein thrombosis in thrombotic stroke. Lancet 1987; 1: 523–527. 11 International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569–1581. 12 McCarthy ST, Turner JJ, Robertson D, Hawkey CJ. Lowdose heparin as a prophylaxis against deep-vein thrombosis after acute stroke. Lancet 1977; 2: 800–801.

Prevalence, risks, and prognosis of PE and DVT


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CHAPTER 20

Pulmonary embolism and deep venous thrombosis in hospitalized adults with chronic obstructive pulmonary disease

When patients with chronic obstructive pulmonary disease (COPD) are routinely evaluated for pulmonary embolism (PE), the rate of diagnosis has been reported as 9 of 31 (29%) and 49 of 197 (25%) [1, 2]. Rates of diagnosis of PE among hospitalized patients with COPD who were not routinely evaluated for PE were much lower than found among patients with COPD who underwent routine testing for PE [3]. Over the 25-year period of evaluation (1979–2003), 58,392,000 adults ≥20 years of age were hospitalized with COPD [3]. Among these patients, PE was diagnosed in 0.65%, DVT (deep venous thrombosis) in 1.08%, and VTE (venous thromboembolism) (PE and/or DVT) in 1.58% [3] (Tables 20.1 and 20.2). Among 789,403,000 adults hospitalized with illnesses other than COPD, PE was diagnosed in 0.34%, DVT in 0.83%, and VTE in 1.09% [3] (Tables 20.1 and 20.2). The relative risk for PE in adults hospitalized with COPD compared with those who did not have COPD was 1.92 [3] (Table 20.1, Figure 20.1) [3]. Among hos-

pitalized patients aged 20–39 years with COPD, the relative risk for PE compared with hospitalized adults the same age who did not have COPD was 5.34 [3]. Among patients aged 40–59 years, the relative risk for PE decreased to 2.02. Among patients aged 60–79 years and 80–99 years, the relative risk for PE was 1.23 and 1.41, respectively. The relative risk for DVT among hospitalized adults with COPD compared with those who did not have COPD was 1.30 and as with patients with PE, the relative risk was high in younger patients (Table 20.2) [3]. In young adults other risk factors in combination with COPD are uncommon, so the contribution of COPD to the risk of PE and DVT becomes more apparent than in older patients. The relative risk for PE and DVT in all patients increases exponentially with age [4]. Congestive heart failure, cancer, and stroke have been shown to be risk factors for VTE [5–7]. The prevalence of these risks, as we showed in this study and as others have shown previously [6, 7], is age dependent. The prevalence of congestive heart failure, cancer, and

Table 20.1 Rates of pulmonary embolism and relative risk in hospitalized patients with COPD. n/N(%) Age group (yrs)

PE, COPD

PE, No COPD

Relative risk

20–39

5,500/846,000 (0.65)

313,000/257,457,000 (0.12)

5.34

40–59

67,000/9,700,000 (0.69)

653,000/190,519,000 (0.34)

2.02

60–79

226,000/35,057,000 (0.64)

1,238,000/236,328,000 (0.52)

1.23

80–99

82,000/12,789,000 (0.64)

479,000/105,099,000 (0.46)

1.41

All adults ≥20

381,000/58,392,000 (0.65)

2,684,000/789,403,000 (0.34)

1.92

PE, pulmonary embolism; COPD, chronic obstructive pulmonary disease; yrs, years. Reprinted from Stein et al. [3], with permission.

101


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Prevalence, risks, and prognosis of PE and DVT

Table 20.2 Rates of deep vein thrombosis and relative risk in hospitalized patients with COPD. n/N(%) Age group (yrs)

DVT, COPD

DVT, No COPD

Relative risk

20–39

8,000/846,000 (0.95)

952,000/257,457,000 (0.37)

2.56

40–59

98,000/9,700,000 (1.01)

1,749,000/190,519,000 (0.92)

1.10

60–79

389,000/35,057,000 (1.11)

2,761,000/236,328,000 (1.17)

0.95

80–99

138,000/12,789,000 (1.08)

1,092,000/105,099,000 (1.04)

1.04

All adults ≥20

632,000/58,392,000 (1.08)

6,554,000/789,403,000 (0.83)

1.30

DVT, deep venous thrombosis; COPD, chronic obstructive pulmonary disease; yrs, years. Reprinted from Stein et al. [3], with permission.

stroke increased with age among patients who did not have COPD [3]. The relative risk of PE in patients with COPD, therefore, decreased with age because of such competing risk factors. In younger patients with COPD, however, comorbid conditions were uncommon in the control population, so the contribution of COPD to the risk of VTE was evident. Symptomatic DVT was found in 3 of 196 (1.5%) of patients hospitalized in a respiratory intensive care unit with an exacerbation of COPD [8]. Subclinical DVT was diagnosed in an additional 18 of 196 (9.2%) [8]. The prevalence of subclinical DVT in other studies of patients with an exacerbation of COPD, each with fewer than 60 patients, ranged from 0 to 45% [9–12]. The prevalence of PE in hospitalized patients throughout the United States with COPD (0.65%),

Table 20.3 Predisposing factors in patients with COPD and suspected acute PE.

6 Relative risk for PE with COPD

compared with the rate of diagnosis of PE in hospitalized patients with COPD, all of whom underwent diagnostic tests for PE, 25–29% [1, 2] indicates that PE in patients with COPD is generally underdiagnosed. The clinical features in 108 patients in PIOPED I who had COPD and were suspected of having PE were evaluated [13]. In patients with COPD, wheezing was less frequent and crackles were more frequent in patients with PE than in those with COPD who did not have PE. The predisposing factors, symptoms, other signs, chest radiographic findings, blood gases, and alveolar–arterial oxygen differences (gradients) did not differ to a statistically significant extent in patients with COPD who had PE compared with patients with COPD who did not have PE [13] (Tables 20.3–20.6,

PE,* No. (%)

No PE, No. (%)

(n = 21)

(n = 87)

Immobilization

9 (43)

36 (41)

Surgery

7 (33)

21 (24)

2

Thrombophlebitis, ever

3 (14)

5 (6)

1 ----------------------------------------------------------

Malignancy

2 (10)

12 (14)

Trauma, lower

1 (5)

7 (8)

Stroke

1 (5)

4 (5)

Estrogen

0 (0)

2 (2)

5 4 3

0

20−39

40−59

60−79

80−99

Age (years) Figure 20.1 Relative risk for pulmonary embolism (PE) in patients with chronic obstructive pulmonary disease (COPD) compared to patients the same decade of age hospitalized without COPD. (Reprinted from Stein et al. [3], with permission.)

extremities

All differences between PE and No PE were not significant. * Some patients had more than one predisposing factor. PE, pulmonary embolism; COPD, chronic obstructive pulmonary disease. Reprinted with permission from Lesser et al. [13].


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Table 20.4 Symptoms in patients with COPD and suspected acute PE.

Table 20.6 Chest radiographs: patients with COPD and suspected acute PE.

PE, No. (%)

No PE, No. (%)

PE, No. (%)

No PE, No. (%)

(n = 21)

(n = 87)

(n = 21)

(n = 87)

Dyspnea

19 (90)

80 (92)

Atelectasis

12 (57)

36 (41)

Cough

13 (62)

48 (55)

Effusion

10 (48)

31 (34)

Pleuritic pain

9 (43)

32 (37)

Volume loss

10 (48)

31 (34)

Leg swelling

9 (43)

23 (26)

Infiltrate

9 (43)

30 (33)

Wheezing

8 (38)

35 (40)

Elevated hemidiaphragm

6 (29)

18 (20)

Leg pain

4 (19)

13 (15)

Oligemia

4 (19)

16 (18)

Hemoptysis

4 (19)

7 (8)

Palpations

2 (10)

16 (18)

Angina-like pain

0 (0)

8 (9)

Figures 20.2 and 20.3). Changes of the alveolar–arterial oxygen gradients from prior values to values at the time of the suspected PE were no greater in those with PE than in those in whom PE was excluded [13] (Figure 20.4). Physicians, when confident of a low-probability clinical assessment, were usually correct in excluding

Table 20.5 Signs of acute PE in patients with COPD and suspected acute PE. PE, No. (%)

No PE, No. (%)

(n = 21)

(n = 87)

Crackles

17 (81)

46 (53)

Tachypnea (≥20/min)

15 (71)

71 (82)

Tachycardia (>100/min)

7 (33)

31 (36)

Wheezes

2 (10)

34 (39)

Deep vein thrombosis

2 (10)

9 (10)

Third heart sound

2 (10)

7 (8)

Diaphoresis

1 (5)

10 (11)

Temperature >38.5◦ C

1 (5)

7 (8)

Cyanosis

1 (5)

3 (3)

Increased pulmonary

0 (0)

11 (13)

component of second

Table 20.7 V–Q findings in 108 patients with COPD and suspected acute PE. V–Q scan probability

PE/total (%)

High

5/5 (100)

Intermediate

14/65 (22)

Low

2/33 (6)

Near normal/normal

0/5 (0)

Total

21/108 (19)

V–Q, ventilation perfusion; PE, pulmonary embolism; COPD, chronic obstructive pulmonary disease. Reprinted with permission from Lesser et al. [13].

75

PaCO2 (mm Hg)

All differences between PE and No PE were not significant. PE, pulmonary embolism; COPD, chronic obstructive pulmonary disease. Reprinted with permission from Lesser et al. [13].

All differences between PE and No PE were not significant. PE, pulmonary embolism; COPD, chronic obstructive pulmonary disease. Reprinted with permission from Lesser et al. [13].

NS

60 45 30 15 0 PE (n = 14)

heart sound Pleural friction rub

0 (0)

4 (5)

Homan’s sign

0 (0)

1 (1)

PE, pulmonary embolism; COPD, chronic obstructive pulmonary disease. Reprinted with permission from Lesser et al. [13].

NO PE (n = 57)

Figure 20.2 Partial pressure of carbon dioxide in arterial blood (PaCO2 ) while breathing room air in patients with pulmonary embolism (PE) and in patients in whom PE was excluded (No PE). The difference was not statistically significant (NS). (Reprinted with permission from Lesser et al. [13].)


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A-a gradient (mm Hg)

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225 200 175 150 125 100 75 50 25 0

Prevalence, risks, and prognosis of PE and DVT

NS

PE (n = 21)

NO PE (n = 83)

Figure 20.3 Alveolar–arterial (A-a) oxygen gradient among patients with pulmonary embolism (PE) and patients in whom PE was excluded (No PE). The difference was not statistically significant (NS). (Reprinted with permission from Lesser et al. [13].)

PE [correct in 29 of 30 (97%)] but physicians most often were uncertain of the diagnosis (67 patients) and rarely were confident of a high probability of PE (correct in 3 of 3) [13]. In patients with COPD, V–Q scans sometimes give diagnostic information, but less often than in those with no cardiopulmonary disease or cardiopulmonary disease exclusive of COPD [13, 14] (Table 20.7). Presumably, contrast enhanced CT is more likely to make or exclude the diagnosis of PE. The majority of ventilation–perfusion scans in patients with COPD, 60%, were interpreted as intermediate (indeterminate) probability for PE [13]. The cause of the perfusion defect, at least in patients with emphysema due to alpha-1

250

PE (n = 10)

250

A-a gradient (mm Hg)

A-a gradient (mm Hg)

150 100 50 0

antitrypsin deficiency, is destruction of the distal pulmonary arterial branches and capillary bed [15]. This is apparent on pulmonary angiograms and wedge angiograms of such patients, compared with the perfused capillary network of normal patients [15, 16] (Figures 20.5 and 20.6) (see normally perfused capillary network illustrated by wedge angiogram in Chapter 71).

NO PE (n = 41)

P < .01

NS 200

Figure 20.5 Pulmonary wedge arteriogram in a patient with emphysema associated with alpha-1 antitrypsin deficiency. There is diminished arborization of small pulmonary artery branches. (Reproduced with permission from Stein et al. [15].)

200 150 100 50 0

Pre Current

Pre

Current

Figure 20.4 Left: Alveolar–arterial (A-a) oxygen gradient among patients with pulmonary embolism (PE) who had both prior assessments and assessments at the time of the PE (current). Right: Prior and current values of A-a gradient among patients in whom PE was excluded. The A-a gradient increased in both, but the difference was not significant comparing those with PE and those who did not have PE. (Reprinted with permission from Lesser et al. [13].)


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PE and DVT in patients with COPD

(a)

(b)

Figure 20.6 (a) Pulmonary arteriogram in a patient with emphysema associated with alpha-1 antitrypsin deficiency. A diminished number of branches is shown in arteries of the lower lung zones. Capillary hypoperfusion in the lower zones shown on this film was confirmed in subsequent films. (Reproduced with permission from Stein et al. [15].) (b) Pulmonary wedge arteriogram in the same patient with emphysema associated with alpha-1 antitrypsin deficiency as shown in Figure 20.6a. There is a prominent reduction in the number of vessels branching from this artery. (Reproduced with permission from Stein et al. [15].)

References 1 Mispeleare D, Glerant JC, Audebert M et al. Pulmonary embolism and sibilant types of chronic obstructive pulmonary disease decompensations. Rev Mal Respir 2002; 19: 415–423. 2 Tillie-Leblond I, Marquette CH, Perez T et al. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med 2006; 144: 390– 396. 3 Stein PD, Beemath A, Meyers FA, Olson RE. Pulmonary embolism and deep venous thrombosis in hospitalized adults with chronic obstructive pulmonary disease. J Cardiovasc Med 2007 (in press). 4 Stein PD, Hull RD, Kayali F et al. Venous thromboembolism according to age: the impact of an aging population. Arch Intern Med 2004; 164: 2260– 2265. 5 Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism—the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 338s–400s. 6 Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 2006; 119(1): 60– 68. 7 Skaf E, Stein PD, Beemath A, Sanchez J, Bustamante MA, Olson RE. Venous thromboembolism in patients with ischemic and hemorrhagic stroke. Am J Cardiol 2005; 96(12): 1731–1733. 8 Schonhofer B, Kohler D. Prevalence of deep-vein thrombosis of the leg in patients with acute exacerbation of chronic obstructive pulmonary disease. Respiration 1998; 65: 173–177. 9 Erelel M, Cuhadaroglu C, Ece T, Arseven O. The frequency of deep venous thrombosis and pulmonary embolus in acute exacerbation of chronic obstructive pulmonary disease. Respir Med 2002; 96: 515–518. 10 Pek WY, Johan A, Stan S et al. Deep vein thrombosis in patients admitted for exacerbation of chronic obstructive pulmonary disease. Singapore Med J 2001; 42: 308–311. 11 Prescott SM, Richards KL, Tikoff G et al. Venous thromboembolism in decompensated chronic obstructive pulmonary disease. A prospective study. Am Rev Respir Dis 1981; 123: 32–36. 12 Winter JH, Buckler PW, Bautista AP et al. Frequency of venous thrombosis in patients with an exacerbation of chronic obstructive lung disease. Thorax 1983; 38: 605– 608. 13 Lesser BA, Leeper KV, Stein PD et al. The diagnosis of acute pulmonary embolism in patients with chronic


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obstructive pulmonary disease. Chest 1992; 102: 17– 22. 14 Stein PD, Terrin ML, Hales CA et al. Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no preexisting cardiac or pulmonary disease. Chest 1991; 100: 598–603.

15 Stein PD, Leu JD, Welch MH, Guenter CA. Pathophysiology of the pulmonary circulation in emphysema associated with alpha antitrypsin deficiency. Circulation 1971; 43: 227–239. 16 Stein PD. Wedge arteriography for the identification of pulmonary emboli in small vessels. Am Heart J 1971; 82: 618–623.

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CHAPTER 21

Pulmonary embolism and deep venous thrombosis in hospitalized patients with asthma

Asthma is not included among the recognized risk factors for pulmonary embolism (PE) or deep venous thrombosis (DVT) [1–3]. The association of PE with asthma had been described only in case reports [4, 5]. However, among 18,041,000 patients ≥20 years of age who were hospitalized with asthma from 1979 to 2003, based on data from the National Hospital Discharge Survey (NHDS), PE was diagnosed in 93,000 (0.51%) and DVT was diagnosed in 169,000 (0.93%). Venous thromboembolism (VTE) (PE and/or DVT) occurred in 242,000 (0.97%) (Stein et al., unpublished data from the National Hospital Discharge Survey). On average, the risk for PE in patients hospitalized with asthma was higher than the risk for PE in patients who did not have asthma (relative risk 1.21) (Stein et al., unpublished data from the National Hospital Discharge Survey). The relative risk was age-dependent (Figure 21.1). Among patients aged 20–39 years, the relative risk for PE was 2.58. Among patients aged

40–59 years, the relative risk for PE decreased to 1.31. The relative risk in older patients ranged from 0.86 to 1.21 (Stein et al., unpublished data from the National Hospital Discharge Survey) (Figure 21.1). The risk for DVT in patients hospitalized with asthma, on average, was not higher than the risk for DVT in patients who did not have asthma (relative risk 0.94) (Stein et al., unpublished data from the National Hospital Discharge Survey). However, the relative risk was higher in younger patients aged 20–39 years (relative risk 1.36) (Figure 21.2). These observations indicate that young adults hospitalized with asthma have a high risk for PE and DVT in comparison to hospitalized patients the same age who do not have asthma. With increasing age and its accompanying risk factors for PE and DVT, other risk factors balance or outweigh the risk of asthma alone. In older patients, therefore, a higher relative risk for VTE in patients with asthma is thereby eliminated.

2

2

1 ----------------------------------------------------------

0

20−39

40−59

60−79

80−99

Age (years) Figure 21.1 Relative risk for pulmonary embolism (PE) in hospitalized patients with asthma compared to patients who did not have asthma shown in relation to age. The relative risk was age-dependent.

Relative risk for DVT with asthma

Relative risk for PE with asthma

3

1 ----------------------------------------------------------

0

20−39

40−59

60−79

80−99

Age (years) Figure 21.2 Relative risk for deep venous thrombosis (DVT) in hospitalized patients with asthma compared to patients who did not have asthma shown in relation to age. The relative risk was higher in younger patients.

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References

3 Cohen AT. Venous thromboembolic disease management of the nonsurgical moderate- and high-risk patient. Semin Hematol 2000; 37: 19–22. 4 Labay Matias MV, Hervas Palazon J, Puges Bassols E, Perez Ferron J. [Status asthmaticus, adult respiratory distress syndrome and pulmonary vascular thrombosis]. An Esp Pediatr 1985; 22: 169–170. 5 Divac A, Djordjevic V, Jovanovic D et al. Recurrent pulmonary embolism in a patient with asthma. Respiration 2004; 71: 428.

1 Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 338S–400S. 2 Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160: 3415– 3420.

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CHAPTER 22

Deep venous thrombosis and pulmonary embolism in hospitalized patients with sickle cell disease

Nearly every component of hemostasis, including platelet function and the procoagulant, anticoagulant, and fibrinolytic states is altered in sickle cell disease (SCD) [1]. This has led to the view that SCD is a hypercoagulable state [1, 2]. Interactions among sickle erythrocytes, other blood cells, and the various matrix proteins that line the endothelium contribute to the multifactorial vaso-occlusive process [1]. Prior to our evaluation of the prevalence of deep venous thrombosis (DVT) in patients with SCD [3], DVT had been described only in case reports [4, 5]. Deep venous thrombosis is not included among the usual complications of SCD [6]. In past years, there may have been a reluctance to fully evaluate patients with SCD who had suspected DVT, because highosmolarity contrast material used for venograms had a potential for inducing sickling [7]. With the ready availability of venous ultrasound after 1991 [8], a definitive noninvasive diagnosis of DVT became possible in these patients. Among 1,804,000 patients hospitalized with SCD from 1979 to 2003, a discharge diagnosis of DVT was made in 11,000 (0.61%) [3]. From 1991 to 2003, when venous ultrasound was in general use, a somewhat higher percentage of patients hospitalized with SCD had DVT, 7800 of 1,107,000 (0.70%). Acute pulmonary embolism (PE) in patients with SCD is a more contentious issue than acute DVT. As would be expected with a hypercoagulable state, pulmonary thromboembolism occurs in SCD [9–11]. Its frequency, however, is undetermined, largely because of difficulties in distinguishing it from thrombosis in situ [10–13]. Pulmonary embolism has been documented in case reports of patients with SCD [14, 15],

and in 25% [16] and 60% [11] of autopsied patients with SCD. The distinction between PE and thrombosis in situ is particularly important in patients with SCD because both perhaps could be the cause of the acute chest syndrome (pulmonary infiltrates, fever, chest pain, and respiratory symptoms) in these patients. The acute chest syndrome is a leading cause of death in patients with SCD [17–19]. Even though pulmonary infarction occurs in 16% of patients with the acute chest syndrome [20], PE generally is not considered a cause [7]. The likely cause of pulmonary infarction in patients with SCD has been suggested to be thrombosis in situ [10, 12, 21]. Others suggested that engorge ment of the small pulmonary vessels, perhaps due to vasospasm and sickling, can produce pulmonary infarction in the absence of thrombosis of these vessels [22–24]. Whether acute PE is an initiating cause of the acute chest syndrome or whether recurrent PE leads to pulmonary hypertension in SCD has been an unsolved issue [9]. Imaging tests for PE were not obtained in a large study of causes of the acute chest syndrome in SCD [20]. Generally considered causes of the acute chest syndrome include infection, fat embolism, bone marrow embolism, fluid overload, hypoxemia, and vascular obstruction due to sickling and endothelial adherence of erythrocytes [7, 25]. Treatment of the acute chest syndrome includes antibiotics, oxygen, fluid management, respiratory therapy, pain management, bronchodilator therapy, and exchange transfusion [20]. Anticoagulant therapy is not included [20] and its role in the treatment of the acute chest syndrome is uncertain [7] or unconvincing [1, 26, 27]. Low doses of oral anticoagulants (average INR = 1.6) have been speculated to be a relevant form of therapy

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because low doses can normalize the hypercoaguable state in patients with SCD [13]. This presumes that PE is not an etiologic factor. However, once pulmonary hypertension occurs following the acute chest syndrome, PE contributes substantially to further morbidity and mortality [12]. Over the 25-year period from 1979 to 2003, a discharge diagnosis of PE was made in 9000 of 1,804,000 patients hospitalized with SCD. (0.50%) [3]. During this same period, among hospitalized African Americans who did not have SCD, 322,000 of 97,463,000 (0.33%) had a discharge diagnosis of PE. Approximately, 7000 of 9000 (78%) patients with SCD who had a discharge diagnosis of PE were <40 years of age. In patients <40 years old, 7000 of 1,581,000 (0.44%) with SCD had a discharge diagnosis of PE, whereas only 59,000 of 48,611,000 (0.12%) of African Americans without SCD had a discharge diagnosis of PE (Figure 22.1). The prevalence of DVT was similar in patients <40 years old with SCD, 7000 of 1,581,000 (0.44%) and in African Americans who did not have SCD, 193,000 of 48,611,000 (0.40%). The relatively high prevalence of apparent PE in patients with SCD, and the comparable prevalences of DVT in both groups are consistent with the possibility of thrombosis in situ. Thrombosis in situ, however, may not be the exclusive cause of pulmonary vascular occlusion in patients with SCD. If the prevalence of PE in SCD patients aged <40 years were the same as in non-SCD African Americans the same age, then 2000 of 1,581,000 (0.13%) of patients with SCD would be

expected to have PE. This accounts for 29% of the 7000 patients with SCD who had a discharge diagnosis of PE. Thrombosis in situ is limited to muscular pulmonary artery branches (<1 mm diameter) and arterioles [12] and cannot be identified by ordinary pulmonary angiography or CT pulmonary angiography. The smallest PE that have been identified in living patients were in 1–2-mm-diameter pulmonary artery branches [28]. These were shown with wedge pulmonary arteriography [28]. Based on pulmonary angiography, PE occurs in main, lobar, or segmental pulmonary arteries in 96% of patients [29]. In view of the fact that thrombosis in situ occurs only in muscular pulmonary arteries or arterioles, the demonstration of thrombi in elastic vessels (>1 mm diameter) is diagnostic of PE. To diagnose PE, an imaging study is required to show an intraluminal filling defect in an elastic artery (>1 mm). Standard pulmonary angiography and CT pulmonary angiography are the commonly used methods for imaging intraluminal filling defects. However, the risk of injection of radio-opaque contrast material requires assessment in view of evidence that ionic contrast material may induce sickling [30]. Whether nonionic contrast material carries the same risk is uncertain. The package insert of nonionic contrast material cautions against its use in patients with SCD [31]. Magnetic resonance angiography has been used in a few patients with PE and shows promise [32–34]. The package insert for gadopentetate dimeglumine, a magnetic resonance contrast agent, warns that deoxygenated sickle erythrocytes align perpendicular to a magnetic field in vitro [35]. This may result in vasoocclusive complications in vivo. Gadopentetate dimeglumine has not been studied in patients with SCD. A ventilation–perfusion lung scan would not contribute to the differentiation between thrombosis in situ and pulmonary thromboembolism. In patients with the acute chest syndrome, if DVT were present it would be reasonable to assume that venous thromboembolism occurred. Clinically apparent DVT, however, is present in only 11% of patients with acute PE [36]. A venous compression ultrasound would be useful if it were positive, but it lacks sensitivity for DVT in patients with suspected PE who do not have clinical evidence of DVT, being positive in only 29% [37]. Pulmonary thromboembolism is not rare in patients with SCD [3]. This raises the issue of whether

Hospitalized patients <age 40 with PE, DVT (%)

110

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

0.44

0.44 0.40

SCD

0.12 Af-Amer No SCD

PE

SCD AfAmer No SCD

DVT

Figure 22.1 Hospitalized patients younger than 40 years of age with sickle cell disease (SCD) who had a discharge diagnosis of pulmonary embolism (PE) or deep venous thrombosis (DVT) (light bars) compared with African Americans (Af-Amer) the same age who did not have SCD (dark bars). (Reprinted from Stein et al. [3], with permission from Elsevier.)

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Patients with sickle cell disease

PE might be an etiologic factor in patients with SCD who have the acute chest syndrome or pulmonary hypertension. In such patients, the risks of an imaging procedure need to be balanced with the advantage of proper diagnosis and treatment.

References 1 Ataga KI, Orringer EP. Hypercoagulability in sickle cell disease: a curious paradox. Am J Med 2003; 115: 721–728. 2 Francis RB, Jr. Platelets, coagulation, and fibrinolysis in sickle cell disease: their possible role in vascular occlusion. Blood Coagul Fibrinolysis 1991 2: 341–353. 3 Stein PD, Beemath A, Meyers FA, Skaf E, Olson RE. Deep venous thrombosis and pulmonary embolism in hospitalized patients with sickle cell disease. Am J Med 2006; 119: 897 e7–11. 4 Brion L, Dupont M, Fondu P, Rutsaert J. Sickle cell anemia and venous thrombosis. Acta Paediatr Belg 1978; 31: 241– 244. 5 Koren A, Zalman L, Levin C et al. Venous thromboembolism, Factor V Leiden, and methylenetetrahydrofolate reductase in a sickle cell anemia patient. Pediatr Hematol Oncol 1999; 16: 469–472. 6 Wang WC, Lukens JN. Sickle cell anemia and other sickling syndromes, In: Lee GR, Paraskevas S, Foerster J, Greer JP et al., eds. Wintrobe’s Clinical Hematology, 10th edn. Williams & Wilkins, Baltimore, 1999: 1346–1357. 7 Kirkpalrick MB, Haynes J. Sickle cell disease and the pulmonary circulation. Semin Respir Crit Care Med 1994; 15: 473–481. 8 Stein PD, Hull RD, Ghali WA et al. Tracking the uptake of evidence: two decades of hospital practice trends for diagnosing deep vein thrombosis and pulmonary embolism. Arch Intern Med 2003; 163: 1213–1219. 9 Serjeant GR. Sickle Cell Disease, 2nd edn. Oxford University Press, Oxford, UK, 1992: 184–187. 10 Moser KM., Shea JG. The relationship between pulmonary infarction, cor pulmonale and the sickle states. Am J Med 1957; 22: 561–579. 11 Oppenheimer EH, Esterly JR. Pulmonary changes in sickle cell disease. Am Rev Respir Dis 1971; 103: 858–859. 12 Adedeji MO, Cespedes J, Allen K, Subramony C, Hughson MD. Pulmonary thrombotic arteriopathy in patients with sickle cell disease. Arch Pathol Lab Med 2001; 125: 1436– 1441. 13 Walker B K, Ballas SK, Burka ER. The diagnosis of pulmonary thromboembolism in sickle cell disease. Am J Hematol 1979; 7: 219–232. 14 Maggi JC, Nussbaum E. Massive pulmonary infarction in sickle cell anemia. Pediatr Emerg Care 1987; 3: 30–32.

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15 Rubler S, Fleischer RA. Sickle cell states and cardiomyopathy. Sudden death due to pulmonary thrombosis and infarction. Am J Cardiol 1967; 19: 867–873. 16 Haupt HM, Moore GW, Bauer TW, Hutchins GM. The lung in sickle cell disease. Chest 1982; 81: 332–337. 17 Vichinsky E. Comprehensive care in sickle cell disease: its impact on morbidity and mortality. Semin Hematol 1991; 28: 220–226. 18 Castro O, Brambilla DJ, Thorington B et al. The acute chest syndrome in sickle cell disease: incidence and risk factors: the Cooperative Study of Sickle Cell Disease. Blood 1994; 84: 643–649. 19 Platt OS, Brambilla DJ, Rosse WF et al. Mortality in sickle cell disease: life expectancy and risk factors for early death. N Engl J Med 1994; 330: 1639–1644. 20 Vichinsky EP, Neumayr LD, Earles AN et al., for National Acute Chest Syndrome Study Group. Causes and outcomes of the acute chest syndrome in sickle cell disease. N Engl J Med 2000; 342: 1855–1865. 21 Durant JR, Cortes FM. Occlusive pulmonary vascular disease associated with hemoglobin SC disease. Am Heart J 1966; 71: 100–106. 22 Athanasou NA, Hatton C, McGee JO, Weatherall DJ. Vascular occlusion and infarction in sickle cell crisis and the sickle chest syndrome. J Clin Pathol 1985; 38: 659– 664. 23 Francis RB, Johnson CS. Vascular occlusive in sickle cell disease: current concepts and unanswered questions. Blood 1991; 77: 1405–1414. 24 Gladwin MT, Rodgers GP. Pathogenesis and treatment of acute chest syndrome of sickle-cell anaemia. Lancet 2000; 355: 1476–1478. 25 Minter KR, Gladwin MT. Pulmonary complications of sickle cell anemia. A need for increased recognition, treatment, and research. Am J Respir Crit Care Med 2001; 164: 2016–2019. 26 Collins FS, Orringer EP. Pulmonary hypertension and cor pulmonale in the sickle hemoglobinopathies. Am J Med 1982; 73: 814–821. 27 Barrett-Connor E. Pneumonia and pulmonary infarction in sickle cell anemia. JAMA 1973; 224: 997–1000. 28 Stein PD. Wedge arteriography for the identification of pulmonary emboli in small vessels. Am Heart J 1971; 82: 618–623. 29 Stein PD, Henry JW. Prevalence of acute pulmonary embolism in central and subsegmental pulmonary arteries and relation to probability interpretation of ventilation/perfusion lung scans. Chest 1997; 111: 1246– 1248. 30 Richards D, Nulsen FE. Angiographic media and the sickling phenomenon. Surg Forum 1971; 22: 403–404. 31 Optiray (Ioversol Injection). Mallinckrodt Inc., St. Louis, Missouri, September 2000.


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32 Meaney JFM, Weg JG, Chenevert TL et al. Diagnosis of pulmonary embolism with magnetic resonance angiography. N Engl J Med 1997; 336: 1422–1427. 33 Oudkerk M, van Beek EJ, Wielopolski P et al. Comparison of contrast-enhanced magnetic resonance angiography and conventional pulmonary angiography for the diagnosis of pulmonary embolism: a prospective study. Lancet 2002; 359: 1643–1647. 34 Gupta A, Frazer CK, Ferguson JM et al. Acute pulmonary embolism: diagnosis with MR angiography. Radiology 1999; 210: 353–359.

35 Magnevist Injection (Brand of Gadopentetate Dimeglumine). Berlix Laboratories, Wayne, New Jersey, May 2000. 36 Stein PD, Terrin ML, Hales CA et al. Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no preexisting cardiac or pulmonary disease. Chest 1991; 100: 598–603. 37 Turkstra F, Kuijer PM, van Beek EJ, Brandjes DP, ten Cate JW, Buller HR. Diagnostic utility of ultrasonography of leg veins in patients suspected of having pulmonary embolism. Ann Intern Med 1997; 126: 775–781.

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CHAPTER 23

Venous thromboembolism in pregnancy

Introduction

Trends in DVT according to age

Pulmonary venous thromboembolism in developed countries is one of the leading causes of maternal death [1–6]. Limited survey data from the United States, Denmark, and the United Kingdom have yielded conflicting findings as to whether venous thromboembolism associated with pregnancy is increasing or declining [3, 7–10]. We used the database of the National Hospital Discharge Survey, available at: http:// www.cdc.gov/nchs/about/major/hdasd/nhds.htm, to assess trends in venous thromboembolism during pregnancy [11].

The rate of pregnancy-associated DVT was higher among women aged 35–44 years than in younger women (Figure 23.2). On average, 91% of maternal patients were 15– 34 years of age (Figure 23.3). The percentage of deliveries in women 35–44 years of age increased over 21 years from 4.5 to 13.1% and the percentage of deliveries in younger women decreased proportionately (Figure 23.3).

Pregnancy-associated DVT according to race

Twenty-one-year trends in rate of diagnosis of deep venous thrombosis

Figure 23.1 Triennial rates of deep venous thrombosis (DVT) in women aged 15–44 years. (Reprinted from Stein et al. [11], with permission from Elsevier.)

Deep venous thrombosis/ 100,000/yr

Pregnancy-associated deep venous thrombosis (DVT) was diagnosed in 93,000 of 80,798,000 women (0.12%) from 1979 to 1999 [11]. The rate of pregnancyassociated DVT (vaginal delivery and cesarean section) increased from 1982–1984 to 1997–1999 (Figure 23.1). The rate of nonpregnancy-associated DVT decreased from 1979–1981 to 1991–1993. Thereafter, the rate of nonpregnancy-associated DVT remained constant.

The rate of pregnancy-associated DVT among black women was higher than among white women during 1979–1988 and 1989–1999 (Figure 23.4). The rate of pregnancy-associated DVT in both black women and white women increased from 1979–1988 to 1989– 1999. Higher rates of pregnancy-associated DVT in black women compared to white women have previously been observed [6, 12]. Higher rates of fatal pulmonary embolism (PE) have also been reported among black maternity patients [9].

200 Pregnancy-associated 150 100 Nonpregnancy-associated

50

0 1979−1981 1982−1984 1985−1987 1988−1990 1991−1993 1994−1996 1997−1999 Years

113


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Deep venous thrombosis/ 100,000/yr

PART I

Prevalence, risks, and prognosis of PE and DVT

350 300 250 200

35−44

150 100 50

25−34 15−24

Figure 23.2 Rates of pregnancy-associated deep venous thrombosis (DVT) according to decades of age, 1979–1988 to 1989–1999. (Data from Stein et al. [11].)

0 1979−1988

1989−1999 Years

The percentage of deliveries in black and white women remained constant over the 21-year period of observation (Figure 23.5). The rate of nonpregnancy-associated DVT was higher in black women than in white women (Figure 23.6). The rates of nonpregnancy-associated DVT decreased from 1979–1988 to 1989–1999 in both black and white women (Figure 23.6). The observation of a higher rate of DVT in black women in the nonmaternal population is compatible with our previous observation of an increased rate of DVT in age-matched blacks compared to whites [13, 14].

Pregnancy-associated DVT according to mode of delivery The rate of diagnosis of DVT following cesarean section and following vaginal delivery increased from 1979–1988 to 1989–1999 (Figure 23.7).

All deliveries (%)

100

The percentage of all cesarean section deliveries among women aged 15–34 years increased from 15.9% in 1979 to 22.6% in 1987. Thereafter, the rate decreased to 17.0% in 1999 (Figure 23.8). Among women aged 35–44 years, the percentage of all cesarean section deliveries increased linearly from 1.1% in 1979 to 3.9% in 1999 (Figure 23.8). Among all women who had cesarean sections, the proportion performed in women aged 35–44 years increased from 6.2% in 1979 to 18.7% in 1999 (Figure 23.9). Concordantly, the proportion of cesarean sections in women aged 15–34 years decreased.

Twenty-one-year trends in the rate of diagnosis of PE The rate of pregnancy-associated PE was lower than the rate of nonpregnancy-associated PE (Figure 23.10). However, the rate of pregnancy-associated DVT was higher than the rate of nonpregnancy-associated DVT.

15−34

50

35−44 0 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 Years

Figure 23.3 Proportion of deliveries according to age. Over the 21-year period of observation, deliveries in women 35–44 years of age increased. (Data from Stein et al. [11].)


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Figure 23.4 Rates of deep venous thrombosis (DVT) between 1979–1988 and 1989–1999 among black and white pregnancy-associated women. (Data from Stein et al. [11].)

Deep venous thrombosis/ 100,000/yr

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200 144

150

118 100

100 61 50 0 White

Black

1979−1988

White

Black

1989−1999

All deliveries (%)

100 White

50

Figure 23.5 The proportion of deliveries in black and white women. The proportions were constant over the 21-year period of observation. (Data from Stein et al. [11].)

Figure 23.7 Rates of DVT following cesarean section and vaginal delivery during 1979–1988 and 1989–1999. (Data from Stein et al. [11].)

0 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999

Deep venous thrombosis/ 100,000/yr

Years

200 150 100

70

55 50

57 30

0

White

Black

1979−1988 Deep venous thrombosis/ 100,000/yr

Figure 23.6 Rates of nonpregnancy-associated deep venous thrombosis (DVT) in black and white women. (Data from Stein et al. [11].)

Black

White

Black

1989−1999

120

104

80

63 47

40

29

0 Vaginal delivery

C-section

1979−1988

Vaginal delivery

C-section

1989−1999


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Prevalence, risks, and prognosis of PE and DVT

30 15 −34

20

10 35 −44 0 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 Years

The ratio of pregnancy-associated DVT to pregnancyassociated PE, 12.8, was higher than the ratio of nonpregnancy-associated DVT to nonpregnancyassociated PE, 2.9 (Figure 23.10). The reason for this difference is unknown and could reflect a difference of the natural history of DVT in pregnancy. It also could reflect a reluctance to expose pregnant women to ionizing radiation associated with imaging for PE resulting in a decreased frequency of diagnosis of PE. Our findings of an increasing rate of pregnancyassociated DVT in the United States [11] is in harmony with that observed in Denmark [7] where a similar upward trend was noted. The upward trend is concordant with reported findings in the United Kingdom for venous thromboembolism [3]. However, some reported a relatively constant rate of antepartum DVT and PE and a decreasing rate of postpartum PE [10]. Our observations support the impression held for many years that pregnancy predisposes to thromboembolism. The rate of pregnancy-associated DVT was twice the rate of nonpregnancy-associated DVT in women the same age [11]. A sixfold increase in the rate of thromboembolism during pregnancy and the

Figure 23.8 Cesarean sections, shown as a percentage of all deliveries according to age groups from 1979 to 1999. (Reprinted from Stein et al. [11], with permission from Elsevier.)

puerperium in comparison to nonpregnant women has been reported by others [15]. The reason for the diverging trends for the rates of diagnosis of pregnancy-associated DVT and nonpregnancy-associated DVT is not apparent. Analysis of covariance showed that age, race, and the percentage of deliveries by cesarean section did not explain the increasing rates of pregnancy-associated DVT over time. Although the percentage of deliveries in women aged 35–44 years increased over the 21-year period of observation, the increased risk of pregnancyassociated DVT was not limited to this age group. In fact, the greatest increase in rates of pregnancyassociated DVT was in younger women. Even though the rate of pregnancy-associated DVT was higher in black women than in white women, the percentage of deliveries in black women remained constant over the 21-year period of observation. Therefore, possible changes of racial characteristics of the maternal population would not explain the increasing rate of pregnancy-associated DVT. The proportion of deliveries by cesarean section decreased during most of the years that the rate of pregnancy-associated DVT was increasing (from 1987 to 1999). Therefore, the

Cesarean section (%)

100

15 −34

50

35 −44 0 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999

Years

Figure 23.9 Percentage of cesarean sections according to age from 1979 to 1999. (Data from Stein et al. [11].)


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Venous thromboembolism in pregnancy

150

Rate per 100,000/yr

11 5 100

49

50

17

9 Figure 23.10 Pregnancy-associated and nonpregnancy-associated deep venous thrombosis (DVT) and pulmonary embolism (PE) from 1979 to 1999. (Data From Stein et al. [11].)

0

percentage of deliveries by cesarean section could not explain the increasing rate of pregnancy-associated DVT. Increasing pregnancy-associated comorbidity due to acute and chronic medical conditions and comorbidity, which previously precluded conception may be co-factors, but this could not be assessed. Regarding nonpregnancy-associated DVT, a decreasing rate from 1973–1975 to 1988–1990 in the general population of women (pregnancy-associated and nonpregnancy-associated) was reported in women aged 15–44 years [16]. We observed the same trend during this time period in women of all ages, but from 1991 to 1999 the rate increased [14]. Our observations support the need for continued vigilance in the prevention of pregnancy-associated DVT. Further understanding is needed of the factors that contribute to this trend for an increasing rate of a potentially lethal condition in young healthy women.

References 1 Atrash HK, Koonin LM, Lawson HW, Franks AL, Smith JC. Maternal mortality in the United States, 1979–1986. Obstet Gynecol 1990; 76: 1055–1060. 2 Koonin LM, MacKay AP, Berg CJ, Atrash HK, Smith JC. Pregnancy-related mortality surveillance-United States, 1987–1990. MMWR 1997; 46: 17–36. 3 Department of Health, Welsh Office, Scottish Office Department of Health, Department of Health and Social Services, Northern Ireland. Why Mothers Die. Report

DVT

PE

Pregnancyassociated

4

5

6

7

8

9

10

11

12

DVT

PE

Nonpregnancyassociated

on Confidential Enquiries into Maternal Deaths in the United Kingdom, 1994–1996. 1998; Chapt 2. Hogberg U, Innala E, Sandstrom A. Maternal mortality in Sweden, 1980–1988. Obstet Gynecol 1994; 84: 240– 244. Berg CJ, Atrash HK, Koonin LM, Tucker M. Pregnancyrelated mortality in the United States, 1987–1990. Obstet Gynecol 1996; 88: 161–167. Rochat RW, Koonin LM, Atrash HK, Jewett JF. Maternal mortality in the United States: report from the Maternal Mortality Collaborative. Obstet Gynecol 1988; 72: 91– 97. Andersen BS, Steffensen FH, Sorensen HT, Nielsen GL, Olsen J. The cumulative incidence of venous thromboembolism during pregnancy and puerperium—an 11 year Danish population-based study of 63,000 pregnancies. Acta Obstet Gynecol Scand 1998; 77: 170–173. Macklon NS, Greer IA. Venous thromboembolic disease in obstetrics and gynecology: the Scottish experience. Scot Med J 1996; 41: 83–86. Franks AL, Atrash HK, Lawson HW, Colberg KS. Obstetrical pulmonary embolism mortality, United States, 1970–85. Am J Pub Health 1990; 80: 720–722. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ, 3rd. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005; 143: 697–706. Stein PD, Hull RD, Kayali F et al. Venous thromboembolism in pregnancy: 21 year trends. Am J Med 2004; 117: 121–125. Buehler JW, Kaunitz AM, Hogue CJR, Hughes JM, Smith JC, Rochat RW. Maternal mortality in women aged 35 years or older: United States. JAMA 1986; 255: 53–57.


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13 Stein PD, Hull RD, Patel KC et al. Venous thromboembolic disease: comparison of the diagnostic process in blacks and whites. Arch Intern Med 2003; 163: 1843–1848. 14 Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Meyers FA. Venous thromboembolic disease: comparison of the diagnostic process in men and women. Arch Intern Med 2003; 163: 1689–1694.

15 Anonymous. Oral contraception and thrombo-embolic disease. J R Coll Gen Pract 1967; 13: 267–279. 16 Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton, LJ, III. Trends in the incidence of deep vein thrombosis and pulmonary embolism. A 25-year population-based study. Arch Intern Med 1998; 158: 585–593.

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CHAPTER 24

Air travel as a risk for pulmonary embolism and deep venous thrombosis

Introduction Air travel was suggested to be a risk for deep venous thrombosis (DVT) and pulmonary embolism (PE) in 1954, presumably induced by stasis [1]. However, the entire gamut of risk factors for venous thromboembolism has been suggested to participate in the occurrence of venous thromboembolic disease (VTE) following air travel [2]. The possibility of VTE after travel is not unique to air travel, having been reported with various modes of transportation [1, 3, 4]. Prolonged periods in cramped quarters, irrespective of travel, can lead to PE [5]. The term “economy class syndrome” was introduced in 1988 [6], but has since been replaced with “flight-related DVT” in recognition of the fact that all travelers are at risk, irrespective of the class of travel [7]. Systematic review indicates that there is a strong and significant association between prolonged air travel and PE and DVT [8]. Those with preexisting risk factors for VTE were most vulnerable [8, 9]. Flight duration between 3 and 18 hours appears to be a risk for DVT [9–13] and fatal PE [14]. Among patients who died of PE during flight, 10 of 11 died during travel lasting 12–18 hours [14]. Among 6.58 million passengers who arrived at Sydney International Airport following travel of ≥9 hours duration, 17 passengers had acute PE upon arrival (2.6 PE/million travelers) [15] (Figure 24.1). Among passengers who arrived at Madrid-Barajas Airport, 15 of 9.07 million passengers (1.65/million passengers) who traveled ≥8 hours had acute PE on arrival [16]. Only 1 of 3.93 million passengers who traveled 6–8 hours (0.25 per million) had acute PE on arrival and 0 of 28.04 million passengers who traveled ≤6 hours had acute PE on arrival [16] (Figure 24.1).

In a prospective investigation of travelers who traveled ≥10 hours, 4 of 878 (0.5%) developed PE and 5 of 878 (0.6%) developed DVT [17]. In terms of distance traveled, among those who traveled >6200 miles, 4.8 passengers per million passenger arrivals required transfer to a hospital by a French emergency medical team for acute PE [18]. Among those who traveled 4650–6199 miles, 2.7 passengers per million passenger arrivals had acute PE. The proportion with acute PE decreased to 0.4 passengers per million passenger arrivals with 3100–4649 miles traveled, 0.1 acute PE passengers per million passenger arrivals with 1550–3099 miles traveled, and no acute PE with <1549 miles traveled [18]. Recent travel has shown a positive association with DVT and PE in some [19–21], but not all investigations [22, 23]. Among inpatients, 41 of 168 (24.4%) with DVT or PE reported recent travel >4 hours by plane compared with 12 of 160 (7.5%) with other illnesses [19]. Other patients with DVT reported long distance travel in 62 of 494 (12.6%), whereas only 31 of 494 (6.3%) patients who did not have DVT reported long distance travel [20]. Still others showed that 20 of 185 patients with DVT (10.8%) traveled >3 hours compared with 31 of 383 (8.1%) who did not have DVT [21]. Regarding studies that showed no association of VTE with travel, 9 of 186 (5%) patients with DVT traveled ≥3 hours by train, car, or boat within the past 4 weeks, whereas even a somewhat higher proportion with no DVT, 42 of 602 (7%) also traveled >3 hours [22]. Similarly, 14 of 198 (7.1%) patients with DVT traveled >3 hours during the past 4 weeks, whereas the same proportion, 44 of 615 (7.2%) with no DVT also traveled >3 hours during the past 4 weeks [23]. The positive reports suggest a contribution of travel to the risk of PE and DVT, but the apparently negative

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3 2.6 2.5 2 1.7 1.5 1 0.5 0

0.3 0 <6

≥8 6−8 Flight duration (hours)

studies failed to exclude a moderate effect because controls may have been identified, in part, by a history of recent travel [24].

Trials of prophylactic agents Elastic stockings appear to be effective in preventing flight-related DVT. Pooled data of randomized trials showed asymptomatic DVT, identified by screening with ultrasound, in 1 of 868 passengers (0.1%) who received elastic stockings and 38 of 883 passengers (4.3%) who received no prophylaxis [25–29]. Low-molecular-weight heparin, in small numbers of patients, also appeared to prevent DVT. No DVT was found in 84 passengers who received enoxaparin 1 mg/kg 2–4 hours before travel, whereas 4 of 82 (4.9%) untreated passengers developed DVT [30]. Aspirin, in small numbers of patients, was ineffective in preventing flight-related DVT. Among patients who received aspirin 400 mg/day for 3 days, starting 12 hours before travel, DVT (usually asymptomatic) developed in 3 of 84 (3.6%) versus 4 of 82 (4.9%) in controls [30].

Recommendations Recommendations of the American College of Chest Physicians for travel ≥6 hours are [31]. General measures (Clear risk/benefit, strong recommendation):

1 Avoid constrictive clothing around the lower extremities or waist. 2 Avoid dehydration.

≥9

Figure 24.1 Prevalence of pulmonary embolism (PE) per million passenger arrivals according to duration of flight. (Data from Hertzberg et al. [15] and Perez-Rodriguez et al. [16].)

3 Stretch calf muscles frequently. Specific measures:

1 Below knee graduated compression stockings providing 15–30 mm Hg at the ankle (Unclear risk/benefit, weak recommendation), or 2 Single prophylactic dose of low-molecularweight heparin injected prior to departure (Unclear risk/benefit, weak recommendation), 3 It is recommended that aspirin not be used (Clear risk/benefit, strong recommendation).

References 1 Homans J. Thrombosis of the deep leg veins due to prolonged sitting. N Engl J Med 1954; 250: 148–149. 2 Giangrande PL. Air travel and thrombosis. Br J Haematol 2002; 117: 509–512. 3 Symington IS, Stack BH. Pulmonary thromboembolism after travel. Br J Dis Chest 1977; 71: 138–140. 4 Tardy B, Page Y, Zeni F et al. Phlebitis following travel. Presse Med 1993; 22: 811–814. 5 Simpson K. Shelter deaths from pulmonary embolism. Lancet 1940; 2: 744. 6 Cruickshank JM, Gorlin R, Jennett B. Air travel and thrombotic episodes: the economy class syndrome. Lancet 1988; 2: 497–498. 7 Collins J. Thromboembolic disease related to air travel: what you need to know. Semin Roentgen 2005; 40: 1–2. 8 Ansari MT, Cheung BM, Qing Huang J, Eklof B, Karlberg JP. Traveler’s thrombosis: a systematic review. J Travel Med 2005; 12: 142–154. 9 Arfvidsson B. Risk factors for venous thromboembolism following prolonged air travel: a “prospective” study. Cardiovasc Surg 2001; 9: 158–159.


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10 Paganin F, Laurent Y, Gauzere BA, Blanc P, Roblin X. Pulmonary embolism on non-stop flights between France and Reunion Island. Lancet 1996; 347: 1195–1196. 11 Ribier G, Zizka V, Cysique J, Donatien Y, Glaudon G, Ramialison C. Venous thromboembolic complications following air travel. Retrospective study of 40 cases recorded in Martinique. Rev Med Interne 1997; 18: 601– 604. 12 Eklof B, Kistner RL, Masuda EM, Sonntag BV, Wong HP. Venous thromboembolism in association with prolonged air travel. Dermatol Surg 1996; 22: 637–641. 13 Mercer A, Brown JD. Venous thromboembolism associated with air travel: a report of 33 patients. Aviat Space Environ Med 1998; 69: 154–157. 14 Sarvesvaran R. Sudden natural deaths associated with commercial air travel. Med Sci Law 1986; 26: 35–38. 15 Hertzberg SR, Roy S, Hollis G, Brieger D, Chan A, Walsh W. Acute symptomatic pulmonary embolism associated with long haul air travel to Sydney. Vasc Med 2003; 8: 21–23. 16 Perez-Rodriguez E, Jimenez D, Diaz G et al. Incidence of air travel-related pulmonary embolism at the Madrid-Barajas airport. Arch Intern Med 2003; 163: 2766– 2770. 17 Hughes RJ, Hopkins RJ, Hill S et al. Frequency of venous thromboembolism in low to moderate risk long distance air travellers: the New Zealand Air Traveller’s Thrombosis (NZATT) study. Lancet 2003; 362: 2039–2044. 18 Lapostolle F, Surget V, Borron SW et al. Severe pulmonary embolism associated with air travel. N Engl J Med 2001; 345: 779–783. 19 Ferrari E, Chevallier T, Chapelier A, Baudouy M. Travel as a risk factor for venous thromboembolic disease: a casecontrol study. Chest 1999; 115: 440–444. 20 Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160: 3415–3420. 21 Arya R, Barnes JA, Hossain U, Patel RK, Cohen AT. Longhaul flights and deep vein thrombosis: a significant risk

22

23

24 25

26

27

28

29

30

31

only when additional factors are also present. Br J Haematol 2002; 116: 653–654. Kraaijenhagen RA, Haverkamp D, Koopman MM, Prandoni P, Piovella F, Buller HR. Travel and risk of venous thrombosis. Lancet 2000; 356: 1492–1493. Ten Wolde M, Kraaijenhagen RA, Schiereck J et al. Travel and the risk of symptomatic venous thromboembolism. Thromb Haemost 2003; 89: 499–505. Gallus AS, Goghlan DC. Travel and venous thrombosis. Curr Opin Pulm Med 2002; 8: 372–388. Belcaro G, Geroulakos G, Nicolaides AN, Myers KA, Winford M. Venous thromboembolism from air travel: the LONFLIT study. Angiology 2001; 52: 369–374. Scurr JH, Machin SJ, Bailey-King S, Mackie IJ, McDonald S, Smith PD. Frequency and prevention of symptomless deep-vein thrombosis in long-haul flights: a randomised trial. Lancet 2001; 357: 1485–1489. Belcaro G, Cesarone MR, Shah SS et al. Prevention of edema, flight microangiopathy and venous thrombosis in long flights with elastic stockings. A randomized trial: The LONFLIT 4 Concorde Edema-SSL Study. Angiology 2002; 53: 635–645. Cesarone MR, Belcaro G, Nicolaides AN et al. The LONFLIT4-Concorde–Sigvaris Traveno stockings in long flights (EcoTraS) study: a randomized trial. Angiology 2003; 54: 1–9. Cesarone MR, Belcaro G, Errichi BM et al. The LONFLIT4–Concorde deep venous thrombosis and edema study: prevention with travel stockings. Angiology 2003; 54: 143–154. Cesarone MR, Belcaro G, Nicolaides AN et al. Venous thrombosis from air travel: the LONFLIT3 study– prevention with aspirin vs low-molecular-weight heparin (LMWH) in high-risk subjects: a randomized trial. Angiology 2002; 53: 1–6. Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126: 338S–400S.


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CHAPTER 25

Estrogen-containing oral contraceptives and venous thromboembolism

Risks of venous thromboembolic disease in users of estrogen-containing oral contraceptives compared with nonusers Most preparations of estrogen-containing oral contraceptives consist of a mixture of estrogen and progesterone [1]. The US Food and Drug Administration in 1980 recommended the use of the lowest possible dose of estrogen for birth control [2]. In the past it had been thought that different types of progestins did not affect the risk of deep venous thrombosis (DVT) [3], but more recent data indicate that some third generation progestins have double the risk of second generation progestins [4]. In most countries, medications containing 50 μg of ethinyl estradiol or its equivalent are no longer available except as a shortterm postcoital medication [1]. Modern-day oral contraceptives contain 20–35 μg of ethinyl estradiol [5, 6]. Although the relative risk of VTE is higher among users of oral estrogen-containing contraceptives than nonusers [5, 7], the absolute risk is low [8]. Review by Vandenbroucke et al. [8] showed relative risks for VTE that, in general, ranged from 2.5 to 6.1 [9–12] although one study showed a relative risk of 11 [13]. A review by Lewis [5] of second and third generation estrogen-containing oral contraceptives, showed odds ratios that ranged from 0.8 to 2.3 [5, 9, 14–19]. Importantly, an absolute baseline risk <1/10,000 patients/ year increased to only 3 to 4/10,000 patients/year during the time oral contraceptives are being used [8]. Among 234,218 users of estrogen-containing oral contraceptives from 1980 to 1986, at doses that ranged from <50 μg/day to >50 μg/day, inpatient diagnoses of PE (pulmonary embolism) or DVT were

122

made in only 142 women (5.8/10,000 oral contraceptive users/year) [20]. Others, in women taking <50 μg/day of estrogen-containing contraceptives, reported VTE in 4.2/10,000 users/year [20], 4.7/10,000 [6] and 2.5/10,000 users/year [21]. Pooled data showed VTE in 127/417,915 patient-years (3.0/10,000 contraceptive users/year) [6, 20, 21]. Users of a patch designed to deliver 20 μg of ethinyl estradiol/day and 150 μg of norelgestromin/day over a period of 1 week [22] showed VTE in 4.1/10,000 users/year [21] and 5.3/10,000 users/year [6]. With earlier generation estrogen-containing oral contraceptives evaluated in 1961–1969, the incidence of DVT among users was higher than reported in recent years, 9 of 4965 (18/10,000), but higher rates were also reported among nonusers, 8 of 4933 (16/10,000) [23].

Relative risk in relation to dose The relative risk for VTE in women using oral contraceptives containing 50 μg of estrogen, compared with users of oral contraceptives that contained <50 μg was 1.5 [20]. The relative risk for VTE in women using oral contraceptives containing >50 μg of estrogen, compared with users of oral contraceptives that contained <50 μg was 1.7 [20]. No difference in the risk of VTE was found with various levels of low doses of 20, 30, 40, and 50 μg/day [3]. With doses of estrogen of 50 μg/day, the rate of VTE was 7.0/10,000 contraceptive users/year and with >50 μg/day, the rate of VTE was 10.0/10,000 oral contraceptive users/year [20] (Figure 25.1). Some, however, found no appreciable difference in the relative risk of VTE in relation to low or higher estrogen doses [11].


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VTE/10,000 estrogen users/yr

10.0 10 9 8 7 6 5 4 3 2 1 0

123

Estrogen-containing oral contraceptives and VTE

7.0

3.0

Relative risk of VTE (estrogen users vs. nonusers)

BLUK077-Stein

4 3.5 3 2.5 2 1.5 1 0.5 0

3.7

1.9 1.0

<20

1.2

21−25

26−30

>30

Body mass index (kg/m2) <50

50 Estrogen (μg/day)

>50

Figure 25.1 Venous thromboembolism (VTE) per 10,000 estrogen using patients per year according to daily dose. (Data from Gerstman et al. [20], Jick et al. [6] and Drug Safety Final Report [21]. Data with estrogen <50 μg/day were pooled.)

Relative risk according to duration of use Reports of risk of VTE in relation to the duration of use of oral contraceptives are inconsistent. Some showed relative risks increased as the duration of use of estrogen-containing oral contraceptives increased [13]. The relative risks were 0.7 in women who used oral contraceptives <1 year, 1.4 for those who used oral contraceptives 1–4 years and 1.8 in those who used it ≥5 years [13]. Others showed quite the opposite effect with a decreasing relative risk with duration of use [3]. The relative risk for DVT or PE was 5.1 with use <1 year, 2.5 with use 1–5 years, and 2.1 with use >5 years [3]. Finally, some showed the risk to be unaffected by the duration of use [11].

Estrogen-containing oral contraceptives in combination with smoking Users of oral contraceptives in Europe who smoked ≥10 cigarettes/day had odds ratios of 2.59 compared with users of oral contraceptives who did not smoke [11]. Users of oral contraceptives in developing countries who smoked ≥10 cigarettes/day had odds ratios of 1.22 compared with users of oral contraceptives who did not smoke [11]. Users of oral contraceptives who smoked <10 cigarettes/day did not have an increased risk of VTE compared to users of oral contraceptives who did not smoke [11].

Figure 25.2 Relative risk of venous thromboembolism (VTE) comparing estrogen users to nonusers shown in relation to body mass index (BMI). (Data from Lidegaard et al. [3].)

Estrogen-containing oral contraceptives and obesity The odds ratio for VTE comparing users of oral estrogen-containing oral contraceptives with matched nonusers of various body mass indexes (BMIs), showed that the combination of obesity with oral contraceptives carried a higher relative risk [3] (Figure 25.2). The World Health Organization reported higher odds ratios with oral contraceptives among women with BMIs >25 kg/m2 [11].

Estrogen-containing oral contraceptives and postoperative VTE The possibility of an increased risk of postoperative thromboembolism with oral contraceptive use was raised by Vessey et al. in 1970 [24]. The risk of postoperative PE appears to have increased in women who use oral contraceptives, even when the oral contraceptives have a low estrogen content [2]. In PIOPED, if PE was suspected, and if the women who underwent surgery used oral contraceptives, 50% had PE. If PE was suspected, and if the women who underwent surgery did not use oral contraceptives, 12% had PE [2].

References 1 Carter CJ. Epidemiology of venous thromboembolism. In: Hull RD & Pineo GF, eds. Disorders of Thrombosis. W. B. Saunders Co., Philadelphia, PA, 1996: 159–174. 2 Quinn DA, Thompson BT, Terrin ML et al. A prospective investigation of pulmonary embolism in women and men. JAMA 1992; 268: 1689–1696.


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3 Lidegaard O, Edstrom B, Kreiner S. Oral contraceptives and venous thromboembolism. A case–control study. Contraception 1998; 57: 291–301. 4 Tanis BC, Rosendaal FR. Venous and arterial thrombosis during oral contraceptive use: risks and risk factors. Semin Cardiovasc Med 2003; 3: 69–83. 5 Lewis MA. The epidemiology of oral contraceptive use: a critical review of the studies on oral contraceptives and the health of young women. Am J Obstet Gynecol 1998; 179: 1086–1097. 6 Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception 2006; 73: 223–228. 7 Realini JP, Goldzieher JW. Oral contraceptives and cardiovascular disease: a critique of the epidemiologic studies. Am J Obstet Gynecol 1985; 152: 729–798. 8 Vandenbroucke JP, Rosing J, Bloemenkamp KW et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344: 1527–1535. 9 Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589–1593. 10 Vessey M, Mant D, Smith A, Yeates D. Oral contraceptives and venous thromboembolism: findings in a large prospective study. BMJ (Clin Res Ed) 1986; 292: 526. 11 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case– control study. Lancet 1995; 346: 1575–1582. 12 Lewis MA, Heinemann LA, MacRae KD, Bruppacher R, Spitzer WO, The increased risk of venous thromboembolism and the use of third generation progestagens: role of bias in observational research. Transitional Research Group on Oral Contraceptives and the Health of Young Women. Contraception, 1996; 54: 5–13. [Erratum, Contraception 1996; 54: 121.] 13 Helmrich SP, Rosenberg L, Kaufman DW, Strom B, Shapiro S. Venous thromboembolism in relation to oral contraceptive use. Obstet Gynecol 1987; 69: 91–95. 14 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contracep-

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Prevalence, risks, and prognosis of PE and DVT

tion. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995; 346: 1582–1588. Spitzer WO, Lewis MA, Heinemann LA, Thorogood M, MacRae KD, for Transnational Research Group on Oral Contraceptives and the Health of Young Women. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case–control study. BMJ 1996; 312: 83–88. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a thirdgeneration progestagen. Lancet 1995; 346: 1593–1596. Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low oestrogen oral contraceptives. J Obstet Gynaecol 1995; 1: 13–20. Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349: 83–88. Herings RMC, de Boer A, Urquhart J, Leufkens HGM. Non-causal explanations for the increased risk of venous thromboembolism among users of third generation oral contraceptives [Abstract]. Pharmacoepidemiol Drug Saf 1996; 5(suppl 1): S88. Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol 1991; 133: 32–37. i3 Drug Safety Final Report. The risk of venous thromboembolism, myocardial infarction, and ischemic stroke among women using the transdermal contraceptive system compared to women using norgestimate-containing oral contraceptives with 35 μg of ethinyl estradiol. Prepared for Johnson and Johnson PRD, August 3, 2006. Abrams LS, Skee D, Natarajan J, Wong FA. Pharmacokinetic overview of Ortho EvraTM /EvraTM . Fertility Sterility 2002; 77(Suppl 2): S3–S12. Fuertes-de la Haba A, Curet JO, Pelegrina I, Bangdiwala I. Thrombophlebitis among oral and nonoral contraceptive users. Obstet Gynecol 1971; 38: 259–263. Vessey M, Doll R, Fairbain A, Glober G. Postoperative thromboembolism and the use of oral contraceptives. BMJ 1970; 3: 123–126.


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CHAPTER 26

Obesity as a risk factor in venous thromboembolism

Obesity was shown to be a risk factor for pulmonary embolism (PE) and deep venous thrombosis (DVT) [1]. Among hospitalized patients diagnosed with obesity, based on data from the National Hospital Discharge Survey (NHDS) [2], 91,000 of 12,015,000 (0.8%) had PE [1] (Figure 26.1). Among hospitalized patients who were not diagnosed with obesity, PE was diagnosed in 2,366,000 of 691,000,000 (0.3%). Deep venous thrombosis was diagnosed in 243,000 of 12,015,000 (2.0%) patients diagnosed with obesity, and in 5,524,000 of 691,000,000 (0.8%) who were not diagnosed with obesity. The relative risk of PE, comparing obese patients with non-obese patients, was 2.21 and for DVT it was 2.50 [1]. The relative risks for PE and DVT were agedependent (Table 26.1). Obesity had the greatest impact on patients <40 years of age, in whom the relative risk for PE in obese patients was 5.19 and the relative risk for DVT was 5.20 (Table 26.1) [1]. Obese females had a greater relative risk for DVT than obese males, 2.75 versus 2.02 [1]. The prevalence of both PE and DVT in hospitalized obese females was

PE, DVT (%)

2.5

DVT

2 2.0 1.5 PE

1

DVT PE

0.8

0.5 0

0.8

0.3 Non-obese

Obese

Figure 26.1 Pulmonary embolism (PE) and deep venous thrombosis (DVT) in hospitalized patients from 1979 to 1999 showing the prevalence in obese and non-obese patients. (Data based on Stein et al. [1].)

higher than in obese males (Figure 26.2). In females <40 years of age, the relative risk for DVT comparing obese to non-obese patients was 6.10. In males <40 years of age, the relative risk for DVT was 3.71. The proportion of hospitalized patients diagnosed with obesity was within a narrow range (1.4–2.4%) over the 21-year period of observation from 1979 to 1999, indicating consistency in the diagnostic process

Table 26.1 Relative risks of pulmonary embolism and deep venous thrombosis according to age among obese and non-obese patients. Obese vs. non-obese Pulmonary embolism Age groups

Relative risk

(95% CI)

Deep venous thrombosis Relative risk

(95% CI)

<40

5.19

(5.11–5.28)

5.20

(5.15–5.25)

40–49

1.94

(1.91–1.97)

2.13

(2.11–2.15)

50–59

1.25

(1.23–1.27)

1.67

(1.65–1.68)

60–69

1.42

(1.40–1.44)

1.88

(1.87–1.90) (1.87–1.91)

70–79

2.07

(2.04–2.10)

1.89

>80

3.15

(3.08–3.22)

2.16

(2.12–2.20)

All ages

2.21

(2.20–2.23)

2.50

(2.49–2.51)

Reprinted from Stein et al. [1], with permission from Elsevier.

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DVT

PE, DVT (%)

2.5 DVT

2 1.5 1 0.5 0

PE

PE

2.2

1.7

0.6 Obese male

0.8 Obese females

Figure 26.2 Pulmonary embolism (PE) and deep venous thrombosis (DVT) in hospitalized patients from 1979 to 1999 showing the prevalence in obese men and obese women. (Data based on Stein et al. [1].)

[1]. Previous investigators used several indices of obesity including a body mass index (BMI) >35 kg/m2 as well as BMI 30–35 kg/m2 [3], >30 kg/m2 [4, 5], BMI ≥29 kg/m2 [6], weight >20% of median recommended weight for height [3], and waist circumference ≥100 cm [7]. In 28–33% of patients reported by Anderson and associates, the physicians’ assessment was accepted [8, 9]. It is likely that all patients diagnosed with obesity in the NHDS database were in fact obese, irrespective of the criteria used. However, some obese patients may not have had a listed discharge diagnosis of obesity, and they would have been included in the non-obese group. This would have tended to reduce the relative risk of obesity in venous thromboembolism (VTE). The relative risks for PE and DVT were similar to relative risks reported in smaller investigations that used defined criteria for obesity. In women with a BMI >30 kg/m2 , the relative risk for DVT, compared to non-obese women was 2.4 [10]. In women with a BMI ≥29 kg/m2 , the relative risk for PE was 2.9 [6]. In the Framingham Study, obesity was a risk factor only in women [4]. Coon and Coller also showed that obesity was a risk factor only in women. Oral contraceptives in obese women increased the relative risk of DVT to 9.8 [10]. Men with a waist circumference ≥100 cm had a relative risk of 3.9 for VTE compared to men with smaller waists [7]. Among men and women together, the risk ratio for DVT, comparing obese to non-obese patients, was 2.39 [11]. Some found that obesity was not an independent risk factor for VTE [12]. Obesity has been suggested to be a risk factor for fatal PE since 1927 [13]. Investigations that reported an increased risk due to obesity have been criticized because they failed to control for hospital confinement

Prevalence, risks, and prognosis of PE and DVT

or other risk factors [12]. High proportions of patients with venous thromboembolic disease have been found to be obese [8, 9], but the importance of the association is diminished because of the high proportion of obesity in the general population [14]. Some investigations showed an increased risk ratio for DVT or PE, in women [4, 6, 10, 15], but data in men were less compelling. One investigation showed obesity to be a risk factor in men [7] and two did not [4, 15]. Some found no evidence that obesity was an independent risk factor in men or women [12]. Case series of morbidly obese patients (>100 pounds overweight or twice ideal weight) who underwent gastric bypass surgery, showed only a small incidence of postoperative VTE [5, 16]. Enoxaparin was shown to be effective for thromboprophylaxis in morbidly obese patients following bariatric surgery [17]. With various dosing regimens among 544 patients, PE occurred in 0.7% and none developed DVT [17]. All PE occurred after the cessation of enoxaparin, 7 days to 1 month after operation.

References 1 Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med 2005; 118: 978–980. 2 US Department of Health and Human Services, Public Health Service, National Center for Health Statistics National Hospital Discharge Survey 1979–1999 Multiyear Public-Use Data File Documentation. Available at: http://www.cdc.gov/nchs/about/major/hdasd/nhds.htm. 3 Farmer RD, Lawrenson RA, Todd JC et al. A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives. Br J Clin Pharmacol 2000; 49: 580–590. 4 Goldhaber SZ, Savage DD, Garrison RJ et al. Risk factors for pulmonary embolism. The Framingham Study. Am J Med 1983; 74: 1023–1028. 5 Printen KJ, Miller EV, Mason EE, Barnes RW. Venous thromboembolism in the morbidly obese. Surg Gynecol Obstet 1978; 147: 63–64. 6 Goldhaber SZ, Grodstein F, Stampfer MJ et al. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277: 642–645. 7 Hansson PO, Eriksson H, Welin L, Svardsudd K, Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: “the study of men born in 1913.” Arch Intern Med 1999; 159: 1886–1890. 8 Anderson FA, Jr, Wheeler HB, Goldberg RJ et al. A population-based perspective of the hospital incidence


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Obesity as a risk factor in VTE

and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933–938. Anderson FA, Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Forcier A. The prevalence of risk factors for venous thromboembolism among hospital patients. Arch Intern Med 1992; 152: 1660–1664. Abdollahi M, Cushman M, Rosendaal FR. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb Haemost 2003; 89: 493–498. Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160: 3415–3420. Heit JA, Silverstein MD, Mohr DN et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001; 86: 452–463.

127

13 Snell AM. The relation of obesity to fatal postoperative pulmonary embolism. Arch Surg 1927; 15: 237– 244. 14 Hedley AA, Ogden CL, Johnson CL et al. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 2004; 291: 2847–2850. 15 Coon WW, Coller FA. Some epidemiologic considerations of thromboembolism. Surg Gynecol Obstet 1959; 109: 487–501. 16 Kerstein MD, McSwain NE, Jr, O’Connell RC, Webb WR, Brennan LA. Obesity: is it really a risk factor in thrombophlebitis? South Med J 1987; 80: 1236–1238. 17 Hamad GG, Choban PS. Enoxaparin for thromboprophylaxis in morbidly obese patients undergoing bariatric surgery: findings of prophylaxis against VTE outcomes in bariatric surgery patients receiving enoxaparin (PROBE) study. Obesity Surg 2005; 15: 1368–1374.


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CHAPTER 27

Hypercoagulable syndrome

Inherited thrombophilia Patients with inherited thrombophilia (Table 27.1) tend to have clinical episodes of venous thromboembolism (VTE) before 45 years of age, and episodes tend to be recurrent [1].

Antithrombin III deficiency Antithrombin III is a naturally occurring anticoagulant that inactivates a number of enzymes in the coagulation cascade (factors IIa, IXa, Xa, XIa, and XIIa) (Figure 27.1). A diagram of the coagulation cascade is shown in Chapter 85, Figure 85.1. Antithrombin III deficiency is inherited as an autosomal dominant trait with heterozygotes having an increased risk of VTE [2]. There are two types of antithrombin III deficiency [3]. In type I deficiency, there is a reduction of functional antithrombin and in type II deficiency, there is an abnormal molecule [3]. Heterozygosity for antithrombin III deficiency is found in about 4% of families with inherited thrombophilia, in 1% of patients with a first episode of deep venous thrombosis (DVT), and

in 0.02% of healthy individuals [4] (Table 27.2). The prevalence of antithrombin III deficiency among patients with thrombosis (predominantly venous thrombosis) ranges from 0.5 to 8% [5]. Deep venous thrombosis, with or without pulmonary embolism was present in 90% of patients with antithrombin III deficiency [1]. Patients with antithrombin III deficiency have a 8â&#x20AC;&#x201C;10 times greater risk of developing thrombosis than individuals with normal coagulation [1, 6]. The antithrombinâ&#x20AC;&#x201C;heparin cofactor assay using a factor Xa and a thrombin inhibition assay are laboratory screening tests for this disorder. Since antithrombin III is a cofactor for heparin, heparin will not be effective in patients with antithrombin III deficiency [7]. In fact, heparin resistance may be an indication of antithrombin III deficiency [7].

Protein C deficiency Protein C deficiency is inherited as an autosomal dominant disorder and heterozygosity is a significant risk factor for VTE [8]. Two types of protein C deficiency have been reported [9]. Type I deficiency is a quantitative deficiency with decreased amounts protein C

Table 27.1 Inherited and acquired thrombophilic factors. Inherited thrombophilic factors Antithrombin III deficiency

Antiphospholipid syndrome

Protein C deficiency

Heparin induced thrombocytopenia

Protein S deficiency

Dysfibrinogenemia

Factor V Leiden

Myeloproliferative disorders

Prothrombin 20210A mutation

Malignancy

Elevated levels of factor VIII Elevated levels of factor XI Heparin cofactor II deficiency Dysfibrinogenemia Decreased levels of plasminogen Decreased levels of plasminogen activator Hyperhomocystenemia Sticky platelet syndrome

128

Acquired thrombophilic factors


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129

Hypercoagulable syndrome in VTE

XIIa

Tissue factor (TF) VIIa TF/VIIa complex

XIa

XI IX X

AT III IXa AT III

VIIIa Figure 27.1 Simplified coagulation cascade showing sites of action of antithrombin III (AT III). Deficiency of AT III results in failure to naturally inhibit the action of factors XIIa, XIa, IXa, Xa, and IIa.

activity due to reduced synthesis. Type II deficiency is a qualitative defect due to a defective protein C molecule [9]. Heterozygosity for protein C deficiency is found in about 6% of families with inherited thrombophilia, in 3% of patients with a first episode of unexplained DVT, and in 0.3% of healthy individuals [4] (Table 27.2). The prevalence of protein C deficiency among patients with thrombosis ranges from 1.5 to 11.5% [5]. Deep venous thrombosis, with or without pulmonary embolism was present in 88% of patients with protein C deficiency [1]. Patients with Protein C deficiency have a 4â&#x20AC;&#x201C;10 times greater risk of thrombosis as compared with control groups with normal coagulation [1, 6, 10]. The best screening tests for deficiencies of protein C are functional assays that detect both quantitative and qualitative defects of protein C. Immunologic assays detect only quantitative deficiencies of protein C [7]. Coagulation assays for protein C can give falsely low values if the factor V Leiden mutation is present, and as a result, the presence of factor V Leiden mutation should be assessed prior to application of coagulation assays for protein C. Short-term management of thrombosis among patients with protein C deficiency should be with heparin or low-molecular-weight heparin. A vitamin K antagonist such as warfarin should be considered for long-term treatment [7].

Xa IIa II prothrombin Va thrombin I fibrinogen

Ia fibrin

inadequate amount of normally functional protein S present in both the free and bound forms. Type II deficiency is a defective protein S molecule. Type III protein S deficiency is characterized by a low amount of free protein S, but an overall normal amount of total protein S. The large majority of patients with protein S deficiency have a type I deficiency, the prevalence of which is 6% in families with inherited thrombophilia and 1â&#x20AC;&#x201C;2% of patients with first time unexplained DVT [4] (Table 27.2). The prevalence of protein S deficiency among patients with thrombosis ranges from 1.5 to 13.2% [5]. Among patients with protein S deficiency, 74% develop DVT and 72% develop superficial thrombophlebitis [11]. Others reported DVT, with or without PE, to be present in 100% of patients with protein S deficiency [1]. Patients with protein S deficiency have an 8â&#x20AC;&#x201C;10 times higher risk of thrombosis compared with individuals with normal coagulation [1, 6]. As with protein C deficiency, the screening tests for protein S deficiency are functional assays that are most reliable when factor V Leiden mutation is ruled out. It is important to measure free protein S, since some patients with hereditary protein S deficiency may have normal or borderline total protein S levels. Treatment for protein S deficiency is the same as in protein C deficiency.

Protein S deficiency Protein S deficiency is inherited as an autosomal dominant disorder, with heterozygotes having an increased risk of VTE when compared with their unaffected family members [11]. There are three classifications of protein S deficiency. Type I deficiency results from an

Activated protein C resistance associated with factor V mutation (factor V Leiden) The Leiden mutation of factor V is the most common genetic abnormality associated with VTE. It is found in


130 —

6 — — — — — — —

Protein S deficiency

Factor V Leiden

Prothrombin 20210A mutation

Elevated factor VIII levels

Elevated factor XI levels

Heparin cofactor II deficiency

Dysfibrinogenemia

Malignancy

25

1–2

Prevalence of

10

25

6

20

1.5–13.2

1.5–11.5

0.5–8

unexplained VTE (%)

disorders in Pts with

* Prevalence of disorder among Caucasians in general population. Pts, patients; Gen’l, general; DVT, deep venous thrombosis; VTE, venous thromboembolism.

Antiphospholipid syndrome

Acquired thrombophilic factors

Hyperhomocystenemia

6

3

4

1

DVT (%)

Protein C deficiency

thrombophilia (%)

Antithrombin III deficiency

Inherited thrombophilic factors

Thrombophilic disorders

Patients with first episode of

family members with

5–10

2* 11*

— 5*

0.3

0.02

population (%)

disorders in Gen’l

Prevalence of

15–50

29–55

10

36

6

57

74–100

88

90

disorder (%)

VTE with

Frequency of

2

11

2.5

2.2

5–6

2.8

2–8

8–10

4–10

8–10

VTE

risk For

Relative

[38, 39]

[33–35]

[7, 10, 13, 23]

[22]

[21]

[10, 19]

[10, 13, 16]

[3, 10, 13]

[1, 10, 13]

[1, 4, 6, 11]

[1, 4, 6, 10]

[1, 4, 6]

References

April 6, 2007

Incidence of disorder among

Table 27.2 Incidence of various thrombophilic disorders and associated venous thromboembolism.

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Hypercoagulable syndrome in VTE

Tissue factor (TF)

XIIa

VIIa TF/VIIa complex

XI

XIa IX

IXa

X VIIIa

Figure 27.2 Simplified coagulation cascade showing the involvement of factor V Leiden in the coagulation pathway. Activated factor V Leiden is resistant to inhibition by activated protein C.

about 5% of Caucasians, but is extremely rare in people of African and Asian descent [7, 12, 13]. Factor V Leiden is an autosomal dominant condition in which the mutated factor V is resistant to inactivation by activated protein C (Figure 27.2). About 4â&#x20AC;&#x201C;7% of the general population is heterozygous for factor V Leiden and about 0.06â&#x20AC;&#x201C;0.25% of the population is homozygous for factor V Leiden [1] (Table 27.2). The prevalence of factor V Leiden among patients with unexplained venous thrombosis is 20% [13]. Deep venous thrombosis, with or without pulmonary embolism, was present in 57% of patients with factor V Leiden mutations [1]. Patients with factor V Leiden mutation presented with a 2- to 8-fold increase risk of thrombosis compared with individuals with normal coagulation [1, 10]. The relative risk of thrombosis for carriers was shown to have increased 7-fold for heterozygotes and 80-fold for homozygotes among patients <70 years of age with no malignancy [14]. One way to test for the factor V Leiden mutation is to measure the plasma clotting time in the absence and presence of activated protein C [3]. Newer versions of this test can be performed when patients are receiving anticoagulants [15]. The most direct test for factor V Leiden is DNA testing (polymerase chain reactionbased test) [3].

Prothrombin 20210A mutation The prothrombin 20210A allele is due to a glycine-toarginine transition in position 20210 of the prothrombin gene [3]. The abnormal gene causes increased concentrations of prothrombin. It is thought that the increased amount of circulating prothrombin upreg-

Xa Va Leiden II prothrombin

V Leiden Activated protein C

IIa thrombin

I fibrinogen

Ia fibrin

ulates the coagulation cascade [3]. The prevalence of prothrombin 20210A mutation among Caucasians in the general population is 2% [13]. About 6.2% of patients with the prothrombin 20210A gene mutation had venous thrombosis [3, 10, 13]. The diagnosis of prothrombin 20210A is based entirely on DNA analysis of the genes since it is the only genetic coagulation defect that cannot be reliably diagnosed by functional or immunological tests [3].

Elevated factor VIII levels The prevalence of elevated factor VIII levels among Caucasians in the general population is 11% [13]. Patients with high levels of factor VIII (>1500 IU/L) had a 5-fold increase risk for thrombosis when compared to patients with lower levels of factor VIII (<1000 IU/L) [16]. Among patients presenting with an initial episode of unexplained DVT, 25% had factor VIII levels above 1500 IU/L [10, 13]. For every 100 IU/L rise in levels of factor VIII, the risk for a single episode of DVT increased 10% and the risk for recurrent DVT increased 24% [17]. Factor VIII may be increased during an acute illness [18]. A C-reactive protein level should therefore be measured to determine if the increase of factor VIII is likely to be an acute phase reactant [18]. Pregnancy and use of oral contraceptives may also raise levels of factor VIII [7].

Elevated factor XI levels Increased levels of factor XI, a component of the intrinsic pathway, has been implicated as a risk factor for VTE [19]. A 120.8% increase in levels of factor XI


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PART I

was associated with a 2.2-fold increased risk of venous thrombosis [10, 19].

Disorders of plasmin generation

Heparin cofactor II deficiency Heparin cofactor II, also known as heparin cofactor A or dermatan sulfate cofactor, inhibits thrombin by forming a heparin cofactor II-thrombin complex [20]. The physiologic function of the molecule is unclear, but it may serve as a natural antithrombotic agent in the presence of dermatan sulfate. Inherited deficiency of heparin cofactor II is rare. It is inherited as an autosomal dominant trait. Limited studies have shown that heterozygosity for heparin cofactor II deficiency is not a likely risk for thrombosis without other concomitant risk factors [21]. Some, however, have reported thrombotic episodes in 36% of individuals with the deficiency [21].

Inherited dysfibrinogenemias A number of abnormal fibrinogens are associated with the hypercoagulable syndrome of dysfibrinogenemias. Ten percent of patients with dysfibrinogenemias develop venous thrombosis with arterial thrombosis being rare [22]. Hereditary dysfibrinogenemias is an autosomal dominant trait except for a few cases that appear to be recessive traits [22]. The thrombin time (TT) is the most sensitive screening test for dysfibrinogenemias. The thrombin time may be prolonged or shortened and reptilase time is also prolonged. Patients with recurrent thrombotic events may require long-term anticoagulation with Coumadin or subcutaneous heparin [20].

Prevalence, risks, and prognosis of PE and DVT

Dysplasminogenemia, decreased levels of plasminogen, decreased synthesis or release of tissue plasminogen activator, and increased levels of plasminogen activator inhibitor are associated with impaired fibrinolysis (Figure 27.3). Routine screening is thought not to be cost-effective and is not indicated [20]. Long-term treatment is with warfarin or low-molecular-weight heparin [7].

Hyperhomocystenemia Elevated plasma homocysteine levels constitute a risk factor for venous as well as arterial thrombosis [23]. Some suggest that hyperhomocystenemia contributes to venous and arterial thrombosis by its toxic effect on the vascular endothelium and on the clotting cascade [23]. Hyperhomocystenemia occurs in 5â&#x20AC;&#x201C;10% of the general population [7] and in 10% of patients with VTE [13], with a relative risk of venous thromboembolism of 2.5 [10, 23]. Hyperhomocystenemia can be diagnosed by measuring fasting homocysteine plasma levels [15]. Hyperhomocysteinemia can also be diagnosed by fluorescence polarization immunoassays [24]. Thrombosis is treated in a standard fashion in addition to vitamin B6, B12, and folic acid supplementation [7].

Sticky platelet syndrome Sticky platelet syndrome is inherited in an autosomal dominant trait that results in platelets that are hyperaggregable to epinephrine and/or adenosine

Thrombin Fibrinogen

Fibrin

Plasmin

Plasminogen

PA inhibitor

tPA

Fibrin degradation products Figure 27.3 Fibrinolysis pathway. Dysplasminogenemia, decreased levels of plasminogen, decreased synthesis or release of tissue plasminogen activator (tPA), and increased levels of plasminogen activator inhibitor (PAI) contribute to the maintenance of fibrin, thereby promoting a hypercoagulable state.


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Hypercoagulable syndrome in VTE

phosphate [7]. Both arterial, and to a lesser-degree venous thrombi may occur in patients with sticky platelet syndrome [25]. Treatment is with either 81 mg or 325 mg aspirin daily [25]. If aspirin fails, an adenosine diphosphate receptor agonist such as clopidrogel, may be used [25].

Acquired thrombophilia The antiphospholipid syndrome Antiphospholipid antibodies are associated with both arterial and venous thrombosis [26]. The most commonly detected subgroups of antiphospholipid antibodies are lupus anticoagulant antibodies, anticardiolipin antibodies, and anti-B2 -glycoprotein I antibodies [27]. Increased expression and activity of tissue factor is mediated by antibodies against phospholipidbinding proteins present in endothelial cells or other cells. The antigen–antibody reaction releases tissue factor which initiates the coagulation cascade leading to the prothrombotic state [27–29]. The exact mechanism by which these antibodies induce the transduction signal to produce tissue factor are not yet clarified [28]. Primary antiphospholipid syndrome occurs in patients without clinical evidence of an autoimmune disease, whereas secondary antiphospholipid syndrome occurs in association with autoimmune diseases. Systemic lupus erythematosus (SLE) is the most common autoimmune disorder associated with the antiphospholipd syndrome [27]. Among patients with SLE who had the antiphospholipid antibodies, anticardiolipin antibodies were present in 12–30% [30, 31] and lupus anticoagulant antibodies were present in 15–34% [31, 32]. Deep venous thrombosis, the most common manifestation of the antiphospolipid syndrome, occurs in 29–55% of patients with the syndrome, and about half of these patients have pulmonary emboli [33–35]. The estimated relative risk for a first episode of venous thromboembolism in patients with a thrombophilic defect as compared to healthy individuals is 11 [6]. Arterial thrombosis is less common than venous thrombosis in patients with antiphospholipid syndrome [33– 35]. Since there is no definitive association between specific clinical manifestations and particular subgroups of antiphospholipid antibodies, and patients may be negative according to one test and positive for another,

multiple tests for antiphospholipid antibodies are recommended [27].

Heparin-induced thrombocytopenia In patients with heparin-induced thrombocytopenia, platelet activation occurs due to the binding of heparin to platelet factor 4. This forms a platelet– heparin complex that causes endothelial cell injury and activates tissue factor and the coagulation cascade [20, 36]. Thrombosis, either venous or arterial, occurs in about 20% of patients with heparininduced thrombocytopenia [20]. Platelet transfusion in patients with heparin-induced thrombocytopenia is contraindicated because in such patients intravascular platelet aggregation also occurs, thus further contributing to the thrombosis [20]. Management involves cessation of heparin and switching to alternative anticoagulant options.

Acquired dysfibrinogenemia Acquired dysfibrinogenemia occurs most often in patients with severe liver disease [22]. The impairment of the fibrinogen is due to a structural defect caused by an increased carbohydrate content impairing the polymerization of the fibrin, depending on the degree of abnormality of the fibrinogen molecule [22]. Screening tests and treatment are the same as with acquired dysfibrinogenemia.

Myeloproliferative disorders Polycythemia vera, essential thrombocytopenia, and agnogenic myeloid metaplasia are associated with thrombocytosis and an increase in whole blood viscosity [20], thereby contributing to the hypercoagulable state. These complications may result because of altered interactions between platelets, white blood cells, or endothelial cells, due to either altered receptor expression, receptor–ligand interactions, or signaling events. Thrombosis may occur in arteries or veins [37].

Malignancy Cancer is the second most common cause of hypercoagulability, accounting for 10–20% of spontaneous DVTS [7]. Approximately 15% of patients with cancer


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have clinical thombosis and up to 50% have thrombosis on autopsy [38]. The mechanism by which tumor cells contribute to thrombosis is not clear. It has been shown that tumor cells interact with thrombin and plasmin and directly influence thrombus formation [20]. Patients with malignancy have a 2-fold increase of developing venous thromboembolism [39].

Diagnostic approach to patients suspected of thrombophilia “Strongly” thrombophilic patients are those patients who sustained their first VTE event before 50 years of age, have a history of recurrent thrombosis, or have a first-degree relative with documented VTE events occurring before 50 years of age [40]. If one or more of these features are present, a complete evaluation for hereditary thrombophilia is appropriate [40]. Testing should be extended to their first-degree family members as well. Because most of the tests are not reliable during anticoagulation, it is preferable to postpone laboratory testing until after discontinuation of treatment [40].

References 1 Martinelli I, Mannucci PM, De Stefano V et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood 1998; 92: 2353–2358. 2 Thaler E, Lechner K. Antithrombin III deficiency and thromboembolism. Clin Haematol 1981; 10: 369–390. 3 Bertina RM. Factor V Leiden and other coagulation factor mutations affecting thrombotic risk. Clin Chem 1997; 43: 1678–1683. 4 Lane DA, Mannucci PM, Bauer KA et al. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76: 651–662. 5 Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism—results of the Spanish Multicentric Study on Thrombophilia (EMET-Study). Thromb Haemost 1997; 77: 444–451. 6 Weitz JI, Middeldorp S, Geerts W, Heit JA. Thrombophilia and new anticoagulant drugs. Hematology (Am Soc Hematol Educ Program) 2004: 424–438. 7 Thomas RH. Hypercoagulability syndromes. Arch Intern Med 2001; 161: 2433–2439. 8 Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briet E. Increased risk of venous thrombosis in carri-

PART I

9

10

11

12

13 14

15 16

17

18

19

20 21

22 23

24

Prevalence, risks, and prognosis of PE and DVT

ers of hereditary protein C deficiency defect. Lancet 1993; 341: 134–138. Reitsma PH, Bernardi F, Doig RG et al. Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995; 73: 876–889. Kamphuisen PW, Rosendaal FR. Thrombophilia screening: a matter of debate. Neth J Med 2004; 62: 180– 187. Engesser L, Broekmans AW, Briet E, Brommer EJ, Bertina RM. Hereditary protein S deficiency: clinical manifestations. Ann Intern Med 1987; 106: 677–682. Bounameaux H. Factor V Leiden paradox: risk of deepvein thrombosis but not of pulmonary embolism. Lancet 2000; 356: 182–183. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167–1173. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504–1508. Federman DG, Kirsner RS. An update on hypercoagulable disorders. Arch Intern Med 2001; 161: 1051–1056. Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152–155. Kraaijenhagen RA, in’t Anker PS, Koopman MM et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5–9. Cumming AM, Shiach CR. The investigation and management of inherited thrombophilia. Clin Lab Haematol 1999; 21: 77–92. Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342: 696–701. Nachman RL, Silverstein R. Hypercoagulable states. Ann Intern Med 1993; 119: 819–827. Adcock DM, Jensen R, Johns CS, Macy PA. Coagulation Handbook. Esoterix Coagulation, Aurora, Colorado, 2002: 25–27. Brick W, Burgess R, Faguet GB. Dysfibrinogenemia. WebMD. www.webmd.com. Last accessed June 26, 2006. den Heijer M, Koster T, Blom HJ et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759–762. Tripodi A, Negri B, Bertina RM, Mannucci PM. Screening for the FV:Q506 mutation–evaluation of thirteen plasmabased methods for their diagnostic efficacy in comparison with DNA analysis. Thromb Haemost 1997; 77: 436–439.


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25 Mammen EF. Sticky platelet syndrome. Semin Thromb Hemost 1999; 25: 361–365. 26 Greaves M. Antiphospholipid antibodies and thrombosis. Lancet 1999; 353: 1348–1353. 27 Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346: 752–763. 28 Amengual O, Atsumi T, Khamashta MA. Tissue factor in antiphospholipid syndrome: shifting the focus from coagulation to endothelium. Rheumatology (Oxford) 2003; 42: 1029–1031. 29 Ames PR. Antiphospholipid antibodies, thrombosis and atherosclerosis in systemic lupus erythematosus: a unifying ‘membrane stress syndrome’ hypothesis. Lupus 1994; 3: 371–377. 30 Merkel PA, Chang Y, Pierangeli SS, Convery K, Harris EN, Polisson RP. The prevalence and clinical associations of anticardiolipin antibodies in a large inception cohort of patients with connective tissue diseases. Am J Med 1996; 101: 576–583. 31 Cervera R, Khamashta MA, Font J et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore) 1993; 72: 113–124. 32 Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990; 112: 682–698.

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33 Asherson RA, Khamashta MA, Ordi-Ros J et al. The “primary” antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore) 1989; 68: 366– 374. 34 Alarcon-Segovia D, Perez-Vazquez ME, Villa AR, Drenkard C, Cabiedes J. Preliminary classification criteria for the antiphospholipid syndrome within systemic lupus erythematosus. Semin Arthritis Rheum 1992; 21: 275– 286. 35 Vianna JL, Khamashta MA, Ordi-Ros J et al. Comparison of the primary and secondary antiphospholipid syndrome: a European Multicenter Study of 114 patients. Am J Med 1994; 96: 3–9. 36 Arepally GM, Mayer IMM. Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin8. Blood 2001; 98: 1252–1254. 37 Kessler CM. Propensity for hemorrhage and thrombosis in chronic myeloproliferative disorders. Semin Hematol 2004; 41: 10–14. 38 Luzzatto G, Schafer AI. The prethrombotic state in cancer. Semin Oncol 1990; 17: 147–159. 39 Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 2006; 119: 60– 68. 40 Bauer KA. The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Intern Med 2001; 135: 367–373.


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Diagnosis of deep venous thrombosis

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CHAPTER 28

Deep venous thrombosis of the lower extremities: clinical evaluation

Physical examination remains the initial diagnostic modality that calls attention to the potential diagnosis and upon which physicians must rely. Only 13 of 32 patients (41%) with autopsy proven deep venous thrombosis (DVT) who died of trauma or burns were diagnosed antemortem, and 63 of 118 patients (53%) with autopsy proven DVT who died of pulmonary embolism (PE) had antemortem clinical signs of DVT [1, 2]. Among 37 legs of patients screened by 125 I fibrinogen scans, the clinical signs showed a similar sensitivity (49%) [3]. The specificity of clinical signs among 16 legs evaluated by venography was also low (56%), but these data are biased because patients were selected due to clinical findings [4]. In 12 extremities of patients with DVT shown by dissection at autopsy, the sensitivity of ankle asymmetry ≥1.27 cm was 83%, Homans’ sign was 8%, and local tenderness was 41% [5]. The specificity among 18 extremities of patients in whom DVT was excluded by dissection at autopsy for both ankle asymmetry and Homans’ sign was 94% and the specificity of local tenderness was 89% [5]. Homans’ sign is active and/or passive dorsiflexion of the foot associated with any of the following: (1) pain, (2) incomplete dorsiflexion (with equal pressure applied) to prevent pain, or (3) flexion of the knee to release tension in the posterior muscles with dorsiflexion [6]. A Homans’ sign was present in 44% of patients with DVT of the lower leg, and in 60% of patients with femoral venous thrombosis [7]. The elicitation of pain with inflation of a blood pressure cuff around the calf to 60–150 mm Hg has been recommended as a test for DVT [8]. This test, however, was not shown to be more helpful than the assessment of direct tenderness or leg circumference [7].

Calf asymmetry indicates a need for noninvasive diagnostic tests of the lower extremities to determine whether DVT is present [9]. Asymmetry of the circumference of the ankle, calf, or thigh ≥1 cm has been shown in 90% of patients with DVT, but such asymmetry was also shown in 92% of patients with suspected DVT in whom the diagnosis was excluded [10]. A difference ≥3 cm of calf circumference, however, was associated with a high likelihood of having DVT [11, 12]. A difference of circumference of the calves ≥1 cm, measured 10 cm below the tibial tuberosity, is abnormal [9] and was defined as a quantitative sign. As the difference of calf circumference increased from ≥1 cm to ≥4 cm, the sensitivity decreased from 43% or 53% to 4% or 10% and the specificity increased from 57–98% (Table 28.1, Figure 28.1) [13]. The sensitivity and specificity of signs of DVT in two different diagnostic categories of patients was assessed, the results of which gave an envelope of values [13]. The first diagnostic category was 350 patients from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED I) [14] with PE proven by pulmonary angiography. Deep venous thrombosis was assumed to be present based on the 83% and 91% incidence of DVT at autopsy of patients with PE [2, 15]. This category is advantageous for the investigation of the sensitivity of signs of DVT because more than 99% of these patients were identified on the basis of respiratory complaints associated with PE [16]. Although DVT was presumably present, the patients were not selected for evaluation because of signs of DVT in this diagnostic category. The second diagnostic category was 30 patients with suspected PE in PIOPED I in whom DVT was

139


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Diagnosis of DVT

Table 28.1 Calf asymmetry with deep venous thrombosis. Positive leg test

PE +, Assumed DVT

Negative leg test

Circum diff (cm)

sensitivity [N/n (%)]

sensitivity [N/n (%)]

specificity [N1 /n1 (%)]

≥1

16/30 (53)

149/350 (43)

27/47 (57)

≥2

8/30 (27)

59/350 (17)

41/47 (87)

≥3

4/30 (13)

23/350 (7)

45/47 (96)

≥4

3/30 (10)

13/350 (4)

46/47 (98)

N, number of patients with sign; n, number of patients with deep venous thrombosis; N1 , number of patients with no sign; n1 , number of patients with no deep venous thrombosis; Circum diff, circumference difference of calves. Stein et al. [13], and based on unpublished data from PIOPED I.

diagnosed by objective leg tests of the lower extremities. The advantage of this diagnostic category is that the diagnosis of DVT was made with confidence. The disadvantage is that many patients presumably had leg tests obtained because of clinical manifestations suggestive of DVT. This bias would increase the apparent sensitivity of clinical findings. However, among the entire group of patients in whom leg tests were performed (30 with DVT and 47 with no DVT) 48 of 77 (62%) had no qualitative signs of DVT, and 29 of 77 (38%) had no qualitative signs or measured asymmetry. Therefore, a significant number of patients were referred for objective leg tests only because they had a suspicion of PE. The individual qualitative signs of DVT (edema, erythema, calf tenderness, palpable cord, Homans’ sign) showed a sensitivity of 47% or less, irrespective of whether DVT was diagnosed by objective tests of the

lower extremities or whether it was assumed to be present in patients with PE (Table 28.2) [13]. Edema was the most sensitive sign. Unilateral edema was not statistically significantly more sensitive or specific than bilateral edema. All signs showed a specificity of 83% or higher (Table 28.2). The specificities of signs did not differ to a statistically significant extent. The presence of any sign (edema, erythema, calf tenderness, palpable cord, or Homans’ sign) or measured asymmetry of the calves increased the sensitivity for detection of DVT above the sensitivity of a physical sign alone or asymmetry alone (Table 28.3). The specificity varied inversely with the sensitivity [13]. The combination of a sign on physical examination (edema, erythema, calf tenderness, palpable cord, or Homans’ sign) plus ipsilateral asymmetry was associated with a sensitivity of 33% or lower, but the specificity was 87% or higher (Table 28.4). Among the

100

Sensitivity (%)

80

60

Leg test +

40

PE +

20 0 0

20

40

60

False positives (%)

80

100

Figure 28.1 Relation of sensitivity of measured calf asymmetry to the frequency of false-positive findings. The upper curve (leg test +) shows data of patients in whom objective tests of the lower extremities showed deep venous thrombosis (DVT) to be present or absent. The lower curve (PE +) shows data of patients in whom DVT was estimated to be present because of pulmonary embolism (PE). The numbers indicate the measured difference of calf circumference. (Data from Stein et al. [13], based on unpublished data from PIOPED I.)


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Table 28.2 Signs of deep venous thrombosis. Positive leg test

PE +, Assumed DVT

Negative leg test

Sign

sensitivity [N/n (%)]

sensitivity [N/n (%)]

specificity [ N1 /n1 (%)]

Edema, any

14/30 (47)

79/350 (23)

40/47 (85)

Edema, unilat

30/350 (9)

43/47 (91)

Edema, bilat

49/350 (14)

44/47 (94)

21/350 (6)

43/47 (91)

Erythema

5/30 (17)

Calf tender

5/30 (17)

47/350 (13)

39/47 (83)

Palp cord

0/30 (0)

8/350 (2)

46/47 (98)

Homan’s sig

1/30 (3)

9/350 (3)

44/47 (94)

Unilat, unilateral; bilat, bilateral; N, number of patients with sign; n, number of patients with deep venous thrombosis; N1 , number of patients with no sign; n1 , number of patients with no deep venous thrombosis. Stein et al. [13], and based on unpublished data from PIOPED I.

Table 28.3 Signs of deep venous thrombosis and/or calf asymmetry. Sign +/or circum

Positive leg test

PE +, Assumed DVT

Negative leg test

diff (cm)

sensitivity [N/n (%)]

sensitivity [N/n (%)]

specificity [N1 /n1 (%)]

Any sign +/or ≥1 cm

24/30 (80)

192/350 (55)

23/47 (49)

Any sign +/or ≥2 cm

20/30 (67)

131/350 (37)

33/47 (70)

Any sign +/or ≥3 cm

19/30 (63)

111/350 (32)

35/47 (74)

Any sign +/or ≥4 cm

18/30 (60)

104/350 (30)

35/47 (74)

N, number of patients with sign; n, number of patients with deep venous thrombosis; N1 , number of patients with no sign; n1 , number of patients with no deep venous thrombosis; circum diff, circumference difference of calves. Stein et al. [13], and based on unpublished data from PIOPED I.

Table 28.4 Ipsilateral signs of deep venous thrombosis and calf asymmetry. Sign and circum

Positive leg test

PE +, Assumed DVT

Negative leg test

diff (cm)

sensitivity [N/n (%)]

sensitivity [N/n (%)]

specificity [N1 /n1 (%)]

Any sign and ≥1

10/30 (33)

52/350 (15)

41/47 (87)

Any sign and ≥2

5/30 (17)

27/350 (8)

43/47 (91)

Any sign and ≥3

3/30 (10)

11/350 (3)

45/47 (96)

Any sign and ≥4

2/30 (7)

8/350 (2)

46/47 (98)

N, number of patients with sign; n, number of patients with deep venous thrombosis; N1 , number of patients with no sign; n1 , number of patients with no deep venous thrombosis; circum diff, circumference difference of calves. Stein et al. [13], and based on unpublished data from PIOPED I.


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Figure 28.2 Relation of sensitivity of combinations of qualitative signs and measured calf asymmetry to the frequency of false-positive findings. The upper curve (leg test +) shows data of patients in whom objective tests of the lower extremities showed deep venous thrombosis (DVT). The lower curve (PE +) shows data of patients in whom DVT was estimated to be present because of pulmonary embolism (PE). The numbers indicate the measured difference of calf circumference. Sign +/or asym indicates patients who had a qualitative sign and/or asymmetry. Sign + ipsi asym indicates patients who had a qualitative sign plus ipsilateral asymmetry. (Data from Stein et al. [13], based on unpublished data from PIOPED I.)

3–10% of patients who had one or more qualitative signs plus ≥3 cm calf asymmetry, the specificity for DVT was 96% [13]. Among patients in whom DVT was diagnosed by objective leg tests, signs of DVT or measured asymmetry showed a higher sensitivity than in patients in whom DVT was estimated to be present because of PE (Figure 28.2) [13]. If either a qualitative sign or measured asymmetry was present, the presence of one or both was more sensitive than a qualitative sign plus measured asymmetry. The former, however, showed more false-positive values than patients with qualitative signs and ipsilateral measured calf swelling. As the measured difference of calve circumferences increased from ≥1 cm to ≥4 cm in combination with qualitative signs, the sensitivity diminished, and the presence of false-positive values also diminished. Among patients with DVT diagnosed by objective leg tests, 2 of 30 (7%) had leg pain, but no qualitative signs or asymmetry ≥1 cm. An additional 1 of 30 (3%) reported swelling in the leg or foot, but had no leg pain, qualitative signs, or asymmetry ≥1 cm. The sensitivity for the detection of DVT of one or more symptoms, qualitative signs, or asymmetry ≥1 cm was 27 of 30 (90%). Among patients with DVT estimated to be present on the basis of PE, the addition of symptoms of tenderness or swelling to the qualitative or quantitative signs increased the sensitivity for the detection of DVT to 229 of 350 (65%) [13]. The addition of symptoms of tenderness or swelling to qualitative signs or measured asymmetry ≥1 cm

decreased the specificity of one or more of any of these findings to 18 of 47 (38%) [13]. These data show, therefore, that combinations of qualitative signs and measured asymmetry of the calves do not reliably identify patients with DVT, nor does the absence of such signs exclude DVT. However, in patients who have ≥3 cm asymmetry of the calves, the finding is 96% specific [13]. Meta-analysis identified covariates that provided diagnostic accuracy for DVT. Only malignancy and previous DVT were useful for ruling in DVT and recent immobilization, difference in calf diameter, and recent surgery were of borderline value [17]. The positive likelihood ratios [18] ranged from 1.76 to 2.71 indicating that none provided high certainty for a diagnosis [17]. Only absence of calf swelling and absence of a difference in calf diameter were somewhat (borderline) useful for ruling out DVT [17]. The negative likelihood ratios were 0.67 and 0.57 [17].

References 1 Sevitt S, Gallagher N. Venous thrombosis and pulmonary embolism: a clinico-pathological study in injured and burned patients. Br J Surg 1961; 48: 475–489. 2 Byrne JJ, O’Neil EE. Fatal pulmonary emboli. A study of 130 autopsy-proven fatal emboli. Am J Surg 1952; 83: 47–49. 3 Milne RM, Gunn AA, Griffiths JMT, Ruckley CX. Postoperative deep venous thrombosis: a comparison of diagnostic techniques. Lancet 1971; 2: 445–447. 4 Johnson WC. Evaluation of newer techniques for the diagnosis of venous thrombosis. J Surg Res 1974; 16: 473–481.


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5 McLachlin J, Richards T, Paterson JC. An evaluation of clinical signs in the diagnosis of venous thrombosis. Arch Surg 1962; 85: 738–744. 6 Homans J. Disease of the veins. N Engl J Med 1944; 231: 51–60. 7 DeWeese JA, Rogoff SM. Phlebographic patterns of acute deep venous thrombosis of the leg. Surgery 1963; 53: 99– 108. 8 Lowenberg RI. Early diagnosis of phlebothrombosis with aid of a new clinical test. JAMA 1954; 155: 1566–1570. 9 Stein PD, Henry JW, Gopalakrishnan D, Relyea B. Asymmetry of the calves in the assessment of patients with suspected acute pulmonary embolism. Chest 1995; 107: 936–939. 10 Cranley JJ, Canos AJ, Sull WJ. The diagnosis of deep venous thrombosis: fallibility of clinical symptoms and signs. Arch Surg 1976; 111: 34–36. 11 Lambie JM, Mahaffy RG, Barber DC, Karmody AM, Scott MM, Matheson NA. Diagnostic accuracy in venous thrombosis. BMJ 1970; 2: 142–143. 12 Nypaver TJ, Shepard AD, Kiell CS, McPharlin M, Fenn N, Ernst CB. Outpatient duplex scanning for deep vein thrombosis: parameters predictive of a negative study result. J Vasc Surg 1993; 18: 821–826.

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13 Stein PD, Henry JW, Relyea B. Sensitivity and specificity of physical examination of the lower extremity in evaluation of deep venous thrombosis. Unpublished data from PIOPED I. 14 A Collaborative Study by the PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA 1990; 263: 2753–2759. 15 Short DS. A survey of pulmonary embolism in a general hospital. BMJ 1952; 1: 790–796. 16 Stein PD, Saltzman HA, Weg JG. Clinical characteristics of patients with acute pulmonary embolism. Am J Cardiol 1991; 68: 1723–1724. 17 Goodacre SG, Sutton AJ, Sampson FC. Meta-analysis: the value of clinical assessment in the diagnosis of deep venous thrombosis. Ann Intern Med 2005; 143: 129– 139. 18 Jaeschke R, Guyatt GH, Sackett DL, for The EvidenceBased Medicine Working Group. Users’ guides to the medical literature. III. How to use an article about a diagnostic test. B. What are the results and will they help me in caring for my patients? JAMA 1994; 271: 703– 707.


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CHAPTER 29

Clinical model for assessment of deep venous thrombosis

Scoring systems for deep venous thrombosis Recognizing the difficulty in making a clinical diagnosis of acute deep venous thrombosis (DVT), a clinical model was developed which permits an assessment of the clinical probability [1] (Table 29.1). An earlier model with more features had been developed by the same group [2]. Although it gave good results, it was more complex and seems to have been abandoned. A clinical model for assessment of probability of DVT may be particularly useful when combined with another test, such as D-dimer. This will be discussed in Chapter 32.

Table 29.1 Clinical model for assessment of probability of deep venous thrombosis. Feature Active cancer (treatment ongoing or within

Score 1

previous 6 months or palliative) Paralysis, paresis, or recent immobilization of lower

1

extremities Recently bedridden >3 days or major surgery within

1

4 weeks Localized tenderness along the deep venous system

1

Entire leg swollen

1

Calf swelling >3 cm compared with the

1

asymptomatic leg (measured 10 cm below tibial tuberosity) Pitting edema (greater in the symptomatic leg) Collateral superficial veins (non-varicose) Alternative diagnosis as likely or greater than that

1 1 −2

of deep vein thrombosis High probability ≥3; moderate probability 1–2; low probability ≤0. In patients with symptoms in both legs, the more symptomatic leg is used. Based on data from Wells et al. [1].

144

Positive predictive values of the Wells test in patients with suspected DVT are shown in Table 29.2. Among patients with a low probability Wells test, DVT was shown in 3–13% [1–7] (Table 29.2). Among patients with a high probability assessment by the Wells test, DVT was present in 38–75%. Review of the Wells test in a meta-analysis of 22 studies showed that 11% of patients with a low probability Wells score had DVT [8], A low Wells score markedly reduced the probability of DVT (negative likelihood ratio 0.25 [8]. In this meta-analysis, 56% of patients with a high probability Wells score had DVT. A high Wells score markedly increased the probability of DVT (positive likelihood ratio 5.2) [8]. Risk stratification was more accurate for proximal DVT than for distal DVT [8]. Empirical assessment showed that in patients with suspected DVT who had a low probability clinical assessment, DVT was present in 1–13% [3, 5, 9] (Table 29.2, Figure 29.1). With a high probability clinical assessment, DVT was present in 63–100% [3, 5, 9]. In articles reviewed for a meta-analysis, 52% of patients with a high probability empirical assessment had DVT [8]. Meta-analysis showed that empirical assessment gave similar likelihood ratios as the Wells score, but there were a limited number of studies, and the confidence intervals were wide [8]. In patients with suspected DVT who had a low probability clinical assessment, DVT was present in 8% [8]. The Wells scoring system has been criticized because DVT is not entirely excluded in patients with a low score [6]. Resident physicians calculated a probability score for DVT that disagreed with senior staff in 30 of 165 patients (18%) [10]. Awareness of the subjective aspect of some parts of the Wells’ score was recommended before its implementation in clinical practice [10]. Putting this in perspective, the real value of the Wells score (and any clinical decision aid) is its ability to complement, rather than displace, physicians’


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Table 29.2 Positive predictive value of empirical assessment and clinical model for probability of deep venous thrombosis.

Method

First author [Ref]

Low probability

Intermediate probability

High probability

[DVT/ N (%)]

[DVT/ N (%)]

[DVT/ N (%)]

Empirical

Cornuz [5]

11/86 (13)

30/127 (24)

41/65 (63)

Empirical

Perrier [9]

3/29 (1)

56/291 (19)

52/54 (96)

Empirical

Miron [3]

1/78 (1)

30/166 (18)

26/26 (100)

15/193 (8)

116/584 (20)

119/145 (82)

Wells [2]

16/301 (5)

47/143 (33)

72/85 (85) 34/46 (74)

Average Wells expanded Wells

Miron [3]

4/126 (3)

19/98 (19)

Wells

Wells [4]

5/50 (10)

14/71 (20)

22/29 (76)

Wells

Cornuz [5]

14/121 (12)

36/121 (30)

32/48 (67)

Wells

Odega [6]

61/507 (12)

53/321 (17)

175/467 (38)

Wells

Kraaijn’n [7]

71/896 (8)

133/508 (26)

208/322 (65)

Wells

Wells [1]

10/39 (3)

32/193 (17)

53/71 (75)

165/1739 (9)

287/1312 (22)

524/983 (53)

Average

Figure 29.1 Pooled data showing prevalence of deep venous thrombosis (DVT) among patients with low, intermediate, and high probability (prob) assessments based upon empirical (empir) evaluation and upon the Wells scoring system. Data based on values shown in Table 29.2.

Deep vein thrombosis (%)

100

Empir 82%

75 Wells 53%

50

25

Empir Wells 8% 9%

Empir Wells 20% 22%

0 Low prob

empirical assessment [11]. The Wells score will classify the patient into a probability range that is probably correct, but it is up to the physician to apply clinical judgment to fine-tune this estimate of disease probability [11].

4

5

References 1 Wells PS, Anderson DR, Bormanis J et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: 1795–1798. 2 Wells PS, Hirsh J, Anderson DR et al. Accuracy of clinical assessment of deep-vein thrombosis. Lancet 1995; 345: 1326–1330. 3 Miron M-J, Perrier A, Bounameaux H. Clinical assessment of suspected deep vein thrombosis: comparison be-

6

7

Intermediate prob

High prob

tween a score and empirical assessment. J Intern Med 2000; 247: 249–254. Wells PS, Anderson DR, Bormanis J et al. Application of a diagnostic clinical model for the management of hospitalized patients with suspected deep-vein thrombosis. Thromb Haemost 1999; 81: 493–497. Cornuz J, Ghali WA, Hayoz D et al. Clinical prediction of deep venous thrombosis using two risk assessment methods in combination with rapid quantitative D-dimer testing. Am J Med 2002; 112: 198–203. Oudega R, Hoes AW, Moons KGM. The Wells rule does not adequately rule out deep venous thrombosis in primary care patients. Ann Intern Med 2005; 143: 100– 107. Kraaijenhagen RA, Piovella F, Bernardi E et al. Simplification of the diagnostic management of suspected deep vein thrombosis. Arch Intern Med 2002; 162: 907–911.


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8 Goodacre SG, Sutton AJ, Sampson FC. Meta-analysis: the value of clinical assessment in the diagnosis of deep venous thrombosis. Ann Intern Med 2005; 143: 129–139. 9 Perrier A, Desmarais S, Miron M-J et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet 1999; 353: 190–195.

PART II

Diagnosis of DVT

10 Bigaroni A, Perrier A, Bounameaux H. Is clinical probability assessment of deep vein thrombosis by a score really standardized? Thromb Haemost 2000; 83: 788–789. 11 Douketis JD. Use of clinical prediction score in patients with suspected deep venous thrombosis: two steps forward, one step back? Ann Intern Med 2005; 143: 140–142.


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CHAPTER 30

Clinical probability score plus single negative ultrasound for exclusion of deep venous thrombosis

Ultrasonography A clinical model that combines a pretest probability by a scoring system with compression ultrasonography is safe and feasible, and reduces the need for serial ultrasound testing [1]. The Wells point score system for assessment of probability of deep venous thrombosis (DVT) is shown in Chapter 29 [1]. A low probability score for DVT (score ≤0) in combination with a negative compression ultrasound of the lower extremities had a negative predictive value of 97.8–99.7% [1–4]

and an “unlikely” probability (score <2) had a negative predictive value of 98.3–98.9% [5, 6] (Table 30.1). A moderate clinical probability of DVT in combination with a negative ultrasound had a negative predictive value of 96.6–97.0% [1, 2] (Table 30.1). However, if the clinical probability by the point score system was high probability for DVT, a negative venous ultrasound could not be relied upon to exclude DVT. The negative predictive value of a high-probability clinical score and negative ultrasound, in small numbers of patients ranged from 71 to 73% [1, 2] (Table 30.1).

Table 30.1 Negative predictive value in patients with suspected deep vein thrombosis and negative ultrasound according to clinical assessment scores. First author [Ref]

Population

Negative predictive value (%)

Ultrasound negative and low probability or “unlikely” clinical score (Wells score)* Wells score ≤0 (low probability) Wells [2]

Hospitalized

45/46 (97.8)

Wells [1]

Outpatients

317/318 (99.7)

Kraaijenhagen [4]

Outpatients

821/834 (98.4)

Tick [3]

Outpatients

245/250 (98.0)

Wells score <2 (unlikely) Wells [5]*

Outpatients

264/267 (98.9)

Perrier [6]†

Outpatients

234/238 (98.3)

Wells [2]

Hospitalized

58/60 (96.7)

Wells [1]

Outpatients

161/166 (97.0)

Wells [2]

Hospitalized

5/7 (71.4)

Wells [1]

Outpatients

11/15 (73.3)

Wells score 1–2 (moderate probability)

Wells score ≥3 (high probability)

*Unlikely = Wells score <2. † Low or moderate probability. Low probability = Wells score ≤0; moderate probability = Wells score 1–2; high probability = Wells score ≥3.

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References 1 Wells PS, Anderson DR, Bormanis J et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: 1795–1798. 2 Wells P, Anderson D, Bormanis J et al. Application of a diagnostic clinical model for the management of hospitalized patients with suspected deep-vein thrombosis. Thromb Haemost 1999; 81: 493–497. 3 Tick LW, Ton E, van Voorthuizen T et al. Practical diagnostic management of patients with clinically suspected deep vein thrombosis by clinical probability test, compression

ultrasonography and D-dimer test. Am J Med 2002; 113: 630–635. 4 Kraaijenhagen RA, Piovella F, Bernardi E et al. Simplification of the diagnostic management of suspected deep vein thrombosis. Arch Intern Med 2002; 162: 907–911. 5 Wells PS, Anderson DR, Rodger M et al. Evaluation of Ddimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349: 1227–1235. 6 Perrier A, Desmarais S, Miron MJ et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet 1999; 353: 190–195.


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D-dimer for the exclusion of acute deep venous thrombosis

The D-dimer assays in patients with suspected deep venous thrombosis (DVT) differ in sensitivity, specificity, and likelihood ratios from values in patients with suspected pulmonary embolism (PE) [1]. Values of sensitivity of the enzyme-linked immunosorbent assay (ELISA) and quantitative rapid ELISA assays are significantly superior to those for the quantitative latex, semiquantitative latex, and whole blood agglutination assays in patients with suspected DVT [1] (Figure 31.1). The quantitative rapid ELISA assay is more convenient than the conventional ELISA and it provides a high certainty for a negative diagnosis of DVT in patients with a low or intermediate clinical probability (but not high clinical probability) (Chapter 32).

Negative likelihood ratios of the quantitative rapid ELISA assay were 0.09, 0.10, and 0.08 in Tier 1, Tier 2, and Tier 3 studies (Tables 31.1 and 31.2). Tier 1 studies (20 investigations) compared an ELISA assay and at least one other D-dimer assay for exclusion of DVT [2–21] (Table 31.3). Tier 2 included the Tier 1 studies and 29 additional studies [22–50] that met all inclusion criteria (Table 31.4). Tier 3 combined 21 methodologically weaker studies [51–71] with the 49 Tier-2 studies. Negative likelihood ratios <0.1 generate large and often conclusive changes from pretest to posttest probability [72] providing high certainty for excluding DVT. As will be shown, combining a negative rapid ELISA with a low or moderate clinical probability for

Table 31.1 Deep vein thrombosis. Sensitivity

Specificity

Positive likelihood

Negative likelihood

(95% CI)

(95% CI)

ratio (95% CI)

ratio (95% CI)

ELISA

0.96 (0.91–1.00)

0.38 (0.28–0.48)

1.55 (1.32–1.81)

0.12 (0.04–0.33)

Quant rapid ELISA

0.96 (0.90–1.00)

0.44 (0.32–0.55)

1.70 (1.39–2.09)

0.09 (0.02–0.41)

Semiquant rapid ELISA

0.89 (0.81–0.98)

0.39 (0.28–0.50)

1.47 (1.21–1.78)

0.27 (0.12–0.60)

Qual rapid ELISA

0.93 (0.84–1.00)

0.47 (0.30–0.63)

1.75 (1.28–2.39)

0.15 (0.04–0.56)

Quant latex

0.85 (0.74–0.95)

0.66 (0.55–0.78)

2.49 (1.77–3.51)

0.24 (0.12–0.45)

Semiquant latex

0.78 (0.67–0.89)

0.66 (0.56–0.76)

2.30 (1.69–3.13)

0.33 (0.21–0.54)

Whole blood

0.87 (0.68–1.00)

0.83 (0.65–1.00)

4.97 (1.84–13.42)

0.16 (0.04–0.65)

ELISA

0.95 (0.91–0.99)

0.40 (0.32–0.49)

1.60 (1.39–1.83)

0.12 (0.05–0.29)

Quant rapid ELISA

0.96 (0.90–1.00)

0.44 (0.34–0.54)

1.71 (1.43–2.05)

0.10 (0.03–0.36)

Semiquant rapid ELISA

0.90 (0.83–0.98)

0.39 (0.29–0.50)

1.48 (1.24–1.78)

0.25 (0.12–0.55)

Qual rapid ELISA

0.93 (0.87–0.99)

0.46 (0.35–0.57)

1.73 (1.40–2.13)

0.15 (0.07–0.37)

Quant latex

0.86 (0.78–0.94)

0.61 (0.51–0.71)

2.20 (1.70–2.84)

0.23 (0.13–0.41)

Semiquant latex

0.79 (0.69–0.88)

0.66 (0.57–0.75)

2.33 (1.75–3.11)

0.32 (0.20–0.51)

Whole blood

0.86 (0.80–0.93)

0.67 (0.61–0.73)

2.62 (2.17–3.16)

0.20 (0.13–0.32)

Test Tier 1 analysis

Tier 2 analysis

Quant, quantitative; semiquant, semiquantitative; qual, qualitative. Modified and reprinted with permission from Stein et al. [1].

149


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Proportion

Proportion

PART II

Sensitivity

Specificity

Figure 31.1 Boxplots of sensitivity and specificity among the D-dimer assays for patients with suspected deep venous thrombosis (DVT). (Reprinted with permission from Stein et al. [1].)

DVT essentially rules out DVT (Chapter 32). However, a negative D-dimer does not reliably exclude DVT if the clinical probability is high (Chapter 32). Sensitivity and specificity for DVT according to various assays using a cutoff level of 500 ng/mL are shown

in Figure 31.1. In patients with DVT, the least variability for sensitivity was seen with the ELISA, qualitative rapid ELISA, and quantitative rapid ELISA assays. Limited data for sensitivity, specificity, and likelihood ratios were available for cutoff values of 250 ng/mL and


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Table 31.2 Deep vein thrombosis.

Test

Sensitivity

Specificity

Positive likelihood

Negative likelihood

(95% CI)

(95% CI)

ratio (95% CI)

ratio (95% CI)

Cutoff 500 ng/mL – Tier 3 analysis (all data) ELISA

0.94 (0.89–0.98)

0.43 (0.36–0.50)

1.65 (1.46–1.87)

0.15 (0.07–0.30)

Quant rapid ELISA

0.97 (0.92–1.00)

0.42 (0.32–0.52)

1.67 (1.42–1.97)

0.08 (0.02–0.38)

Semiquant rapid ELISA

0.91 (0.85–0.98)

0.43 (0.34–0.52)

1.60 (1.37–1.88)

0.21 (0.10–0.42)

Qual rapid ELISA

0.93 (0.87–0.99)

0.53 (0.43–0.64)

1.99 (1.60–2.48)

0.13 (0.06–0.32)

Quant latex

0.88 (0.80–0.95)

0.59 (0.49–0.69)

2.14 (1.68–2.73)

0.21 (0.12–0.38)

Semiquant latex

0.78 (0.69–0.87)

0.70 (0.62–0.78)

2.60 (1.95–3.46)

0.31 (0.21–0.47)

Whole blood

0.82 (0.76–0.89)

0.70 (0.64–0.76)

2.77 (2.27–3.38)

0.25 (0.18–0.36)

Cutoff 250 ng/mL – All studies meeting inclusion criteria ELISA

NA

NA

NA

NA

Quant rapid ELISA

0.98

0.39

1.58

0.07

Semiquant rapid ELISA

0.92

0.56

2.10

0.14

Qual rapid ELISA

NA

NA

NA

NA

Quant Latex

0.91

0.53

1.96

0.16

Semiquant latex

0.91

0.47

1.73

0.19

Whole blood

0.88

0.66

2.57

0.18

Cutoff 1000 ng/ml – All studies meeting inclusion criteria ELISA

0.90

0.72

3.21

0.14

Quant rapid ELISA

0.93

0.58

2.23

0.13

Semiquant rapid ELISA

0.94

0.57

2.19

0.11

Qual rapid ELISA

NA

NA

NA

NA

Quant latex

0.81

0.70

2.73

0.27

Semiquant latex

0.73

0.78

3.35

0.34

Whole blood

0.88

0.66

2.57

0.18

Quant, quantitative; semiquant, semiquantitative; qual, qualitative. Modified and reprinted with permission from Stein et al. [1].

1000 ng/mL for some but not all of the D-dimer assays (Table 31.2). A negative D-dimer has highest negative predictive values in populations with a low prevalence of DVT. The negative predictive value of the quantitative rapid ELISA for exclusion of acute DVT was estimated based on a sensitivity of 96% and specificity of 44% (Tier 1 and Tier 2 studies), knowing the prevalence of DVT in the population tested. The prevalence of DVT in the included investigations of D-dimer ranged from 20 to 78% (average 36%) [1]. If the prevalence of DVT in the population tested were 36%, the negative predictive value of a negative quantitative rapid ELISA would be 95%. If the prevalence of DVT were 20%, the neg-

ative predictive value would be 98%. If the prevalence of DVT were 78%, the negative predictive value would be only 75% (Figure 31.2). A negative D-dimer may be useful for the exclusion of recurrent DVT as well as the exclusion of a suspected first episode of DVT [73]. The reliability of a negative D-dimer for the exclusion of DVT is highest in populations with a low prevalence of DVT and limited when the prevalence is high. Non-ELISA assays should not be used as stand-alone tests [74] given their inferior sensitivity and negative likelihood ratio values. However, in patients with a low clinical probability, non-ELISA assays provide a reasonable certainty for ruling out DVT [1].


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Table 31.3 Patients with suspected DVT.

Study

Year

D-dimer type

Cutoff analyzed (ng/mL)

No. Pts enrolled

Patients with DVT (%)

1989

ELISA,

<500

56

37.5

<500

100

45.0

<500

97

40.2

<500

116

29.3

<500

32

78.1

Quant rapid ELISA,

<500

100

40.0

semiquant rapid ELISA,

<250 <500

114

42.1

ELISA,

<250

96

37.5

semiquant latex

<500

ELISA,

<500

171

43.9

Quant rapid ELISA,

<500

81

51.9

semiquant rapid ELISA,

<250

Tier 1 analysis Bounameaux [3]

semiquant latex Elias [6]

1990

ELISA, semiquant latex

Speiser [18]

1990

Quant rapid ELISA, qual latex

Boneu [2]

1991

ELISA, semiquant latex

Chang-Liem [4]

1991

Quant rapid ELISA, quant latex

Dale [5]

1994

quant latex Hansson [10]

1994

ELISA, quant latex, semiquant latex

Tengborn [19] Elias [7]

1994 1996

Quant rapid ELISA, semiquant rapid ELISA, qual rapid ELISA, semiquant latex Legnani [12]

1997

qual rapid ELISA, ELISA, quant latex, semiquant latex Mayer [15]

1997

Semiquant rapid ELISA, whole blood

<500

108

30.6

Escoffre-Barbe [8]

1998

ELISA,

<500

464

59.5

<250

180

33.3

99

39.4

97

39.2

177

20.3

99

50.5

quant latex Lindahl [14]

1998

Semiquant rapid ELISA, semiquant latex

Legnani [13]

˚ Wahlander [21]

1999

1999

Quant rapid ELISA,

<700

ELISA,

<155

quant latex

<70

Quant rapid ELISA,

≤ 500 ≤ 1000

semiquant rapid ELISA,

<500

Qual rapid ELISA, ELISA, semiquant latex Sadouk [16] van der Graaf [20]

2000 2000

Quant rapid ELISA,

<500

quant latex

<250

Quant rapid ELISA,

<500

semiquant rapid ELISA,

<1000

qual rapid ELISA,

<250

ELISA, quant latex, semiquant latex, whole blood (Continued )

152


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Table 31.3 Patients with suspected DVT (Continued ).

Study

Year

D-dimer type

Cutoff analyzed (ng/mL)

No. Pts enrolled

Patients with DVT (%)

Funfsinn [9]

2001

Quant rapid ELISA,

<500

106

44.3

108

25.0, 20.4, 26.9

113

43.4

ELISA, quant latex Shitrit [17]

Larsen [11]

2001

2002

Quant rapid ELISA,

<1000

quant latex,

<500

semiquant latex

<250

Quant rapid ELISA,

<500

semiquant rapid ELISA, quant latex

DVT, deep venous thrombosis; semiquant, semiquantitative; quant, quantitative; qual, qualitative. Modified and reprinted with permission from Stein et al. [1]. Table 31.4 Tier 2 analysis (Tier 2 includes Tier 1 and the following investigations).

Study

Year

D-dimer type

Cutoff analyzed (ng/mL)

No. Pts enrolled

Patients with DVT (%)

Van Bergen [47]

1989

ELISA

<250

239

24.7

de Boer [28]

1991

Qual latex

<200

33

63.6

Kroneman [39]

1991

Quant rapid ELISA

<268

239

24.7

Ibrahim [34]

1992

Semiquant latex

<250

85

45.9

Jossang [37]

1992

Semiquant latex

<500

69

53.6

Heijboer [33]

1992

ELISA

<300

474

12.2

Pini [45]

1993

Semiquant latex

<200

425

45.9

Wells [49]

1995

Whole blood

214

24.8

D’Angelo [27]

1996

Quant rapid ELISA

<500

103

21.4

<1000 Gavaud [30]

1996

ELISA

<370

80

32.5

Borg [23]

1997

ELISA

<500

76

42.1

Gauzzaloca [31]

1997

Qual rapid ELISA

<500

68

52.9

Jacq [35]

1997

Whole blood

50

48.0

Knecht [38]

1997

Quant latex

<500

154

38.3

Leroyer [42]

1997

Qual rapid ELISA,

<500

448

59.2

ELISA Khaira [37]

1998

Semiquant rapid ELISA

<500

79

36.7

Wijns [50]

1998

Quant rapid ELISA,

<1000

74

43.2

qual rapid ELISA,

<500

ELISA Aschwanden [22]

1999

Whole blood

343

24.2

Caliezi [26]

1999

ELISA

<500

106

44.3

Legnani [40]

1999

Quant latex

<230

92

38.0

Lennox [41]

1999

Whole blood

200

23.0

Lindahl [43]

1999

Quant latex

<700

236

43.2

Wells [48]

1999

Whole blood

150

26.0

Bradley [24]

2000

Semiquant rapid ELISA

<300

138

31.9

Farrell [29]

2000

Whole blood

198

8.1

Permpikul [44]

2000

Whole blood

65

66.2

Bucek [25]

2001

Quant latex,

<500

100

35.0

Harper [32]

2001

<250

235

21.7, 21.3

1739

24.4

whole blood Quant latex, whole blood ten Wolde [42]

2002

Whole blood

DVT, deep venous thrombosis; qual, qualitative; quant, quantitative; semiquant, semiquantitative. Modified and reprinted with permission from Stein et al. [1].

153


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154

PART II

Diagnosis of DVT

Negative predictive value (%)

100 98

95

80 75

60 40 20 0 20

36 Prevalence of DVT (%)

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Figure 31.2 Negative predictive value for deep venous thrombosis (DVT) of quantitative rapid ELISA shown in relation to prevalence of DVT in population studied. (Data from Stein et al. [1].)

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