Phlebological Review 2/2018

ISSN 1232-7174

2018; Vol. 26, 2

Official Journal of the Polish Society of Phlebology

Official Journal of the Polish Society of Phlebology

Founded in 1993 by Dr Tomasz Drążkiewicz Official Journal of the Polish Society of Phlebology

Editorial Staff Editor-in-Chief Honorary Editor-in-Chief Associate Editor

Marian Simka (Poland) Tomasz Drążkiewicz (Poland) Zbigniew Rybak (Poland)

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Biophysics in phlebology Fausto Passariello (Italy)

Endovascular treatment Marzia Lugli (Italy)

Laser & RF treatment Uldis Maurins (Latvia)

Leg ulcers & chronic wounds Zbigniew Rybak (Poland)

Lymphatic disorders Waldemar Olszewski (Poland)

MR imaging E. Mark Haacke (USA)

Thromboembolic disorders Evi Kalodiki (UK)

Ultrasonography Paolo Zamboni (Italy)

Vascular malformations Byung-Boong Lee (USA)

Venous disorders of the central nervous system Stefano Bastianello (Italy)

Venous & lymphatic disorders in tropical countries Surgical treatment of varicose veins Malay Patel (India) Arkadiusz Jawień (Poland) Dermatological disorders & Cosmetic treatment in phlebology Eberhard Rabe (Germany)

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contents 2/2018

Original paper

Venous thromboembolism awareness among medical students – intervention needed

Tomasz Urbanek, Maciej Wołkowski, Marcela Zembura, Jagoda Witkowska, Eliza Wojciechowska, Wacław Kuczmik

29

Original paper

Predictive value of plasma fibrinogen levels for outcome of aneurysmal subarachnoid haemorrhage during the first week of illness

36

Bartosz Sokół, Norbert Wąsik, Cathy Olczyk, Barbara Więckowska, Robert Juszkat, Roman Jankowski Review paper

A review of the risk of deep vein thrombosis in surgical and minimally invasive treatment of varicose veins Krzysztof Wołkowski, Tomasz Urbanek

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Abstracts

9th International Congress of Polish Society of Phlebology, Lublin, 21-23 June 2018

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In this issue‌ Dear Colleagues and Friends, In this issue of Phlebological Review you can read abstracts from the ninth congress of our Society, which took place in Lublin from 21st to 23rd June 2018.

There are also two original contributions: the first one on venous thromboembolism awareness among medical students, and the second on the predictive value of plasma fibrinogen in patients with subarachnoid haemorrhage.

Then there is a review paper on the risk of deep vein thrombosis after treatment for varicose veins.

I hope you enjoy your read.

Sincerely, Marian Simka, MD PhD Editor-in-Chief

Venous thromboembolism awareness among medical students – intervention needed Tomasz Urbanek1,2, Maciej Wołkowski3, Marcela Zembura3, Jagoda Witkowska3, Eliza Wojciechowska3, Wacław Kuczmik1 Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Medical University of Silesia, Katowice, Poland 2 European Centre of Phlebology, Katowice, Poland 3 Student research group of Students’ Scientific Society, Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Medical University of Silesia, Katowice 1

Abstract

Objectives: Venous thromboembolism (VTE) is one of the most common causes of death associated with cardiovascular diseases. Despite the relatively high incidence rate, awareness and access to information about VTE risk factors as well as knowledge concerning effective prevention possibilities remain limited, including among health care professionals. The aim of the study was to assess the knowledge and awareness concerning venous thromboembolism among students of the Medical University of Silesia.

Material and methods: The study was performed on a group of 400 medical students from the Medical University of Silesia in Katowice from years 3 to 6, recruiting 100 people from each of the clinical years. The study was conducted based on a survey which included 27 questions concerning knowledge of the definition of venous thromboembolism, pathogenesis, epidemiology, risk factors, symptoms and diagnostics related to this group of patients.

Results: The proper definition of venous thromboembolism was indicated by 60% of the respondents and the proper components of Virchow’s triad, which underlies the pathogenesis of deep vein thrombosis, were defined by 69%. The further question answers revealed that although the study programme includes venous thromboembolism, the knowledge of the students in the field of epidemiology, symptomatology and risk factors of this affliction is still limited.

Conclusions: According to the results of the study, it is advisable to take action, including educative effort, to increase the awareness of the future medical staff about problems related to VTE.

Original paper Phlebological Review 2018; 26, 2: 29–35 DOI: https://doi.org/10.5114/pr.2018.81009 Submitted: 27.05.2018 Accepted: 8.08.2018

Address for correspondence Tomasz Urbanek European Centre of Phlebology 13 D Fabryczna St. 40-635 Katowice, Poland e-mail: urbanek.tom@interia.pl

Key words: deep venous thrombosis, education, symptoms, venous thromboembolism.

Introduction Venous thromboembolism (VTE), which manifests itself as deep vein thrombosis (DVT) and/or pulmonary embolism (PE), still remains a significant problem of today’s medicine. Despite increasing knowledge within this area, VTE is one of the most underestimated issues of 21st century medicine. The estimated VTE incidence rate is 1-2/1000 people per year in the world’s population. In Poland, the estimated incidence of VTE is 5700 people annually [1].

Despite development of diagnostic methods, most cases of DVT remain unrecognized. It applies to both proximal DVT (popliteal vein, femoral vein, iliac vein and inferior vena cava), which is diagnosed only in

Phlebological Review 2018

50% of cases, and distal DVT, which is symptomatic and is diagnosed only in 20% of the subjects suffering from this disease [2]. The potential cause of this situation is frequent absence of the symptoms or the presence of non-specific symptoms which patients disregard and which are hard for doctors to clarify. In many cases pulmonary embolism, which is a result of migration of a thrombus from the lower limb and pelvis venous system, is the first diagnosed symptom of this disease.

It is crucial because it can result in a fatal embolism of the pulmonary artery. Embolic changes in image explorations of pulmonary arteries can affect up to 50% of patients with proximal DVT [2].

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Tomasz Urbanek, Maciej Wołkowski, Marcela Zembura, Jagoda Witkowska, Eliza Wojciechowska, Wacław Kuczmik

In terms of epidemiology, knowledge about symptoms of disease, potential risk factors and ways of proper anti-thrombotic prophylaxis are crucial.

Based on different diagnostic methods in this scope, clinical effectiveness of anti-thrombotic prophylaxis in various situations is unquestioned. It is advisable to assess every patient individually regarding risk factors and efficacy of preventive procedures. VTE is a cause of in-hospital deaths which could mostly be prevented [3].

Prevalence of VTE increases during hospitalization and presence of other risk factors of this disease [4]. Among hospitalized patients, 78% of those admitted to hospitals have more than 1 VTE risk factor and 20% of them have at least 3 risk factors at once [4]. In the USA, pulmonary embolism is a cause of 200 000 deaths per year [5].

In the USA and Europe VTE leads to more deaths than AIDS, breast cancer, prostate cancer and car accidents combined [6].

Venous thromboembolism is one of the most underrated diseases among both patients and medical staff because of the common lack of symptoms, non-specific symptoms and inadequate awareness of this issue [7-9].

Actions that lead to increased awareness of prevalence of this problem, its consequences, diagnostics and prevention should be carried out both in hospital and in outpatient treatment [8]. Awareness about VT’s occurrence should be raised among patients as well [9].

Education about prevalence, consequences, prophylaxis possibilities and treatment of VTE is part of medical faculties’ curriculum at medical universities in Poland.

Future doctors’ task is to acquire knowledge about the pathophysiological basis as well as proper procedures in the group of predisposed patients. In this paper an attempt has been made to assess medical students’ awareness about VTE from different clinical years.

Material and methods

100 90 80 70 60 50 40 30 20 10 0

The proper definition of venous thromboembolism as an affliction manifesting as deep vein thrombosis (DVT) and/or pulmonary embolism (PE) was pointed out by 60% of interviewees and an alarmingly low rate of correct answers among 100 consecutive students of the 6th year (25%) (Fig. 1).

According to the majority of students (52%) venous thromboembolism is only the 5th cause of death due to vascular problems. The correct answer, venous thromboembolism being the 3rd cause of death due to cardiovascular diseases (after coronary heart disease and cerebrovascular events), was given by only 50% and the most (55%) by students of the 5th year of studies and the least by students of the 4th and 6th year – 38% and 40% of correct answers respectively. Proper components of Virchow’s triad, which underlies the pathogenesis of deep vein thrombosis, were defined by 69% and the best result was achieved by students of the 5th year of studies (Fig. 2).

73 60

64

25

3rd year 4th year 5th year 6th year

Fig. 1. Percentage of correct answers for definition of venous thromboembolism as a condition including deep vein thrombosis and/or pulmonary embolism

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Results

Percentage

Percentage

The study was performed on a group of 400 medical students from the Medical University of Silesia in Kato-

wice from years 3 to 6, recruiting 100 people from each of the clinical years. The study was conducted based on a survey which included 27 questions concerning knowledge of the definition of venous thromboembolism, pathogenesis and epidemiology of this affliction. In the questionnaire questions regarding risk factors, symptoms and diagnostics related to this group of patients were asked. 77% of interviewees were women and 23% were men, aged 21-28 years old. Respondents based their answers on the knowledge acquired at the university during studies.

The survey was anonymous and it was conducted between 15 October 2016 and 28 February 2017. The aim of the authors of the research tool was its clarity and preservation of an appropriate number of categorized questions, giving an opportunity to choose one answer and closed questions. Results were edited taking information about the study year of interviewees into consideration and statistically evaluated.

100 90 80 70 60 50 40 30 20 10 0

87 66

70

75

3rd 4th 5th 6th

Fig. 2. Percentage of correct answers for Virchows’ triad components

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100 90 80 70 60 50 40 30 20 10 0

63 41 30

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3rd year 4th year 5th year 6th year

Percentage

Fig. 3. Percentage of correct answers for incidence rate of DVT in the population 100 90 80 70 60 50 40 30 20 10 0

27 16

25

14

3rd year 4th year 5th year 6th year

Fig. 4. Percentage of correct answers for risk factors of venous thromboembolism

Percentage

Deep veins of lower limbs as the most frequent place of deep vein thrombosis and potential thrombotic material formation was indicated by 85% of respondents. Asked about the incidence of thrombosis in the population, less than half of respondents pointed out the correct answer, with a significantly higher rate of the proper answers chosen by students of the 6th year of the university (Fig. 3).

Referring to the question about symptomatology of venous thromboembolism, 3.75% of respondents responded that venous thromboembolism is always symptomatic. 26% of students claim that in most cases pulmonary embolism is the first manifestation of venous thromboembolism (from 10% of students of the 4th year to 40% of the 5th year). The answer that venous thromboembolism could often be non-symptomatic and this is the reason why it is so hard to identify was chosen by 13.75% of the respondents only. The statement that deep vein thrombosis often causes pain of lower limbs and swelling, and such symptoms suggest that it may be deep vein thrombosis (so you could and should do more tests), was chosen by 52.75% of respondents (the least by students of the 4th year, 41%, and the most by students of the 6th year, 70%).

When we asked the students about symptoms which can occur in patients with deep venous thrombosis, swelling of the lower limbs was indicated by 6.25% of respondents (the most from the 3rd year – 9%), tenderness and pain was indicated by 1.75%, and positive Homans’ symptom was chosen by 2%. 87.5% of interviewees claim that all of the symptoms may suggest occurrence of deep vein thrombosis (including most of the 4th and 6th years).

The next question referred to the problem of specific symptoms of the venous thromboembolism – 61.25% of respondents were aware that, unfortunately, there are no specific symptoms of this disease (including most future physicians of the 6th year – 80%). When we asked about the possible risk factors for development of venous thromboembolism (multi-organ injury, long-term immobilization, obesity, venous thromboembolism in the interview, heart failure, stroke, cancers or all of them) the correct answer, indicating all of them, was given by only 17% of students (Fig. 4).

The twentieth question of the questionnaire was “what tests would you recommend to identify deep vein thrombosis, when there is a patient with swollen lower limbs after long-term immobilization during travel?”. There were the following answers available: D-dimer assessment in urine, D-dimer assessment in serum, ultrasound compression test, ascending venography, and US duplex Doppler examination, or a combination of them. The correct answer (ultrasound compression test or duplex Doppler examination) was indicated by 30% of respondents (30% of 3rd year students, 14% of 4th year students, 24% of 5th year students, and the most, 50%, of 6th year students).

Responding to the question “what is the first test you will do to identify or exclude the pulmonary embolism?”,

Percentage

Venous thromboembolism awareness among medical students – intervention needed

100 90 80 70 60 50 40 30 20 10 0

88 79 68 57

3rd year 4th year 5th year 6th year

Fig. 5. Percentage of correct answers for first-choice diagnostic method in confirming/excluding PE (angio-CT)

66% of students from the Medical University of Silesia indicated the correct answer, which was angio-CT, and 6th year students got the best result (Fig. 5).

Asked about pharmacological treatment of deep vein thrombosis, antiplatelet drugs were indicated by 71.5% of the respondents (the most, 75%, by 6th year students, and the least, 67%, by 3rd year students). The rest of the interviewees stated that anticoagulation treatment should be used. In the question where the respondents were asked to select an inappropriate method of VTE prophylaxis (which was the use of acetylsalicylic acid for primary thromboprophylaxis), the correct answer was chosen by

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Tomasz Urbanek, Maciej Wołkowski, Marcela Zembura, Jagoda Witkowska, Eliza Wojciechowska, Wacław Kuczmik

29% of students only. The proposed VTE prophylaxis methods in this question included: early mobilization, graduated elastic stockings, intermittent pneumatic compression and anticoagulant use. Correct answers were indicated by 80% of 6th year students, 55% of 5th year students, 20% of 4th year students and 17% of 3rd year students. Concerning the question involving the problem of venous thromboembolism during long immobilization during long distance air flights, 35% of respondents were aware of the risk factors and that some methods of VTE prophylaxis should be implemented during long haul flights if needed (correct answers were stated by 40% of 3rd year students, in 39% of 5th year students and in 33% of 6th year students).

Answering the question concerning the level of the current and obtained knowledge (information) about VTE on a scale from 1 to 10, respondents stated it at the average level of 3.8 (4.09 in 3rd year, 3.4 in 4th, 4.7 in 5th and 3 in 6th year students). Students of every clinical year stated that they were not taught enough about diagnosis and treatment of deep vein thrombosis. 76% of respondents claim that lecturers and classes during medical studies do not pay enough attention and devote insufficient time to deep vein thrombosis and pulmonary embolism (60% in 3rd year, 64% in 4th year, 83% in 5th year and 83% in 6th year students).

Discussion The lack of proper awareness concerning the disease as well as the lack of knowledge concerning the proper approach to VTE prophylaxis and treatment are definitively two important factors significantly related to the still very high mortality and morbidity rate in this group of patients [10]. Several other factors responsible for the poor clinical implementation of the proposed VTE prophylaxis and treatment guidelines are also identified including: physician-related factors (lack of familiarity with the guidelines, lack of agreement with the guidelines, lack of outcome expectancy, concerns about bleeding risk, difficulty of use of oral anticoagulation, lack of self-efficacy – inability to follow the guidelines), environmental factors (lack of time, lack of staff, poor reimbursement and increased practice costs, lack of reminder system) as well as guideline-related factors (confusing disagreement between the guidelines, guidelines are not easy or inconvenient to use, difficulties in adding new behaviour instead of changing an existing one, some of the guidelines are cumbersome) [11].

Taking into account the conditions mentioned above, the discrepancy between the guideline recommendations and the real world clinical approach to the problem of venous thromboembolism in the hospital as well as ambulatory settings is also potentially related to the proper health care provider education. In the study, both the questionnaire answers and student knowledge

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self-assessment suggest the need of medical high school education improvement in the VTE field. VTE-related subjects are part of the medical education and training at the medical faculty along the study course from the very early part of the clinical education. This subject is presented and discussed with students during the courses of physiology, pathology, pharmacology, internal medicine, surgery and vascular surgery.

In the performed study, we realized the lack of the proper students’ knowledge concerning VTE symptomatology and pathogenesis in all the examined years of the medical faculty training, including in the 6th (last) year students. Among 100 consecutive 6th year students asked, 25% of the respondents could not specify Virchow’s triad elements and only 25% of them knew the proper VTE definition (based on the presence of DVT and/or of PE).

Several problems with the identification of VTE and DVT symptoms were also identified among the respondents – the lack of knowledge concerning the often asymptomatic disease course as well as the limited understanding of the low specificity of potentially VTE-related symptoms should be especially emphasized. In this context the relatively low rate of correct answers to the question about proper DVT diagnostics in the symptomatic patient should be pointed out: only 29.5% of students identified ultrasound venous the compression test as well as venous duplex Doppler US as the screening diagnostic method in DVT patients (30% of 3rd year, and 14%, 24%, 50% in years 4-6 respectively). Also in the PE field, the insufficient knowledge concerning angio-CT as the diagnostic method of choice to confirm the clinical suspicion should be mentioned (this method was indicated by 68%, 57%, 79% and 88% of the students from the medical faculty, in the 3rd, 4th, 5th and 6th year respectively).

In the performed study, apart from the problems with the proper identification of the VTE risk factors, there are also problems related to the VTE prophylaxis rules. Only 29% of the students identified aspirin as the inappropriate way of pharmacological thromboprophylaxis. The proper methods of VTE prophylaxis were specified by 17% of students of the 3rd year of the medical study, by 20% in the 4th year and by 55% and 80% in the 5th and 6th year respectively. According to the presented results and students’ self-assessment, in the programme of the medical faculty more attention should be paid to the education in the field of venous thromboembolism. This, in turn, can potentially improve and ensure safe and high quality medical care in the potential VTE patient population.

Continuous education in this field should be continued not only during the medical study but also afterwards and should concern all health care providers. In the VTE START study, based on a population of 258 556 hospitalized patients, 68 278 patients (26.4%) were determined to be at risk of venous thromboembolism in various hospital departments. The rates of patients who received the appropriate type, dose, and duration of thromboprophy-

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Venous thromboembolism awareness among medical students – intervention needed

laxis in critical care, medical and surgical patient wards were 10.5%, 9.8%, and 17.9% respectively. Among the patients at risk, 36.8% received no thromboprophylaxis.

The study publication was summarized with the conclusion concerning the need for physicians and health systems to improve awareness and implementation of recommended thromboprophylaxis [12].

According to the ENDORSE study based on a population of 68 183 hospitalized patients in 32 countries, the proper VTE prophylaxis was used in 59% of the surgical patients at VTE risk and only in 40% of the medical patients at risk of VTE development (assessed according to risk factor presence) [13]. Tang et al. explored how the medical staff of intensive care units in China comprehend and practice VTE prophylaxis. In the questioned group of 1861 physicians and nurses, 36.5% of physicians and 22.2% of nurses were aware of the VTE guidelines, and 19.0% of physicians and 9.5% of nurses comprehended the latest ACCP Guideline edition (9th Edition – 2012) – 37.6% of the medical staff chose the VTE prophylaxis method based on the related guidelines [14].

One of the most significant problems related to the difficulties in the VTE prophylaxis and treatment guidelines implementation is the lack of proper VTE awareness among the medical staff. It concerns both risk factor evaluation with proper VTE risk stratification and diagnostic awareness in the potential DVT/PE patients. VTE can often be prevented, but in many cases the course of the disease can be potentially unpredictable, with very few clinical symptoms suggesting the disease occurrence [15-17]. Many VTE cases are still not diagnosed clinically and detected during the autopsy – this observation concerns especially the medical patient group but it can also happen in surgical patients at risk of VTE development [18]. The incidence of VTE increases during hospitalization as well as in the cases of coincidence of significant VTE risk factors [19].

The current VTE prophylaxis and treatment measures, including new medical therapies based on direct oral anticoagulants, significantly simplify both prophylaxis and treatment of this disease [20-23]. Despite the progress in the therapy, a significant proportion of VTE patients remain undiagnosed due to the asymptomatic or barely symptomatic disease course. This concerns both proximal and (especially) distal DVT as well as the number of PE cases. In term of the often asymptomatic VTE course, knowledge concerning risk factors as well as risk stratification has important value [24, 25].

Education as well as activities focusing on an increase of the awareness concerning venous thromboembolism can be addressed to the patient community, which seems to be much less informed about the disease risk consequences and symptoms. In a study published in 2017 by Almodaimegh et al. the Saudi Arabia in-hospital patients’ awareness of VTE and their perceptions of thromboprophylaxis were evaluated. Among the 174 patients stud-

Phlebological Review 2018

ied, only 32% were familiar with the risk and possibility of DVT occurrence, while for PE the rate was even lower, 15%. Only 5% of the patients with knowledge of DVT identified leg swelling as a potential DVT symptom [26].

In the general (non-hospital) population the knowledge and awareness of VTE also seems to be very low and significantly lower than the knowledge concerning other cardiovascular diseases such as stroke or heart infarction.

In a study assessing the global public VTE awareness, 800 respondents from 9 countries were questioned [27].

The rates of respondents who were aware of thrombosis, DVT and PE were 68%, 44% and 54%, and this was significantly lower than the proportion that were aware of other thrombotic disorders, such as heart attack and stroke (88% and 85% respectively). In the same study, the awareness of cancer, hospitalization and surgery as the risk factors turned out to be very low (16%, 25% and 36% respectively) and only 45% of the respondents were aware that blood clots are preventable.

Looking for the possibility to improve this situation, in the AVTERS study, Tomkowski and co-workers focus on the efficacy of the public awareness campaign on the incidence of symptomatic objectively confirmed deep vein thrombosis [27]. In this controlled study a campaign to raise public awareness of DVT was performed during one year in an urban population of 100 000 and compared with the control group in terms of the symptomatic DVT referrals and confirmations by general practitioners by compression ultrasound. The one year incidence of diagnosed DVT was 36/100 000 in the population that underwent education and 14/100 000 in the control (without the educative approach). Of course, for the wider implementation of such an approach, the significant costs should be taken into consideration. As this is probably not possible at this moment as a worldwide strategy, at least medical staff and all medical health care providers should be aware and sufficiently educated in the field of risk factor assessment, prophylaxis as well as diagnostics and treatment of DVT and/or PE. This education should remain an important part of the pre- and post-graduate training as well as part of the continuous education in most of the medical specialties.

The present study demonstrates the lack of sufficient awareness of VTE, DVT, and PE as well as the lack of sufficient knowledge concerning the pathogenesis, risk factors, and diagnostics among medical students, including the last year of medical faculty student group. Based on our study results, action towards an increase of medical high school students’ awareness as well as action towards more practical education in this field in the medical faculty of the medical university should be proposed.

Conclusions Although the study programme includes venous thromboembolism, the knowledge of students in the field

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Tomasz Urbanek, Maciej Wołkowski, Marcela Zembura, Jagoda Witkowska, Eliza Wojciechowska, Wacław Kuczmik

of epidemiology, symptomatology and risk factors of this affliction is still limited. According to the results of the study, it is advisable to take action, including educative effort, which should lead to increased awareness of the future medical staff about problems related to VTE. This research was supported by research grant no.

KNW 1-185/N/6/K from Medical University of Silesia in Katowice.

The authors declare no conflict of interest.

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18. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 20952128.

19. Vaitkus PT, Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Goldhaber SZ, Group PMTS. Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients.

Thromb Haemost 2005; 93: 76-79.

20. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149: 315-352.

21. Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129: 764-772.

22. Prins MH, Lensing AW, Bauersachs R, van Bellen B, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Raskob GE, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies.

Thromb J 2013; 11: 21.

23. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Berkowitz SD, Wells PS; EINSTEIN Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369: 799-808.

24. Zawilska K, Bała M, Błędowski P, Chmielewski DW, Dobrowolski Z, Frączek M, Frołow M, Gajewski P, Guzik T, Jaeschke R, Korman T, Kotarski J, Kozubski W, Krawczyk M, Kruszewski W, Kulikowski J, Kutaj-Wąsikowska H, Mayzner-Zawadzka E, Mrozikiewicz PM, Musiał J, Niżankowski R, Pasierski T, Poręba R, Tomkowski W, Torbicki A, Undas A, Urbanek T, Wojtu-

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Venous thromboembolism awareness among medical students – intervention needed

kiewicz MZ, Woroń J, Wroński J. Polskie wytyczne profilaktyki i leczenia żylnej choroby zakrzepowo-zatorowej – aktualizacja 2012. Medycyna Praktyczna, Kraków 2012.

25. Tomkowski W, Kuca P, Urbanek T, Chmielewski D, Krasiński Z, Pruszczyk P, Windyga J, Oszkinis G, Jawień A, Burakowski J, Dybowska M, Kęsik J, Zubilewicz T. Żylna choroba zakrzepowo-zatorowa – wytyczne profilaktyki, diagnostyki i terapii Konsensus Polski 2017. Acta Angiol 2017; 23: 73-113.

26. Almodaimegh H, Alfehaid L, Alsuhebany N, Bustami R, Raharbi S, Alkatheri A, Albekairy A. Awareness of venous thromboembolism and thromboprophylaxis among hospitalized patients: a cross-sectional study. Thromb J 2017; 15: 19.

27. Wendelboe AM, McCumber M, Hylek EM, Buller H, Weitz JI, Raskob G, for the ISTH Steering Committee for World Thrombosis Day. Global public awareness of venous thromboembolism. J Thromb Haemost 2015; 13: 1365-1371.

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Predictive value of plasma fibrinogen levels for outcome of aneurysmal subarachnoid haemorrhage during the first week of illness Bartosz Sokół1, Norbert Wąsik1, Cathy Olczyk1, Barbara Więckowska2, Robert Juszkat1,3, Roman Jankowski1 Department and Clinic of Neurosurgery and Neurotraumatology, Poznan University of Medical Sciences, Poznan, Poland 2 Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland 3 Department of General and Interventional Radiology, Poznan University of Medical Sciences, Poznan, Poland

Original paper Phlebological Review 2018; 26, 2: 36–43 DOI: https://doi.org/10.5114/pr.2018.81011

1

Abstract

Objectives: Aneurysmal subarachnoid haemorrhage (SAH) is an acute cerebrovascular event characterised by the rupture of an aneurysm within the subarachnoid space.

Secondary injuries increase both mortality and morbidity in patients who survive the primary haemorrhage. Inflammation and coagulation play critical roles in the pathophysiology of SAH. Fibrinogen is involved in both, yet despite wide availability, its prognostic value in aneurysmal SAH is not clear.

Material and methods: A prospectively collected database of 97 aneurysmal SAH patients was reviewed for plasma fibrinogen level results. All patients admitted within 24 hours of aneurysm rupture and treated endovascularly within 48 hours were included. The outcome was assessed at three months according to the Glasgow Outcome Scale (GOS). Correlation with the outcome and analysis for patients’ death and unfavourable outcome were performed.

Results: Fibrinogen level on day 2 significantly correlates with GOS at 3 months. The analysis for mortality revealed that high levels of fibrinogen on days 1, 2 and 3-4 were significant, but not independent predictors for mortality. Univariate analysis for unfavourable outcome indicated no significant prognostic value of fibrinogen levels. Statistically significant elevation of fibrinogen level was found on day 2 in patients with an intraventricular haematoma (p < 0.01). We also noted that fibrinogen level was elevated in patients with a Glasgow Coma Scale score less than 13 (p = 0.013).

Conclusions: Fibrinogen level might serve as an accessory prognostic tool for patients’ death. Fibrinogen level was significantly elevated in patients with intraventricular haematoma and in patients with a poor clinical condition on admission.

Submitted: 27.05.2018 Accepted: 8.08.2018

Address for correspondence Bartosz Sokół Department and Clinic of Neurosurgery and Neurotraumatology Poznan University of Medical Sciences 49 Przybyszewskiego St. 60-355 Poznan, Poland e-mail: bartosz.sokol@ump.edu.pl

Key words: subarachnoid haemorrhage, early brain injury, outcome.

Introduction The annual incidence of cerebral aneurysm rupture is 1 in 10,000 for the general population. This devastating condition kills or severely disables 70% of victims [1-3]. Those who survive aneurysmal haemorrhage often suffer delayed ischaemic neurological deficits (DINDs).

Unfortunately, despite the significant consequences of DINDs, prompt diagnosis can be elusive, and may result in delay of administering effective treatment and compromise patient outcome. Despite the improvement of treatment options, the outlook remains serious. Therefore, all available data should be used to characterise

36

adverse factors and indicate pathophysiological mechanisms leading to deterioration [4]. Currently, the most widely used markers of aneurysmal subarachnoid haemorrhage (SAH) prognosis are age, neurological state, volume of subarachnoid blood measured by computed tomography (CT) at admission, pre-existing hypertension, and complications such as aneurysmal rebleeding or angiographic vasospasm [5, 6]. Several scales, including the Glasgow Outcome Scale (GOS) [7], Hunt and Hess scale (HH) [8], World Federation of Neurological Societies scale (WFNS) [9], and Fisher scale [10], are known to be associated with SAH clinical outcomes [11]. It has been suggested that factors other than SAH

Phlebological Review 2018

Predictive value of plasma fibrinogen levels for outcome of aneurysmal subarachnoid haemorrhage during the first week of illness

alone may play a role in the development of vasospasm.

The possibility of exploring genetic links to vasospasm was raised by Rabb et al. in 1994 [12]. Early brain injury (EBI), defined as damage sustained within 72 hours of the ictus, has been attributed to an interplay between alterations in cerebral blood flow (CBF) autoregulation, disrupted cerebral metabolism, altered permeability of the blood-brain barrier (BBB), as well as inflammatory cytokines, leukocytes and pro-thrombotic pathways [13, 14]. Results from CONSCIOUS trials have suggested that early brain injury immediately follows SAH and precedes the onset of delayed vasospasm [15-17]. EBI is a result of increased intracranial pressure and decreased CBF, causing cerebral ischaemia. These early events are followed by neuroinflammation, BBB breakdown, and neuronal apoptosis [18, 19]. After SAH, brain injuries from the initial haemorrhage occurring within 72 hours and cerebral vasospasm developing 3-7 days after rupture are the most important causes of mortality and morbidity [20]. Numerous studies suggest that inflammation and coagulation play key roles in the pathophysiology of SAH and contribute to the functional and cognitive outcomes [21-23]. Identifying a plasma biomarker with early prognostic value for SAH outcome is attracting increased attention [24, 25] and could aid in identifying high-risk patients, guide treatment and improve outcome.

Unfortunately, clinically reliable blood biomarkers are still not available. In this study, changes in plasma fibrinogen levels were measured in patients diagnosed with SAH in an attempt to correlate levels of this biomarker with clinical outcomes.

Material and methods Patient population This prospective observational study was conducted at a single academic tertiary care centre over a one-year period. All patients were admitted within 24 hours of confirmed aneurysmal SAH. The diagnosis was based on computed tomography and catheter angiography. None of the enrolled patients had a history of any chronic neurological disorder or chronic inflammatory disease; there was no history of surgical procedures or nosocomial infection within four weeks of SAH onset. All patients underwent cerebral angiography with arterial catheterisation or multislice CT angiography within 48 hours of onset.

Ethics and consent This prospective observational study was conducted in accordance with the Declaration of Helsinki. The Poznan University of Medical Sciences Bioethics Committee approved the study protocol, consenting protocol and consent forms. Patients were assessed by two specialists (a neurosurgeon and an anaesthesiologist) as to

Phlebological Review 2018

their ability to give informed consent for inclusion in the study, and permission to use blinded medical data for analysis and publication.

Population: inclusion and exclusion criteria Ninety-seven patients with SAH (confirmed by non-contrast CT) were referred to our department during the study recruitment period from October 2015 to October 2016. Data were collected prospectively and analysed retrospectively. All patients had an aneurysmal SAH treated endovascularly within 48 hours of rupture. Exclusion criteria were: 1) history of central nervous system (CNS) disease, 2) active CNS infection, 3) active systemic disease (diabetes mellitus, rheumatoid arthritis, malignancy, cirrhosis, renal failure), 4) age under 18, 5) pregnancy.

Management, definitions, endpoints On admission the clinical status was assessed using the GCS and specific SAH-grading scales (HH [26], WFNS [27]). Patients received a continuous infusion of nimodipine for at least ten days, hypotension was avoided using vasopressors and euvolaemia was maintained. Induced hypertension (20-30% above baseline levels) was used to treat patients diagnosed with delayed cerebral ischaemia (DCI), based on the appearance of a new focal deficit, or a drop of at least two points on the GCS lasting at least two hours after the exclusion of systematic causes. The primary end point was the treatment outcome assessed at three months using GOS [28]. Patients were divided into two groups according to the GOS. The good outcome group consisted of those with no disability, moderate disability or severe disability (GOS grades 5, 4 and 3); the poor outcome group consisted of those with a persistent vegetative state or death (GOS grades 2 and 1). DCIrelated infarction was defined as a new cerebral infarction identified on a head CT scan within six weeks of rupture and not present on the immediate post-treatment scan (as proposed by Vergouwen et al. [17]).

Fibrinogen assay During hospitalisation, decisions regarding type and timing of laboratory tests (including fibrinogen levels) were left solely to the judgement of the physician. Consequently, the number of subjects available for analysis at each time point varied. The fibrinogen level was assessed using the automatic analyser ACL TOP 500 (Instrumentation Laboratory, Italy).

Statistical analysis Statistica 12 software (Stat Soft Inc., Tulsa, OK, USA) was used to perform all analyses. The Shapiro-Wilk test was used to test the normality of the data distribu-

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Bartosz Sokół, Norbert Wąsik, Cathy Olczyk, Barbara Więckowska, Robert Juszkat, Roman Jankowski

Table 1. Patient characteristics Variables

Descriptive statistics n = 97 (%)

Male

47 (48)

Age (years)

56.0 ±14.2

Aneurysm location Middle cerebral artery

22 (22.7)

Anterior communicating artery

27 (27.8)

Internal carotid artery

22 (22.7)

Anterior cerebral artery

7 (7.2)

Basilar artery

10 (10.3)

Posterior cerebral artery

1 (1)

Vertebral artery

3 (3.1)

Posterior inferior cerebellar artery

5 (5.2)

Aneurysmal size (mm)

5.5 ±2.8

Fisher CT scale

4 (4; 4)

Modified Fisher CT scale

3 (2; 4)

HH grade on admission

4 (2; 5)

WFNS grade on admission

4 (2; 5)

GCS on admission

7 (4; 13)

Treatment outcome according to GOS at 3 months 5 (no/low disability)

19 (19.6)

4 (moderate disability)

10 (10.3)

3 (severe disability)

25 (25.8)

2 (persistent vegetative state)

13 (13.4)

1 (death)

30 (30.9)

Values are presented as: 1) mean ±standard deviation for numerical data, 2) median (lower quartile, upper quartile) for ordinal data, 3) count (percentage) for categorical/ ordinal data. WFNS – World Federation of Neurosurgical Societies scale; HH – Hunt and Hess scale; GCS – Glasgow Coma Scale; GOS – Glasgow Outcome Scale.

tion. Student’s t-test, Cochran-Cox correction, and the Mann-Whitney test were used for pairwise comparisons, i.e. favourable vs. unfavourable outcome, and survivors vs. non-survivors. Spearman’s test was used to assess correlation: a correlation coefficient (cc) of > 0.4 or < –0.4 was considered significant. To identify independent prognostic factors for unfavourable outcome and mortality, univariate and multivariate logistic regression analysis adjusted for HH and age was performed as appropriate.

Results Ninety-seven subjects (45% males; mean 56 years) were included in the study based on the availability of fibrinogen assay data. On admission, 57% of patients were classified as poor grade (HH grades 4 and 5). At three months, 69% of patients had an unfavourable outcome (GOS scores 1-3), including 31% who died (Table 1).

Pairwise comparison of favourable and unfavourable treatment outcome groups is presented in Table 2.

Both age (p = 0.0226) and clinical status on admission (p < 0.0001 on all three scales) differed significantly between the two groups. The fibrinogen level was unable to differentiate between the favourable and unfavourable groups (Fig. 1). Table 3 and Figure 2 present a pairwise comparison of survivors and non-survivors.

Analysis showed that clinical status on admission was significantly different between the groups (p ≤ 0.0001 on all three scales), but the age rating did not reach significance (p = 0.0642). Significantly higher fibrinogen levels on day 2 (p = 0.0302) and day 3-4 (p = 0.0459) were found in non-survivors (Fig. 2). Correlation analysis for this cohort (Table 4) showed the closest correlation with admission status; the coefficient was –0.679, –0.699 and –0.630 for the GCS, HH and WFNS scores, respectively.

There was a significant association between outcome and

Table 2. Comparison between favourable and unfavourable outcome in subarachnoid haemorrhage patients Variables

Favourable outcome

Unfavourable outcome

p-value

n

mean ±SD/median (Q1; Q3)

n

mean ±SD/median (Q1; Q3)

Age

29

51.0 ±14.9

68

58.1 ±13.4

0.0226*

HH on admission

29

2 (2; 3)

68

5 (4; 5)

< 0.0001*

WFNS on admission

29

1 (1; 3)

68

5 (4; 5)

< 0.0001*

GCS on admission

29

15 (12; 15)

68

6 (3; 9)

< 0.0001*

Fibrinogen (mg/dl), day 0

16

282.3 ±73.5

30

306.2 ±98.5

0.3993

Fibrinogen (mg/dl), day 1

9

274.7 ±83.4

29

348.1 ±130.1

0.1591

Fibrinogen (mg/dl), day 2

9

391.4 ±116.8

20

472.5 ±141.6

0.1454

Fibrinogen (mg/dl), days 3-4

11

447.5 ±177.0

36

603.6 ±251.4

0.0875

Fibrinogen (mg/dl), days 5-7

6

703.8 ±243.7

40

726.4 ±225.4

0.8218

Fibrinogen (mg/dl), days 9-11

6

703.3 ±231.7

37

673.7 ±247.7

0.7855

Statistical significance for pairwise comparisons between the groups of death/survivor was tested by Student’s t-test, Cochran-Cox correction or the Mann-Whitney test as appropriate. Values are presented as: 1) mean ±standard deviation for numerical data, 2) median (lower quartile, upper quartile) for ordinal data. *significant p-value. GCS – Glasgow Coma Scale; HH – Hunt and Hess scale; Q – quartile; SD – standard deviation; WFNS – World Federation of Neurosurgical Societies scale

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Phlebological Review 2018

Predictive value of plasma fibrinogen levels for outcome of aneurysmal subarachnoid haemorrhage during the first week of illness

800

800 Fibrinogen (mg/dl)

1000

Fibrinogen (mg/dl)

1000

600 400 200 0

600 400 200

day 0

day 1 unfavourable

0

day 2 day 3-4 day 5-7 day 9-11

day 0

favourable

day 1

day 2 day 3-4 day 5-7 day 9-11

non-survivors

Fig. 1. Changes in plasma fibrinogen level in time in patients with favourable and unfavourable treatment outcome

survivors

Fig. 2. Changes in plasma fibrinogen level in time in survivors and non-survivors of subarachnoid haemorrhage

Table 3. Comparison between survivors and non-survivors of subarachnoid haemorrhage Variables

Survivors

Non-survivors

p-value

n

mean ±SD/median (Q1; Q3)

n

mean ±SD/median (Q1; Q3)

Age

67

54.5 ±14.0

30

59.3 ±14.3

0.0642

HH on admission

67

3 (2; 4)

30

5 (5; 5)

< 0.0001*

WFNS on admission

67

4 (1; 5)

30

5 (4; 5)

0.0001*

GCS on admission

67

12 (6; 15)

30

4 (3; 6)

< 0.0001*

Fibrinogen (mg/dl), day 0

34

294.5 ±85.0

12

307.6 ±108.1

0.6718

Fibrinogen (mg/dl), day 1

26

301.1 ±84.9

12

394.8 ±169.1

0.0921

Fibrinogen (mg/dl), day 2

20

400.5 ±92.1

9

551.6 ±168.7

0.0302*

Fibrinogen (mg/dl), days 3-4

29

504.0 ±178.7

18

668.6 ±300.5

0.0459*

Fibrinogen (mg/dl), days 5-7

31

700.2 ±182.7

15

771.5 ±296.1

0.4025

Fibrinogen (mg/dl), days 9-11

31

656.5 ±207.9

12

732.9 ±321.1

0.3615

Statistical significance for pairwise comparisons between the groups of death/survivor was tested by Student’s t-test, Cochran-Cox correction or the Mann-Whitney test as appropriate. Values are presented as: 1) mean ±standard deviation for numerical data, 2) median (lower quartile, upper quartile) for ordinal data. *significant p-value. Q – quartile; SD – standard deviation; HH – Hunt and Hess scale; WFNS – World Federation of Neurosurgical Societies scale; GCS – Glasgow Coma Scale

fibrinogen level on day 2 (cc = –0.476), independent of age (cc = –0.229). Univariate analysis of the unfavourable outcomes confirmed that fibrinogen levels failed to differentiate between the two groups (Table 5). However, univariate analysis for mortality indicated that the fibrinogen level on day 1 (OR = 1.90 [1.02; 3.57], p = 0.0444), day 2 (OR = 2.87 [1.15; 7.15], p = 0.0239) and day 3-4 (OR = 1.37 [1.02; 1.85], p = 0.0379) were predictors for mortality. Despite this, multivariate analysis adjusted for age and HH scores showed that the fibrinogen level was not an independent predictor (Table 6). We also analysed the relationship between fibrinogen level on day 2 postSAH, clinical condition on admission and the extent of

Phlebological Review 2018

haemorrhage in imaging studies (Table 7). We found a statistically significant elevation of fibrinogen level on day 2 (correlating with treatment outcome) in patients with an intraventricular haematoma (p < 0.01). We also noted that fibrinogen level was elevated in patients with a GCS score less than 13 (p = 0.013).

Discussion Changes of coagulation and fibrinolytic mechanisms in relation to SAH have been analyzed since 1970 [29].

Elevated fibrinogen level is associated with the severity of the ischaemic event [30], and a sustained increase in

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Bartosz Sokół, Norbert Wąsik, Cathy Olczyk, Barbara Więckowska, Robert Juszkat, Roman Jankowski

the fibrinogen level during a stroke reduces the prospect of a favourable outcome [31]. Patients with DINDs have been reported to have higher levels of fibrinogen on days 3, 6 and 14 [32]. Our study demonstrated a significant difference in fibrinogen levels between survivors and non-survivors on days 1, 2 and 3-4. There was a constant increase in fibrinogen level on consecutive days follow-

Table 4. Correlation between patient age, clinical status on admission, fibrinogen level and outcome Variables

n

Correlation coefficient

p-value

Age

97

–0.229

0.0240

HH on admission

97

–0.669

< 0.0001

WFNS on admission

97

–0.630

< 0.0001

GCS score on admission

97

0.679

< 0.0001

Fibrinogen day 0

46

–0.123

0.4136

Fibrinogen day 1

38

–0.309

0.0588

Fibrinogen day 2

29

–0.476

0.0090

Fibrinogen days 3-4

47

–0.358

0.0135

Fibrinogen days 5-7

46

–0.100

0.5075

Fibrinogen days 9-11

43

–0.052

0.7411

Outcome assessed using Glasgow Outcome Scale at 3 months. Statistical significance was tested by Spearman’s rank correlation test. Correlation coefficient > 0.4 or < –0.4 was considered significant and shown in bold. HH – Hunt and Hess scale; WFNS – World Federation of Neurosurgical Societies scale; GCS – Glasgow Coma Scale

ing SAH with a significant negative correlation between GOS and fibrinogen on day 2. Univariate analysis confirmed that the fibrinogen level on day 2 was a predictor for mortality; however, multivariate analysis showed it was not independent of the HH score. Patient’s age and clinical status at admission were correlated with outcome. Increased fibrinogen levels at baseline and postSAH days 1 to 4 were observed but were not significantly correlated with outcome. Multivariate analysis adjusted for age and HH scores showed that the fibrinogen level was not an independent predictor. Fibrinogen levels were significantly elevated in patients with intraventricular haematoma. On day 2 fibrinogen level was also significantly elevated in patients with a GCS score less than 13.

It is therefore difficult to predict whether fibrinogen level changes represent activation of the coagulation system as the response to the severity of brain tissue damage. Coagulation and inflammation are intricately related processes. A combination of ischaemia and hypoxia precipitates platelet accumulation and fibrinogen deposition almost immediately [33]. Fibrinogen is an acute-phase coagulation factor produced by hepatocytes and is activated by thrombin to form fibrin monomers and polymers [34].

The early blood flow reduction is postulated to be due to microcirculatory constriction and microthrombosis.

Platelet aggregates are found in the major cerebral arteries within two hours of experimental SAH [35]. The elevation of fibrinogen might represent microclot formation within 24 h after SAH [36]. This might be one reason for the beneficial effect of nimodipine [37], which may improve recovery from ischaemia by increasing fibrinolytic activity [38]. On the other hand, previous studies

Table 5. Univariate and multivariate logistic regression analysis for unfavourable outcome Variables

Univariate analysis

Multivariate analysis*

OR (95% CI)†

p-value

OR (95% CI)†

p-value

Age

1.04 (1.00; 1.07)

0.0262

–

–

HH on admission

3.52 (2.13; 5.81)

< 0.0001

–

–

WFNS on admission

2.73 (1.86; 4.01)

< 0.0001

–

–

GCS on admission

0.71 (0.61; 0.82)

< 0.0001

–

–

Fibrinogen (mg/dl), day 0

1.36 (0.67; 2.78)

0.3917

1.18 (0.34; 4.08)

0.7949

Fibrinogen (mg/dl), day 1

1.99 (0.81; 4.86)

0.1325

2.63 (0.58; 12.00)

0.2105

Fibrinogen (mg/dl), day 2

1.72 (0.82; 3.63)

0.1517

1.46 (0.45; 4.73)

0.5292

Fibrinogen (mg/dl), days 3-4

1.48 (0.97; 2.25)

0.0681

1.36 (0.78; 2.38)

0.2798

Fibrinogen (mg/dl), days 5-7

1.05 (0.71; 1.54)

0.8170

1.07 (0.66; 1.74)

0.7921

0.95 (0.67; 1.35)

0.7795

1.01 (0.67; 1.52)

0.9541

Fibrinogen (mg/dl), days 9-11

Model adjusted for age and HH scale; odds ratio corresponds to increase of 100 mg/dl in fibrinogen level and a unit increase in the rest of variables. Significant results are bolded. OR – odds ratio; CI – confidence interval; HH – Hunt and Hess scale; WFNS – World Federation of Neurosurgical Societies scale; GCS – Glasgow Coma Scale *

†

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Phlebological Review 2018

Predictive value of plasma fibrinogen levels for outcome of aneurysmal subarachnoid haemorrhage during the first week of illness

Table 6. Univariate and multivariate logistic regression analysis for mortality Variables

Univariate analysis OR (95% CI)†

Multivariate analysis* p-value

OR (95% CI)†

p-value

Age

1.03 (0.99; 1.06)

0.1315

–

–

HH on admission

3.10 (1.71; 5.61)

0.0002

–

–

WFNS on admission

2.29 (1.39; 3.78)

0.0011

–

–

GCS on admission

0.75 (0.65; 0.87)

0.0001

–

–

Fibrinogen (mg/dl), day 0

1.17 (0.57; 2.42)

0.6641

0.93 (0.31; 2.77)

0.8946

Fibrinogen (mg/dl), day 1

1.90 (1.02; 3.57)

0.0444

1.90 (0.89; 4.07)

0.0968

Fibrinogen (mg/dl), day 2

2.87 (1.15; 7.15)

0.0239

2.26 (0.84; 6.06)

0.1055

Fibrinogen (mg/dl), days 3-4

1.37 (1.02; 1.85)

0.0379

1.33 (0.93; 1.92)

0.1228

Fibrinogen (mg/dl), days 5-7

1.16 (0.87; 1.53)

0.3139

1.30 (0.95; 1.78)

0.1055

Fibrinogen (mg/dl), days 9-11

1.14 (0.86; 1.50)

0.3541

1.21 (0.89; 1.64)

0.2156

Model adjusted for HH scale; †odds ratio corresponds to increase of 100 mg/dl in fibrinogen level and a unit increase in the rest of variables. Significant results are bolded. OR – odds ratio; CI – confidence interval; HH – Hunt and Hess scale; WFNS – World Federation of Neurosurgical Societies scale; GCS – Glasgow Coma Scale *

Table 7. Relationship of fibrinogen level on post-subarachnoid haemorrhage day 2 to clinical condition on admission and extent of haemorrhage on imaging studies Variables

*

Yes

No

p-value

n

mean ±SD

n

mean ±SD

Intraventricular haematoma

21

492.4 ±133.2

8

329.1 ±55.3

< 0.01*

Intracerebral haematoma

15

458.7 ±119.8

14

435.2 ±158.3

0.655

Intraventricular and intracerebral haematoma

13

483.2 ±105.7

16

418.1 ±156.2

0.100

Good clinical condition on admission (GCS 15-13)

9

355.8 ±87.6

20

488.6 ±137.6

0.013*

Significant results; GCS – Glasgow Coma Scale; SD – standard deviation

have also shown that nimodipine is an effective cerebral vasodilator, making it useful in the treatment of cerebral vasospasm [39]. Fibrinogen and its degradation products have a prominent role in the regulation of the inflammatory response in several target tissues [40]. Pathological conditions such as injury, or disease associated with vascular disruption, infection or inflammation, increase the blood concentration of fibrinogen several fold [40].

Fibrinogen has been shown to activate the proinflammatory NF-κβ pathway, which results in the local production of inflammatory cytokines TNF-α and IL-1β [41-43].

Fibrinogen signals either directly or indirectly through a number of other receptors, adhesion molecules and cell-surface proteins that are involved in the inflammatory processes. For example, the toll-like receptor 4 (TLR-4) related to SAH [44] has been implicated in the induction of macrophage activation and the release of several chemokines and cytokines [45, 46]. Some authors have reported increased levels of TAT, thrombin/antithrombin complex (a marker for activation of the coagulation cascade), and D-dimer (marker for plasmatic fibrinolysis) and their association with poor outcome. Additionally,

Phlebological Review 2018

the correlation between fibrinogen and outcome varied and therefore was inconclusive [47-49].

Conclusions This study was designed to investigate the association between plasma fibrinogen levels and patient outcome following SAH. There were three limitations: firstly, data were collected prospectively and analysed retrospectively; secondly, the number of readings available was limited; thirdly, plasma levels may not precisely reflect local changes at the site of SAH. For the patient population in this study, we found a significant negative correlation between GOS and plasma fibrinogen level on day two after SAH. We also found that elevation of fibrinogen levels on day 2 and days 3-4 after SAH was associated with increased mortality. Larger prospective studies will be required to reassess fibrinogen levels following SAH and establish whether they have a role in the development of DINDs. Fibrinogen level on the second day after SAH was significantly elevated in patients with intraventricular haematoma. This significance was not present

41

Bartosz Sokół, Norbert Wąsik, Cathy Olczyk, Barbara Więckowska, Robert Juszkat, Roman Jankowski

in patients with intracerebral haematoma. Patients with a poor clinical condition on admission also had elevated fibrinogen levels on day two.

The authors declare no conflict of interest.

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25. Muroi C, Hugelshofer M, Seule M, Tastan I, Fujioka M, Mishima K, Keller E. Correlation among systemic inflammatory parameter, occurrence of delayed neurological deficits, and outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery 2013; 72: 367-375.

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Predictive value of plasma fibrinogen levels for outcome of aneurysmal subarachnoid haemorrhage during the first week of illness

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30. Del Zoppo GJ, Levy DE, Wasiewski WW, Pancioli AM, Demchuk AM, Trammel J, Demaerschalk BM, Kaste M, Albers GW, Ringelsteinet EB. Hyperfibrinogenemia and Functional Outcome From Acute Ischemic Stroke. Stroke 2009; 40: 1687-1691.

31. Swarowska M, Janowska A, Polczak A, Klimkowicz-Mrowiec A, Pera J, Slowik A, Dziedzic T. The Sustained Increase of Plasma Fibrinogen During Ischemic Stroke Predicts Worse Outcome Independently of Baseline Fibrinogen Level. Inflammation 2014; 37: 1142-1147.

32. Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Koike T, Tanaka R. Serial changes of hemostasis in aneurysmal subarachnoid hemorrhage with special reference to delayed ischemic neurological deficits. J Neurosurg 1997; 86: 594-602.

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43. Perez RL, Ritzenthaler JD, Roman J. Transcriptional regulation of the interleukin-1beta promoter via fibrinogen engagement of the CD18 integrin receptor. Am J Respir Cell Mol Biol 1999; 20: 1059-1066.

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A review of the risk of deep vein thrombosis in surgical and minimally invasive treatment of varicose veins Krzysztof Wołkowski1, Tomasz Urbanek2,3

Review paper

Department of Surgery, Saint Ann’s Hospital, Miechów, Poland European Centre of Phlebology, Katowice, Poland 3 Department of General Surgery, Vascular Surgery, Angiology, and Phlebology, Medical University of Silesia, Katowice, Poland

Submitted: 4.08.2018 Accepted: 10.10.2018

1 2

Abstract

Deep vein thrombosis (DVT) remains one of the most important clinical complications of varicose vein surgery. Despite the fact that procedures employed in the treatment of varicose veins are commonly classified as carrying a low risk of thromboembolism, this risk may vary significantly across different patients due to the presence of individual risk factors. This is a review of the risk of DVT in surgical and minimally invasive treatment of varicose veins. In retrospective studies addressing open varicose vein surgery, the rate of symptomatic DVT has been estimated at approximately 1%, but in prospective imaging-based studies, the risk of DVT in clinical settings seems to be much higher.

The role of risk factors for DVT as well as their proper evaluation and individual risk stratification are significant. Because of population aging, a higher incidence of thromboembolic complications can be expected, suggesting the need for an individualised approach to risk stratification and appropriate risk-adjusted prophylaxis in patients who are candidates for varicose vein treatment. The implementation of new treatment modalities, in particular thermal and non-thermal ablation, does not eliminate the risk of DVT completely despite their relatively minimally invasive nature.

Moreover, these methods can be related to the occurrence of new types of thrombotic complications, such as endovenous heat-induced thrombosis. The limited number of prospective studies regarding thromboembolism prophylaxis in modern phlebological treatment warrants further research on the importance of patient assessment and evaluation of procedure-related risk factors for venous thromboembolism.

Phlebological Review 2018; 26, 2: 44–53 DOI: https://doi.org/10.5114/pr.2018.81012

Address for correspondence Krzysztof Wołkowski Department of Surgery Saint Ann’s Hospital 140 Żeromskiego St. 32-200 Miechów, Poland e-mail: k.wolkowski@poczta.onet.pl

Key words: varicose veins, surgery, endovenous ablation, deep vein thrombosis, prophylaxis.

Introduction The large number of patients suffering from chronic venous disease (CVD) and technological progress in the treatment of venous incompetence have resulted in a continuously increasing number of patients diagnosed with, and treated for, CVD in western countries [1]. This is a review of the risk of deep vein thrombosis (DVT) after surgical and minimally invasive treatment of varicose veins. The factors influencing this increase include the implementation of new treatment methods, a growing number of dedicated vein treatment centres, and growing awareness regarding CVD diagnosis and treatment among patients and physicians [2, 3]. Additionally, the presence of lower leg varicose veins is not only a health problem but also a cosmetic concern for many patients [4].

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DVT remains one of the most important clinical complications of varicose vein surgery and other kinds of invasive treatment for superficial vein incompetence [5-8]. Despite the fact that procedures employed in the treatment of varicose veins are commonly classified as carrying a low risk of thromboembolism, this risk may vary significantly across different patients due to the presence of individual risk factors [9]. An increasing prevalence of varicose veins associated with more advanced age and advanced age of the population in general have led to an increase in the number of procedures performed in older patients. In this group and in some younger patients, many concomitant risk factors for venous thromboembolism (VTE) can be identified [9, 10].

Phlebological Review 2018

A review of the risk of deep vein thrombosis in surgical and minimally invasive treatment of varicose veins

According to the current knowledge, many risk factors for VTE are not only treatment-related (such as surgery and its duration, immobilisation, and anaesthesia) but also patient-related (such as age, previous history of VTE, cancer, thrombophilia, inflammatory bowel diseases, acute infections, and many other conditions) [9, 10]. Various clinical advancements in chronic venous disease, different treatment models with their varying durations and invasiveness, as well as different interpatient VTE risk factors suggest the need for an individualised approach to VTE prophylaxis in patients undergoing invasive treatment of varicose veins. In the ENDORSE study (published in 2008) on the practical implementation of VTE prophylaxis in hospitalised patients undergoing medical treatment and surgery, appropriate antithrombotic prophylaxis was used in only 66% of surgical patients at risk for VTE [11].

Unfortunately, data regarding VTE prophylaxis for varicose vein surgery are not available for this population.

The lack of homogeneity between varicose vein populations (in terms of treatment modalities, treatment extent and the presence of VTE risk factors) creates a significant clinical challenge in proper risk stratification and implementation of adequate prophylaxis. Despite some provnposed protocols for the standardisation of VTE prophylaxis in this group of patients, individual risk assessment and implementation of risk-adjusted prophylaxis seem more reasonable [9, 10].

Deep vein thrombosis and venous thromboembolism incidence in patients undergoing varicose vein surgery and minimally invasive treatment (thermal ablation) The occurrence of clinically symptomatic VTE after varicose vein surgery and its potential influence on procedural mortality and morbidity are low in retrospective studies [12, 13]. However, the significance of VTE as a major potentially avoidable cause of in-hospital death in both surgical and medical patients seems unquestionable [10].

The rate of VTE associated with invasive treatment of varicose veins differs significantly across studies [7, 8, 12-16]. The nature of the study (retrospective or prospective) and methods of assessment (ultrasound or clinical evaluation of symptoms only) are reasons for these significant discrepancies. In most of the retrospective analyses, the reported rate of VTE after varicose vein surgery is approximately 1% or lower and applies mostly to clinically symptomatic cases [12-16]. In a retrospective analysis of the outcomes of 3300 surgical varicose vein operations, Hagmuller found that diagnoses of clinically symptomatic DVT and pulmonary embolism (PE) were established in 0.15% and 0.06% of cases, respectively

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[14]. Miller identified DVT episodes in 0.7% of cases (reduced after the use of antiembolism stockings) in a group of 997 patients who underwent varicose vein surgery [15]. Moreover, Critchley analysed the results of varicose vein surgery on 973 limbs and found that DVT was present in 0.5% of cases (no PE episodes were reported) [16]. In another retrospective analysis of a large cohort of 1063 patients treated surgically for varicose veins, Huber and Bounameux observed clinical manifestation and confirmed pulmonary embolism in 0.56% of cases [17].

In a prospective evaluation of the results from a group in which only 3.7% of patients received pharmacological prophylaxis of VTE, Lemasle et al. reported 17 DVT episodes after 4206 varicose vein operations (0.4%) [18]. In this study, only symptomatic patients had an ultrasound scan performed to confirm the DVT diagnosis. Also, one case of PE was noted (0.02%) in this group. Moreover, the authors found that the risk for VTE was increased after surgery on the small saphenous vein (three times greater than for the GSV) and after re-do surgeries (three times greater than for primary interventions). Most DVT cases involved calf veins (71%), and four occurred in patients who received antithrombotic prophylaxis (out of a total of 155 patients who received pharmacological prophylaxis) [18]. Oesch analysed the results of 8639 vein operations on 12,724 limbs and identified clinically symptomatic VTE episodes in 0.38% of patients and 0.26% of operated legs (22 DVT and 14 PE episodes).

With the exception of low-risk ambulatory phlebectomy cases, antithrombotic prophylaxis was administered to all patients for 1 to 10 days. In an imaging examination performed to confirm DVT, there were no cases of DVT in the proximal thigh, but seven popliteal vein and 15 crural vein events (distal DVT) were identified. As for the type of the surgery, the highest DVT rate (1%) was related to surgery of the small saphenous vein, whereas lower rates were reported for great saphenous vein surgery (0.46%) and ambulatory phlebectomy (0.07%) [19]. In a study based on postoperative duplex imaging of 411 patients who underwent varicose vein surgery, Bhogal and Nyamekye reported a 1.2% incidence of DVT [20].

Some prospective studies, in particular those based on objective imaging evaluations, report higher DVT rates. In Van Rij’s prospective assessment based on Doppler evaluation of 377 patients (performed before and 2-4 weeks after varicose vein surgery, and again at 6-12 months), 5.3% of DVT cases and no PE episodes were identified [7]. In this study, selective VTE prophylaxis involved a single dose of subcutaneous heparin.

Of 20 patients with DVT, only eight were symptomatic (1.6% of patients in the entire population), and 18 cases involved calf veins. Despite a higher DVT rate than previously reported, the clinical significance of most of these events was low. In addition, the procedures in this study were performed under general anaesthesia, and both stripping and phlebectomies were carried out during

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Krzysztof Wołkowski, Tomasz Urbanek

a single surgery. Additionally, as has been mentioned above, pharmacological prophylaxis was used in selected cases only [7]. A higher incidence of DVT after varicose vein treatment, as reported by van Rij, was also suggested

by Puttaswamy, based on a duplex US-supported study of 100 lower legs operated for varicose veins. In this study, the reported rate of postoperative DVT was 4.8% [21].

When considering factors affecting the rate of DVT after varicose vein surgery, not only the study methodology but also the type (phlebectomy, truncal ablation + phlebectomy) and nature (unilateral or bilateral operations) of surgical procedures are significant [5, 13, 22, 23]. In a study based on Hospital Episode statistics, Sutton retrospectively analysed VTE episodes occurring within 12 months of varicose vein surgery. The total incidence of VTE was 0.51%, including 0.54% for open surgery, 0.19% for sclerotherapy, and 0.47% for endovenous laser surgery.

The incidence of VTE was higher for combined procedures (EVLT + phlebectomies) and amounted to 1.26%.

An increased DVT rate was also associated with bilateral treatment (DVT rate: 0.62% vs. 0.3%). Furthermore, re-do surgery and surgery on the short saphenous vein were also associated with increased thrombotic complication rates of 1.62% and 1.16%, respectively [5]. A potentially higher risk in patients undergoing bilateral varicose vein surgery was also suggested in other studies. For instance, Defty et al. reported 0.14% of clinically symptomatic DVT cases after single leg operations and 0.75% in cases of bilateral surgery [22]. Chen et al. investigated the DVT risk in patients undergoing saphenous vein surgical stripping with intraoperative tourniquet application and documented a high rate of DVT. Proximal DVT events occurred in 1.3% of cases and isolated distal DVT events in 6.4% of cases [24]. The authors also enumerated DVT risk factors, which were older age (≥ 65 years), female sex, and gastrocnemius vein dilation [24].

Despite the minimally invasive nature of endovenous thermal and non-thermal ablation, VTE has also been encountered after this form of CVD invasive treatment.

The number/rate of acute thrombotic episodes varies significantly across reports regarding minimally invasive ablation methods. Considering the possibility of local procedure-related complications, such as EHIT (endovenous heat-induced thrombosis), the reported results should be evaluated carefully, and the true rate of DVT events usually remains low. Jacobs et al. prospectively evaluated the results of 277 consecutive office-based radiofrequency ablations (ClosureFast catheters) and performed duplex ultrasound two weeks after the procedures in all patients (86% of the procedures were performed on the great saphenous vein). The DVT, defined by thrombus protrusion with complete occlusion of the femoral or popliteal vein, was visible in only two patients (0.7%) [25]. Marsh et al. analysed outcomes after saphenous vein thermal ablation in a group of patients after RF and EVLT. The DVT events occurred in 0.7% of

46

cases after RF ablation (19 limbs out of 2470 procedures, including four (0.2%) EHIT cases) and in 1% of cases after endovenous laser ablation (four limbs out of 350 procedures, including three (0.9%) EHIT cases). In both groups, a low number of thrombotic complications was noted. However, the authors recommended routine postoperative screening until the significance of EHIT, as a local thrombotic complication, is better understood [26]. Knipp et al. compared the rates of symptomatic DVT that had developed in patients after either endovenous laser ablation alone (308 limbs) or after endovenous laser ablation with concomitant phlebectomy or incompetent perforating vein ligation (135 limbs). The DVT events were found in 2.2% of cases in the combined endovenous and surgical treatment group and in 0% of cases in the endovenous ablation only group. The rates of saphenofemoral thrombus extension (EHIT) were 5.9% and 7.8%, respectively. In 181 patients undergoing endovenous laser treatment only, perioperative antithrombotic prophylaxis was used according to a risk stratification protocol. The authors emphasised that, in their cohort, the use of heparin prophylaxis in patients deemed eligible for ablation and phlebectomy did not have a significant effect on the thrombotic complication rate or on thrombus protrusion into deep veins [27]. Dermody et al. analysed the frequency of thromboembolic complications in endovenous thermal ablation and foam sclerotherapy in the treatment of great saphenous vein insufficiency [28].

In the analysis of 12 randomised controlled trials and a 19-case series of endovenous thermal ablation as well as 12 RCTs and a six-case series of foam sclerotherapy, the estimated incidence of VTE was low, < 1%, and was similar across treatment modalities and study types [28].

Benarroch-Gampel et al. searched the database of the national surgical quality improvement program (NSQIP)/2005-2009/ and identified 3874 patients treated by means of saphenous vein radiofrequency ablation (74.8%) or laser ablation (25.2%) with or without concomitant stab phlebectomy [29]. The incidence of clinically symptomatic DVT was similar in both groups (1.74% for laser ablation and 1.52% for radiofrequency ablation). No difference was observed in the occurrence of clinically overt PE: 0.07% vs. 0%, respectively. The presence of a venous ulcer was identified as a factor that generates a higher DVT rate (2.4-fold higher DVT rate).

According to the authors, ensuring proper positioning of the fibre in the perijunction segment and undertaking preventive measures, including VTE anticoagulant prophylaxis, mobilisation, rapid ambulation, and lower extremity compression, are significant, especially in this group (C6 patients) [29]. Based on systematic reviews, cohort studies, and RCTs addressing endovenous laser treatment in more than 10,000 patients, the Ontario Health Technology Advisory Committee estimated the clinically-registered overall pooled major adverse event rate (including DVT, skin burns, or nerve damage) at 0.63% [30]. How-

Phlebological Review 2018

A review of the risk of deep vein thrombosis in surgical and minimally invasive treatment of varicose veins

ever, a contrasting and interesting observation comes from a report by O’Donnell et al. [31]. This retrospective analysis involved 131,887 patients diagnosed with, and treated for, varicose veins, including 47.8% of patients after multiple therapies, 17.4% after laser ablation, 16.4% after radiofrequency ablation, 9.6% after sclerotherapy, and 8.7% after surgery. The authors followed DVT and PE cases in the medical records of the patients’ insurance systems within 30 days of a claim concerning invasive varicose vein treatment. A DVT (expressed as a percentage of events within each treatment cohort) was identified in 4.4% of the patients treated with radiofrequency thermal ablation, 3.4% of the patients who underwent multiple therapies on the same day, 3.1% of the patients who underwent laser ablation, 2.6% of the patients treated with multiple therapies on different days, 2.4% of the patients treated with varicose vein surgery, and 0.8% of sclerotherapy patients. The authors concluded that the rate of thrombotic complications after invasive treatment of varicose veins in the “real world” is probably higher than expected on the basis of small clinical analyses [31].

In light of the anatomical differences between the great and small saphenous veins, some researchers suggest that a DVT rate is higher in patients treated invasively for SSV incompetence. Paravastu et al. analysed the results of endovenous ablation of the small saphenous vein in a Cochrane analysis from 2016 [32]. According to the analysis of three RCTs comparing laser ablation with surgery and one comparing ultrasound-guided foam sclerotherapy (UGFS) with surgery, the rate of DVT was 0.6% after endovenous laser treatment and 1% in the group treated with surgery [32].

The minimally invasive nature of thermal and non-thermal ablation is associated with a relatively low rate of DVT, not exceeding 1% in most reports [6, 23, 25, 27-29, 31, 33-36]. However, several VTE risk factors identified in patients undergoing this type of procedure can significantly influence the thrombotic event rate.

Several other coexisting factors related to the patient’s clinical condition and history (including age, a previous DVT episode, or other clinically important factors) can result in an increased procedure risk [21, 23, 25].

Rapid mobilisation and compression (used in most centres early after procedures) can at least theoretically decrease the VTE risk. On the other hand, despite the lack of evidence-based guidelines dedicated to thermal ablation applied for the treatment of varicose veins, individualised risk stratification followed by proper prophylaxis implementation (if required) seem reasonable and clinically justified in this context.

Specific thrombotic complications after minimally invasive treatment The introduction of minimally invasive thermal or chemical ablation has elicited the emergence of new

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thrombotic complications related to the mechanism of ablation (thermal or chemical injury of the venous wall), with possible proximal thrombus propagation (endovenous heat-induced thrombosis – EHIT, endovenous foam-induced thrombosis – EFIT, endovenous glueinduced thrombosis – EGIT) [37-39]. Because the rates of these thrombotic events are significant, their nature, natural history, and potential complications should be investigated and clarified. The incidence of EHIT related to thermal ablation was estimated at 0-16% for radiofrequency ablation and at 0-7.7% for laser ablation [40].

The highest EHIT rate was reported by Hingorani et al. in a paper describing the results of the old “closure” radiofrequency system [41]. In this study, based on 66 GSV RF ablation procedures, with 75% of cases also receiving surgical phlebectomy, DVT was found in 12 limbs (16%), including 11 cases of EHIT and one case of crural DVT (without significant clinical consequences) [38].

Further studies with new probes and generators do not confirm this high rate of EHIT after thermal ablation.

Chi et al. studied 360 consecutive patients after endovenous laser ablation in a prospective ultrasound-supported study and found 19 DVT cases (5.2%) in the follow-up period, 18 of which involved either the saphenofemoral or saphenopopliteal junction and should be classified as EHIT (DVT independent of the junction area was found in only one case) [36]. The risk factors affecting the thrombotic event rate in this study included age > 66 years, female gender, and a prior history of superficial vein thrombosis. Sufian et al. investigated risk factors influencing the occurrence of EHIT in patients undergoing radiofrequency ablation [37]. In 6707 treated limbs the incidence of EHIT was 3%. The identified risk factors for the higher EHIT rate were: large vein diameter, male sex and concomitant multiple phlebectomies [37]. Kane et al. retrospectively analysed data regarding endovenous laser procedures performed on 528 veins (GSV 486; SSV 22) and found EHIT in 5.1% of cases, including two patients with EHIT in the popliteal vein after small saphenous vein ablation. All cases resolved completely, and no PE was reported after observation or anticoagulation (depending on EHIT advancement) [42]. According to another research study based on 277 consecutive office-based radiofrequency procedures (86% involving the GSV) followed by Doppler US performed within two weeks of the procedures, EHIT was recognised in 4% of cases and DVT (as ostial thrombus protrusion) in 0.7% of cases. Previous DVT was the only factor associated with post-procedural DVT. The EHIT occurred more frequently in male patients with factor V Leiden deficiency, who underwent small saphenous vein ablation [42].

Currently, two classifications of EHIT are available [38, 43]. According to the one proposed by Kabnick, class I involves saphenous vein thrombosis that develops towards the junction between the superficial and deep

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venous systems (saphenofemoral, saphenopopliteal) but does not extend into the deep venous system; class II is characterised by non-occlusive venous thrombosis, with less than 50% extension (in a cross-sectional area) into the deep system; class III is characterised by non-occlusive venous thrombosis, with more than 50% extension into the deep system; class IV includes cases of occlusive DVT of the femoral/popliteal veins [43]. Lawrence et al. proposed a slightly modified and more detailed EHIT classification system based on six stages: class 1 – a thrombus below the superficial epigastric vein, class 2 – a thrombus at the level of the superficial epigastric vein, class 3 – a thrombus at the level of the femoral vein, class 4 – a thrombus bulging into the femoral vein, class 5 – a thrombus beyond the saphenopopliteal junction adjacent to the wall of the common femoral vein, and class 6 – femoral vein thrombosis [38].

Because most cases of EHIT remain asymptomatic with a very low rate of progression, heat-induced thrombosis seems to be different from typical superficial thromboses unrelated to invasive treatment. The natural history of endovenous heat-induced thrombosis and the possibility of local thrombus retraction, which is supported by clinical observations of EHIT patients, are the basis for the suggestion that thrombotic sequelae of thermal ablation should be subject to treatment. By contrast with ostial thrombus unrelated to endovenous procedures, thermal injury to the venous wall and heat-induced thrombosis make the thrombus more stable. According to Kabnick, clinical and ultrasound-based follow-up without pharmacological treatment should be proposed for class I EHIT. In class II EHIT, the administration of LMWH with ultrasound control until the thrombus resolves to class I EHIT (usually 10-14 days) is suggested. When class 3 or 4 EHIT is identified, therapeutic anticoagulation is recommended [38, 42-44]. Short-term LMWH anticoagulation with repeated ultrasound scans and follow-up until thrombus regression to class I are proposed in certain centres and in class III EHIT (for class IV EHIT, a therapeutic DVT regimen is suggested) due to the possibility of thrombus retraction and regression. The above-mentioned management guidelines adapted for the Lawrence classification are as follows: for classes 1 and 2 only observation and US follow-up are suggested; for class 3 (thrombus up to the level of the femoral venous wall) a decision should be made according to the surgeon’s judgement, including the selection of anticoagulant (LMWH) treatment; for classes 4 and 5 anticoagulation with LMWH is proposed; and for class 6 a full therapeutic DVT treatment regimen is recommended [38]. According to the published outcomes of the clinical implementation of the above-mentioned EHIT management protocol, the stable nature of a thrombus, and low progression and embolisation rates allow safe treatment of most patients [38, 42-45]. Korepta et al. identified 70 patients with EHIT in a study of 4799 ablation procedures. The EHIT patients were treat-

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ed with aspirin (Kabnick classes I and II) and anticoagulation (Kabnick classes III and IV). In the assessed cohort, no thrombus progression in classes III or IV was found upon a repeat US examination. Simultaneously, thrombus (EHIT) progression was evident in two patients with classes I and II (3%) [44]. The low rate of EHIT progression is in line with findings reported by other authors.

Sufian et al. noted EHIT progression in 4.5% of cases during follow-up of 201 patients, all of which resolved within four weeks (the authors used anticoagulation in classes III and IV; cases of class I and II EHIT underwent observation). The factors affecting EHIT occurrence in this study were a large vein, male sex, and simultaneous multiple phlebectomies [37].

Other potential EHIT risk factors have been identified in the literature as well. Some of the most commonly suggested are the size (diameter) of the treated vein, proper procedure execution with an appropriate distance between the device tip and the SFJ, and preservation of the vein washing mechanism (related to the preservation of the patency in the superficial epigastric vein and the restoration of blood inflow into the saphenous vein) [23, 29, 37, 46, 47].

Sermsathanasawadi et al. have suggested that a vein diameter > 10 mm, operative time > 40 min, and a Caprini score > 6 may contribute to a higher EHIT rate in patients treated with radiofrequency ablation [46]. In the study of Rhee et al. EHIT was identified in 4% of cases, including 6.4% after endovenous laser ablation and 2.1% after radiofrequency ablation [48]. Male gender, CEAP classes 3-6, a history of prior thrombosis, and Caprini DVT risk assessment score were also identified as risk factors for EHIT (in the multivariate analysis, Caprini score and male gender remained significant). Jacobs et al. reported EHIT events with thrombus protrusion into the deep system without deep vein occlusion in 4% of cases treated with endovenous ablation [25]. The only identified factor associated with postprocedural DVT was a previous DVT episode. The factors increasing the risk of EHIT were male sex, SSV treatment, aspirin use, and factor V Leiden deficiency [25].

Hicks et al. analysed the role of concomitant phlebectomy and other potential risk factors for EHIT [23]. In a group of 299 patients who underwent radiofrequency ablation (71% of patients also underwent concomitant mini-phlebectomies), an EHIT was identified in 12% of cases (including class 1 EHIT in 5%, class 2 in 4%, class 3 in 1%, and class 4 in 2% of cases). The incidence of EHIT was much higher after concomitant mini-phlebectomy (14% vs. 6%). In the multivariate analysis, concomitant stab phlebectomy and a history of VTE were independently associated with EHIT [23]. Another study suggested pre-treatment coagulation, assessed by D-dimer measurement in patients undergoing radiofrequency ablation of the great saphenous vein [49]. The authors

Phlebological Review 2018

A review of the risk of deep vein thrombosis in surgical and minimally invasive treatment of varicose veins

confirmed a higher rate of thrombotic complications in patients with preoperative elevated D-Dimer levels.

Considering a significant number of patients treated with endovenous thermal ablation of the small saphenous vein, EHIT events may occur in this anatomical location. Taking into account the results of research studies, Harlander-Locke et al. proposed an EHIT classification system dedicated to the small saphenous and popliteal vein anatomy [50]. According to this classification, class A describes cases of thrombus extension at least 1 cm distally from the popliteal vein, class B defines thrombi at the level of the popliteal vein, class C reflects thrombus extension beyond the popliteal vein, and class D represents totally occlusive DVT of the popliteal vein. When applying this classification to a cohort of RF-treated patients with small saphenous vein incompetence, Harlander-Locke et al. found a thrombus extending into the popliteal vein (class C) in 3% of the patients. In all cases, thrombus retracted to the level of the saphenopopliteal junction after a short course of anticoagulation (none of the patients developed DVT – class D). The authors of the classification suggest observation as well as clinical and ultrasound-supported follow-up in cases of small saphenous vein EHIT of classes A and B. In patients with class C EHIT, the surgeon’s judgement should be followed (anticoagulation or observation). In patients with class D EHIT, therapeutic anticoagulation is recommended [50, 51].

Considering the number of performed procedures, the natural history of EHIT, especially in class I and class II, and low progression and embolisation rates reported in the literature, an interesting discussion can arise regarding cost effectiveness of routine post-procedural ultrasound examinations of the lower leg venous system.

Since the initial introduction of thermal ablation, mandatory post-procedural ultrasound examinations have been performed in most centres (usually within the first weeks after the procedure).

The main goals of ultrasound are to confirm venous occlusion and identify EHIT. Some researchers question this approach because of the generally unknown time of EHIT occurrence and the unclear clinical significance of the findings relative to the significant health care costs.

Ryer et al. investigated 842 patients who underwent great saphenous vein endovenous thermal ablation. All patients were examined by US one day after the procedure, and 79% of patients had the second examination performed one week after the procedure [52]. The EHIT events were more likely in patients with prior DVT and large great saphenous veins, with 5.1% of cases requiring anticoagulant treatment. Interestingly, only 47% of EHIT cases were visible in the initial US examination performed 24 hours after the procedure, and 44% of EHIT cases were not identified in the first examination but progressed until EHIT was visible on the second US scan.

Additionally, late DVT was identified in four patients

Phlebological Review 2018

(9%). All of them were diagnosed in another hospital and were not identified during the routine examination protocol. Based on a United States health care pricelist from 2014, the two-ultrasound surveillance algorithm was associated with significant health care charges of 3109 US dollars per delayed VTE event identified. In the conclusion of this study, the authors emphasised the high cost of the EHIT surveillance program and suggested the need for further research to establish cost-effective care for patients after thermal ablation treatment [52].

Because the natural history of EHIT is poorly defined and does not seem to be comparable to unprovoked large superficial vein thrombosis, other authors also question the necessity of routine US examinations after endovenous thermal ablation. In an analysis of endovenous ablation of 13,845 treated limbs, Suarez et al. calculated the number of tests (ultrasound scans) required to detect one case of EHIT/DVT and the total cost of VTE detection according to Medicare fees in the United States of America. The estimated cost related to one case of ultrasound-based VTE detection was 14,667 US dollars. The authors concluded that the low incidence of EHIT and DVT, the unclear clinical significance of ultrasound findings, the mostly benign course of endovenous heat-induced thrombosis, and the high cost of detection of each acute case of thrombosis in routine screening should incite revision of the universal post-EVA screening policy [53].

There is no standardised follow-up protocol dedicated to patients with EHIT or DVT after phlebectomies and minimally invasive treatment. In most reported cases, the diagnosis of DVT has been based on clinical assessment. In patients undergoing open varicose vein procedures, a DVT rate of 0.15% to 5.3% can be expected, which is much higher than that reported in prospective ultrasound-based follow-up after varicose vein surgery [7]. The reported rate of DVT in patients undergoing thermal ablation does not appear to exceed 1%, but the above-mentioned thrombotic complications (EHIT) should be taken into account. Considering the low rate of clinically significant DVT, a routine US screening protocol is probably not justifiable from clinical and economical points of view in varicose vein patients undergoing open surgical treatment. The general risk of DVT in patients after thermal ablation seems to be even lower, but some thrombotic cases can be related to procedure-specific complications, such as EHIT, thus justifying the postoperative US-based approach, at least theoretically. The policy of routine postoperative US screening in patients undergoing thermal ablation is now questioned by many researchers due to the mostly benign nature of EHIT, its low clinical significance, low rate of progression, and significant costs of such a protocol. In most patients, EHIT progression to clinically significant VTE is not expected. Further research focussing on EHIT and preoperative DVT risk factors is needed to proper-

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ly identify patients who will require the postprocedural US screening. Some of these factors have already been identified in studies, but the limited knowledge regarding EHIT and its potential sequelae warrants further research in this field, to develop an effective screening protocol.

Venous thromboembolism prophylaxis after varicose vein surgery and thermal ablation Despite the reports about thrombotic complications after varicose vein surgery and minimally invasive procedures, a properly defined protocol for VTE prophylaxis is still needed. The variety of procedures, variable disease progression, differences in patient-related VTE risk factors, the type of anaesthesia, and ambulation time render this patient population very non-homogeneous.

Other significant problems related to the development of a VTE prophylaxis protocol involve the lack of an appropriate VTE risk evaluation model dedicated to varicose vein patients treated invasively and the limited number of clinical studies on VTE prophylaxis in this population. According to the ACCP guidelines, risk evaluation should be performed in all patients undergoing invasive and non-invasive procedures, and this risk evaluation should be followed by appropriate antithrombotic prophylaxis (adjusted to the estimated VTE risk) [54]. As mentioned before, risk evaluation should concern not only the treatment modality but also patient-dependent risk factors. According to the ACCP document, there is no need for routine thromboprophylaxis in vascular surgery patients, but this does not exclude the need for antithrombotic prophylaxis in patients with clinically significant VTE risk factors [10, 54]. In the ACCP document and in most other guidelines, no special protocols or advice concerning varicose vein patients can be found [54]. According to the ACCP guidelines, low-risk, moderate-risk, and even high-risk and very high-risk general surgery patients are candidates for prophylaxis. Most varicose vein procedures are considered low- or moderate-risk surgeries, but in some cases, VTE risk factors can significantly elevate this risk, categorising patients into high-risk and even very high-risk groups. Properly defined risk stratification is therefore crucial for sufficient risk evaluation. Unfortunately, no clinically validated protocol dedicated to varicose vein patients undergoing chronic venous disease treatment has been established.

The Caprini scale, which is commonly used for surgical patients, has only been validated in some populations, such as intensive care patients, surgical patients and those undergoing plastic surgery [54-57], but not for patients undergoing varicose vein surgery or receiving minimally invasive treatment for chronic venous disease. As mentioned before, according to the study of Rhee et al., the Caprini risk score should be considered in the EHIT risk assessment [48]. In this study on thermal ablation, an ele-

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vated Caprini score reflected higher likelihood of EHIT occurrence. Considering this result, further research on Caprini score validation and the implementation of other population-specific scales seems clinically justifiable and urgently needed. For an optimal prophylaxis algorithm in patients undergoing varicose vein surgery and minimally invasive treatment, individualised VTE risk stratification should be proposed. Despite the above-mentioned difficulties of objective risk evaluation, both the procedureand patient-related factors should be considered. The short duration and often minimally invasive character of procedures, rapid mobilisation and ambulation, and the use of compression represent significant factors that may contribute to a low VTE risk in the absence of other significant VTE risk factors. In other patients, including those requiring extended surgical intervention, general or spinal anaesthesia, or in those with thrombosis risk factors, immobilised and with comorbidities, a significantly higher risk of VTE can be expected, and the assessment of these cases should be individualised.

The number and quality of studies addressing invasive treatment of varicose veins and focusing on pharmacological thromboprophylaxis are very limited, and their results are inconclusive. In a randomised controlled trial, San Norberto García et al. prospectively randomised 262 moderate-risk patients undergoing varicose vein surgery to a group receiving LMWH (bemiparin) at a prophylactic dose for 10 days postoperatively with other standard methods (compression, early ambulation) or to a group managed in the standard way only [58]. The primary study endpoint was the composite of DVT (symptomatic or asymptomatic) detected by bilateral duplex scanning.

In the study, no cases of DVT and no clinical cases of PE, death, or major bleeding were found in any of the groups.

The authors suggested that the LMWH routine for perioperative DVT prophylaxis in moderate-risk patients undergoing varicose vein surgery and in patients with postoperative compression and early ambulation is unnecessary [58]. Enoch et al. evaluated a group of 2186 patients with no prior history of VTE episodes, undergoing varicose vein surgery. The authors adjusted pharmacological prophylaxis to the presence of DVT risk factors. A total of four clinically symptomatic VTE episodes occurred in 1283 patients receiving prophylaxis due to pre-existing risk factors [59]. In a group of 2196 patients undergoing high ligation and stripping of the GSV, Wang used four different VTE prophylaxis approaches: A – no pharmacological VTE prophylaxis, B – subcutaneous low-dose unfractionated heparin (LDUH) in three divided doses, C – LMWH 6000 IU once daily, and D – LMWH 4000 IU twice daily. The postoperative DVT and PE incidence was significantly higher in group A (DVT 5.17%, PE 1.48%) compared to groups B (0.56%, 0%), C (0.35%, 0%), and D (0.36%, 0%). No differences were observed between groups B, C, and D in terms of DVT occurrence.

The incidence of haemorrhagic complications was gener-

Phlebological Review 2018

A review of the risk of deep vein thrombosis in surgical and minimally invasive treatment of varicose veins

ally low in each group but was higher in group B (0.75%) compared to the other groups. The authors concluded that postoperative VTE thromboprophylaxis following high ligation and GSV stripping effectively reduces venous thrombosis complications [60]. In another prospective randomised study, 48 women received LMWH prophylaxis two days after surgery and 45 women received LMWH within seven days of surgery [61]. However, no significant difference in DVT rates was observed (five DVT cases documented in US – 4.65%, including two in the short prophylaxis group and three in the prolonged prophylaxis group). Despite prolonged prophylaxis, no improvement in the DVT rate was found [61].

A protocol to decrease the risk and occurrence of DVT after varicose vein surgery was also proposed by Frings et al. [62]. It included a reduction in the duration of the procedure to 45 minutes, limitation in the use of local anaesthesia, rapid mobilisation, and the use of heparin/LMWH [62]. If more time is required to complete a procedure, then a staged approach should be used, with the second procedure performed one day after the initial procedure or within two days of the initial procedure. All 2805 patients were imaged before discharge and 79% returned for follow-up after three months, but only one patient (0.03%) presented with femoropopliteal DVT. To summarise the data regarding perioperative prophylaxis in patients undergoing varicose vein surgery, no consensus exists in terms of indications or the duration for pharmacological prophylaxis in this clinical setting.

As mentioned before, the very non-homogeneous patient group in terms of the type of procedure and individual VTE risk factors, as well as the lack of properly designed trials, do not allow final conclusions to be drawn concerning a proper prophylaxis protocol. Similarly, minimally invasive treatment of varicose veins, including thermal ablation, does not have a dedicated follow-up protocol for the same reasons. Patients at risk for VTE should receive active antithrombotic pharmacological prophylaxis, but further research in this field is urgently needed. In most cases, an individualised approach with an individual risk assessment should be proposed, but there is probably no need for routine and obligatory pharmacological prophylaxis in all patients undergoing varicose vein treatment.

However, patients at risk for VTE should be candidates for active antithrombotic prophylaxis based on general rules adjusted to the VTE risk level as proposed in the ACCP document and in other guidelines. Of course, rapid mobilisation, ambulation, and compression remain the most important mechanical antithrombotic prophylaxis measures for varicose vein patients. Due to the lack of prospective studies with new anticoagulant drugs in this setting, LMWH remains the drug of choice for pharmacological prophylaxis in this group. Some confirmation of this proposed approach can be found in the literature.

In a results survey performed among members of the vascular surgical society of Great Britain and Ireland,

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Campbell and Ridler described the routine use of pharmacological prophylaxis of thromboembolism in 12% of all cases, but prophylaxis implementation based on risk stratification was reported in 71% of cases [13]. Shabbir et al. performed a study among consultant general surgeons in Ireland regarding LMWH prophylaxis in outpatient surgery, including patients undergoing varicose vein surgery. Fifty-nine per cent of all respondents reported that they stratified patients according to individual VTE risk [63].

Conclusions Despite the minimally invasive nature of varicose vein treatment for chronic venous disease, patients are still at risk of VTE. Due to the lack of properly designed clinical trials and non-homogeneity of patients undergoing surgical and minimally invasive treatment of varicose veins, individual VTE risk-adjusted thromboprophylaxis regimens, together with early mobilisation and ambulation, should be proposed.

The authors declare no conflict of interest.

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43. Kabnick LS, Ombrellino M, Agis H, Mortiz M, Almeida J, Baccaglini U, et al. Endovenous heat induced thrombus (EHIT) at the superficial deep venous junction: a new post-treatment clinical entity, classification and potential treatment strategies.

18th Annual Meeting of the American venous Forum, Miami, Florida 2006.

44. Korepta LM, Watson JJ, Mansour MA, Chambers CM, Cuff RF, Slaikeu JD, Wong PY. Outcomes of a single-center experience with classification and treatment of endothermal heat-induced thrombosis after endovenous ablation J Vasc Surg Venous Lymphat Disord 2017; 5: 332-338.

45. Santin BJ, Lohr JM, Panke TW, Neville PM, Felinski MM, Kuhn BA, Recht MH, Muck PE. Venous duplex and pathologic differences in thrombus characteristics between de novo deep vein thrombi and endovenous heat-induced thrombi. J Vasc Surg Venous Lymphat Disord 2015; 3: 184-189.

46. Sermsathanasawadi N, Voravitvet TY, Chinsakchai K, Wongwanit C, Ruangsetakit C, Mutirangura P. Risk factors for endovenous heat-induced thrombosis after endovenous radiofrequency ablation performed in Thailand. Phlebology 2016; 31: 582-587.

47. Ahn S, Jung IM, Chung JK, Lee T. Changes in Saphenous Vein Stump and Low Incidence of Endovenous Heat-Induced Thrombosis After Radiofrequency Ablation of Great Saphenous Vein Incompetence. Dermatol Surg 2016; 42: 515-520.

48. Rhee SJ, Cantelmo NL, Conrad MF, Stoughton J. Factors Influencing the Incidence of Endovenous Heat-Induced Thrombosis (EHIT). Vasc Endovascular Surg 2013; 47: 207-212.

49. Lurie F, Kistner RL. Pretreatment elevated D-dimer levels without systemic inflammatory response are associated with thrombotic complications of thermal ablation of the great saphenous vein. J Vasc Surg Venous Lymphat Disord 2013; 1: 154-158.

50. Harlander-Locke M, Jimenez JC, Lawrence PF, Derubertis BG, Rigberg DA, Gelabert HA, Farley SM. Management of endovenous heat-induced thrombus using a classification system and treatment algorithm following segmental thermal ablation of the small saphenous vein. J Vasc Surg 2013; 58: 427-431.

51. Harlander-Locke M, Jimenez JC, Lawrence PF, Derubertis BG, Rigberg DA, Gelabert HA. Endovenous ablation with concomitant phlebectomy is a safe and effective method of treatment for symptomatic patients with axial reflux and large incompetent tributaries. J Vasc Surg 2013; 58: 166-172.

52. Ryer EJ, Elmore JR, Garvin RP, Cindric MC, Dove JT, Kekulawela S, Franklin DP. Value of delayed duplex ultrasound assessment after endothermal ablation of the great saphenous vein. J Vasc Surg 2016; 64: 446-451.

53. Suarez L, Tangney E, O’Donnell TF, Iafrati MD. Cost analysis and implications of routine deep venous thrombosis duplex ultrasound scanning after endovenous ablation. J Vasc Surg Venous Lymphat Disord 2017; 5: 126-133.

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54. Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, Samama CM. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: 227-277.

55. Caprini JA. Risk assessment as a guide to thrombosis prophylaxis. Curr Opin Pulm Med 2010; 16: 448-452.

56. Shuman AG, Hu HM, Pannucci CJ, Jackson CR, Bradford CR, Bahl V. Stratifying the risk of venous thromboembolism in otolaryngology. Otolaryngol Head Neck Surg 2012; 146: 719-724.

57. Jeong HS, Miller TJ, Davis K, Matthew A, Lysikowski J, Lazcano E, Reed G, Kenkel JM. Application of the Caprini risk assessment model in evaluation of non-venous thromboembolism complications in plastic and reconstructive surgery patients.

Aesthet Surg J 2014; 34: 87-95.

58. San Norberto García EM, Merino B, Taylor JH, Vizcaíno I, Vaquero C. Low-molecular-weight heparin for prevention of venous thromboembolism after varicose vein surgery in moderate-risk patients: a randomized, controlled trial. Ann Vasc Surg 2013; 27: 940-946.

59. Enoch S, Woon E, Blair SD. Thromboprophylaxis can be omitted in selected patients undergoing varicose vein surgery and hernia repair. Br J Surg 2003; 90: 818-820.

60. Wang H, Sun Z, Jiang W, Zhang Y, Li X, Wu Y. Postoperative prophylaxis of venous thromboembolism (VTE) in patients undergoing high ligation and stripping of the great saphenous vein (GSV). Vasc Med 2015; 20: 117-121.

61. Warot M, Synowiec T, Wencel-Warot A, Daroszewski P, Bojar I, Micker M, Chęciński P. Can deep vein thrombosis be predicted after varicose vein operation in women in rural areas? Ann Agric Environ Med 2014; 21: 601-605.

62. Frings N, Glowacki P, Tran P, Schäfer L. Varicose vein surgery Avoiding deep venous thrombosis. Phlebologie 2006; 35: 233236.

63. Shabbir J, Ridgway PF, Shields W, Evoy D, O’Mahony JB, Mealy K. Low molecular weight heparin prophylaxis in day case surgery.

Ir J Med Sci 2006; 175: 26-29.

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Abstracts

9 International Congress of Polish Society of Phlebology, Lublin, 21-23 June 2018 th

Ocena możliwości zastosowania kompresjoterapii na mikrokrążenie skórne u pacjentów z miażdżycowym niedokrwieniem kończyn dolnych Marcin Gabriel1, Karol Szymański2, Zbigniew Krasiński1, Maciej Zieliński1, Karolina Stefaniak1, Katarzyna Pawlaczyk-Gabriel3 Klinika Chirurgii Naczyniowej, Wewnątrznaczyniowej, Angiologii i Flebologii, Uniwersytet Medyczny w Poznaniu 2 Klinika Chirurgii Urazowej, Uniwersytet Medyczny w Poznaniu 3 Klinika Hipertensjologii, Angiologii i Chorób Wewnętrznych, Uniwersytet Medyczny w Poznaniu 1

Wstęp: Istnieją poważne kontrowersje dotyczące możliwości zastosowania kompresjoterapii u pacjentów z miażdżycowym niedokrwieniem kończyn dolnych (PAOD). Rozstrzygnięcie tego problemu jest szczególnie istotne w odniesieniu do pacjentów z mieszanymi owrzodzeniami goleni.

Cel pracy: Celem badania było określenie przydatności i bezpieczeństwa stosowania kompresjoterapii u pacjentów z zaawansowaną postacią przewlekłego niedokrwienia kończyn dolnych.

Materiał i metody: W prospektywnym, nierandomizowanym badaniu uwzględniono 61 chorych z objawami PAOD w kategorii 3 i 4 wg klasyfikacji Rutherforda.

U pacjentów zastosowano kompresję pneumatyczną lub opaski elastyczne o małej rozciągliwości. Parametry perfuzji obwodowej oznaczono przed włączeniem kompresji oraz po 30 dniach jej stosowania.

Wyniki: Niezależnie od badanej grupy obserwowano poprawę parametrów przepływu w mikrokrążeniu w warunkach spoczynkowych (skórnego przepływu krwi i PD pasma śródbłonkowego) oraz w testach stymulacyjnych (skórnego przepływu krwi, PD pasma śródbłonkowego i neurogennego oraz wskaźnika testu stymulacji niedokrwiennej). Nie zaobserwowano obniżenia stopnia ukrwienia skóry.

Wnioski: Zastosowanie kompresjoterapii u pacjentów z PAOD i z wartością wskaźnika kostka–ramię w przedziale 0,6–0,8 nie pogarsza stanu ukrwienia skóry, poprawiając jednocześnie parametry mikrokrążenia.

Cel pracy: Ocena zaburzeń hemodynamicznych i objawów zespołu pozakrzepowego u chorych z przebytą zakrzepicą żylną biodrowo-udową leczoną endowaskularnie (trombektomia farmakomechaniczna AngioJet, tromboliza celowana, angioplastyka).

Materiał i metody: Leczenie endowaskularne zastosowano u 7 chorych z ostrą (< 14 dni) zakrzepicą biodrowo-udową. Aby polepszyć odpływ żylny, w żyłach biodrowych i udowej wspólnej wykonano udrożnienie. Początkowo zastosowano trombektomię farmakomechaniczną AngioJet i trombolizę celowaną, następnie angioplastykę balonową z lub bez stentu. Na podstawie flebografii przed- i pooperacyjnej każdy segment żył głębokich został oceniony w skali punktowej oceniającej stopnień zamknięcia światła przez skrzeplinę. Podczas wizyt kontrolnych wykonywano badanie USG Doppler żył i oceniano dolegliwości chorych na podstawie skali Villalta.

Wyniki: Średnia wieku leczonych chorych wynosiła 50,6 roku (21–70 lat). Wśród nich były 3 kobiety i 4 mężczyzn. Mediana punktacji wyjściowej stopnia zamknięcia żył wynosiła 8 punktów, po udrożnieniu – 1 punkt. Procentowa skuteczność udrożnienia światła żył wynosiła średnio 78,9% (66,7–100%). Podczas wizyt kontrolnych w żyłach poddanych zabiegom endowaskularnym nie stwierdzono niedrożności, 2 segmenty wykazały znaczną rekanalizację, a w 1 segmencie stwierdzono refluks. Z kolei w żyłach niepoddanych udrożnieniu 2 segmenty wykazały całkowitą niedrożność, 3 segmenty mierną rekanalizację, a w 4 stwierdzono refluks.

U żadnego chorego nie rozpoznano zespołu pozakrzepowego wg skali Villalta (mediana 1; min. 0, max. 3).

Wnioski: Endowaskularne udrożnienie ostrej zakrzepicy biodrowo-udowej może znacząco poprawić odpływ krwi żylnej i zmniejszyć ryzyko powstawania zespołu pozakrzepowego.

The appearance of a cutaneous malignant lymphoma of the limb after foam sclerotherapy treatment of the great saphenous trunk – case report and review of the literature Konrad Tałasiewicz1,2, Damian Łasocha2, Beata Jagielska1 Department of Oncology Diagnostics, Cardioncology and Palliative Medicine, Maria Skłodowska-Curie Memorial Cancer Center and Institute, Warsaw, Poland 2 Centrum Flebologii, Warsaw, Poland 1

Czy leczenie endowaskularne ostrej zakrzepicy żylnej biodrowo-udowej zapobiega powstawaniu zespołu pozakrzepowego?

Paweł Brazis, Paweł Wierzchowski, Przemysław Stężała, Arkadiusz Migdalski, Arkadiusz Jawień Klinika Chirurgii Naczyniowej i Angiologii, Szpital Uniwersytecki nr 1, Uniwersytet Mikołaja Kopernika w Toruniu, Collegium Medicum w Bydgoszczy

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Introduction: Phlebologists during their everyday work are often the first doctors to consult patients with atypical leg ulcers, lumps or lymphedema. Suspicious lesions might appear before, during or after the treatment of chronic venous insufficiency without any correlation. Leg malignancies, although rare, can arise from almost every tissue

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including skin, vascular, nervous, smooth muscle, bone and lymphatic tissue.

Case description: A 75-year-old patient was diagnosed with chronic venous insufficiency of both legs (C2-3 Ep As Pr) in both great saphenous (GSV) trunks in 2006. Both veins were treated with foam sclerotherapy with sodium tetradecyl sulfate. The patient remained under observation after a successful treatment series without signs of recurrence until March of 2016 when a recurrence and reflux were confirmed in the right GSV. The vein was treated once again with foam sclerotherapy; vein closure was observed at 2 weeks after the procedure without any medically important sequelae. A few months after the procedure, the patient developed a mild edema on the proximal part of the thigh followed by a rash.

The patient was treated at the onset by a GP, later by a dermatologist for what was assumed to be an allergic reaction, without any improvement. During the initial diagnostic process, deep venous thrombosis was excluded, and a massive edema on the right thigh was present as well as 4-5 enlarged lymph nodes in the right groin region (max. size 30 × 20 mm). Due to the further worsening appearance of the limb, the patient was referred to a surgical out-patient clinic and treated for an acute bacterial skin infection with concomitant general symptoms including fever.

After further dermatological consultation, the team suspected either a possible lymphomatoid papulosis or a rare complication to the foam sclerotherapy injection sequelae.

Due to this fact, the patient was sent for consultation to a phlebology center, from where (February 2017) the patient was directly transferred to a hospital due to a poor performance status (ECOG 4) in order to exclude a possible malignancy. During admission, the patient was in a poor general condition, confined to bed, with disturbed verbal and logical contact, with somatic delirium symptoms, as well as severe nausea and exhibiting signs of dehydration. An extensive erythematous-ulcerative skin infiltration of the proximal part of the thigh and groin was present with a serious leak and fibrotic lymphedema. The patient was suffering from long-lasting fever > 38°C degrees.

The laboratory results showed significant hypercalcemia with corrected calcium levels of 4.59 mmol/l (2.2-2.65), renal insufficiency, and elevated uric acid 10 mg/dl (2.6-6) and LDH 855 IU/ml (< 248). Due to the life-threatening medical condition and clinical symptoms observed, we decided to perform a fine-needle aspiration biopsy (FNAB) instead of a histopathological biopsy. The FNAB suspension was examined in flow cytometry, and after a few hours a diagnosis of primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL, NOS) with massive soft tissue and skin involvement CD30+/CD25+ weaker was established.

Due to the fast-growing stage 4 pcPTCL, NOS the patient was qualified for chemotherapy with a preface (cyclophosphamide and steroids) with fast improvement of the patient’s general condition. Up until the present and after six cycles of

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chemotherapy, the patient remains under observation without significant clinical recurrence.

Conclusions: In the medical literature, we could not find a possible link between sclerotherapy treatment and malignant conditions as sequelae. Both disease and vein treatment likely appeared at a similar time without any link between them. Phlebologists treating chronic wounds or lymphedema should pay special attention to each ulcerative lesion that does not decrease in size for 2 months, as well as to any discrete lump, diffuse swelling or soft lesion over 5 cm in max. diameter. Such lesions should be considered suspect and diagnosed properly as they are likely malignant.

Problemy w leczeniu żylaków o rzadko spotykanej lokalizacji Krzysztof Piórek Centrum Medyczne NASMED, Warszawa Nietypowa lokalizacja niewydolności stanowi duży problem podczas diagnostyki, planowania i wykonywania zabiegu. Stosowanie klasycznego (długiego) strippingu czy korzystanie z metod wewnątrznaczyniowych zamykających wydolny główny pień naczyniowy obecnie nie powinno już mieć miejsca. Odnalezienie miejsca wyjścia refluksu i zastosowanie odpowiedniej metody łączącej różne techniki pozwala na skuteczne postępowanie lecznicze.

Praca obejmuje 40 problemów w leczeniu żylaków o rzadko spotykanej lokalizacji: 16 zmian w zakresie żyły odpiszczelowej dodatkowej przedniej u 13 chorych (średnia wieku: 48 lat), 10 zmian żyły Giacominiego zamkniętych technikami endowaskularnymi, 7 żylaków nawrotowych oraz 9 niewydolnych perforatorów powodujących izolowaną niewydolność splotów powierzchownych zamkniętych łącznie z żylakami.

Podczas leczenia zastosowano zarówno techniki termiczne (laser i fale radiowe wysokiej częstotliwości), jak i metody nietermiczne: mechanochemiczne – Clarivein, kleje tkankowe VenaSeal, klasyczną mikroflebektomię oraz skleroterapię. Dla każdego chorego indywidualnie dobierano technikę wykonania zabiegu.

Doświadczenia z pracą VenaSeal vs EVLT Andrzej Nykaza1,2, Naser Dib2 Klinika Chirurgii Naczyniowej i Endowaskularnej, Wojskowy Instytut Medyczny, Warszawa 2 Centrum Medyczne NASMED, Warszawa 1

W materiale przedstawiono efekty pracy zespołu NASMED w leczeniu przewlekłej niewydolności żylnej za pomocą systemu okluzyjnego VenaSeal oraz tradycyjnego postępowania przy użyciu EVLT.

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Ostatnie dziesięciolecie to czas rosnącej popularności kleju – monomeru N-butylocyjanoakrylu (n-butyl cyanoacrylate – NBCA) – stosowanego m.in. w: embolizacji naczyniaków, zamykaniu przetok wysokoprzepływowych w malformacjach tętniczo-żylnych (OUN) i tamowaniu krwawień, m.in. do przewodu pokarmowego.

Pierwsze prezentacje „zjazdowo-kongresowe” miały miejsce podczas: XVII International Congress IUP Boston 2015 r., Charing Cross 2015 r., CIRSE 2015 r. Lisbona.

Oparte zostały na badaniach doświadczalnych: Wang YM („Histopathological study of vascular changes after intra-arterial and intravenous injection of N-butyl-2-cyanoacrylate” z 2006 r.), Almeida JI („Vein closure using cyanoacrylate adhesive: 60 day swine model results” z 2011 r. i „Novel vein closure procedure using a proprietary cyanoacrylate adhesive: 30 day swine model results” z 2012 r.) oraz klinicznych: Almeida JI („First human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence” z 2013 r. i „Two-year follow-up of first human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence” z 2014 r.), a także Proebstle TM („The European multicenter cohort study on cyanoacrylate embolization of refluxing great saphenous veins” z 2015 r.).

Pierwszy zabieg w Polsce z wykorzystaniem systemu VenaSeal odbył się 25 stycznia 2014 r., przeprowadził go dr n. med. Naser Dib (NASMED, Warszawa).

Coraz szersze stosowanie kleju wynika z jego korzystnych cech fizykochemicznych w odniesieniu do „zamykania” żylaków: jest lepki (ochrona przed migracją poza pożądany obszar zabiegu, lepszy kontakt kleju z powierzchnią błony wewnętrznej naczynia), szybko polimeryzuje (co zapobiega embolizacji poza obszarem zabiegu), jest miękki i elastyczny (dostosowuje się kształtem do ruchu kończyny i jest „niewyczuwalny” dla chorego), silnie wiąże (lepiej zapobiega rekanalizacji), jest bakteriostatyczny. Niebagatelne znaczenie ma również to, że jego stosowanie jest wygodniejsze zarówno dla lekarza, jak i dla chorego: nie wymaga ono znieczulenia nasiękowego (tumescencji) oraz kompresjoterapii i w związku z tym poprawia mobilność pooperacyjną (możliwość wykonania zabiegu w dowolnym gabinecie posiadającym USG), klej można swobodnie stosować bez względu na porę roku, a jego działanie ma niewielkie efekty uboczne, które są dobrze tolerowane. Ponadto ma nieco szersze wskazania: m.in. obrzęki limfatyczne, przewlekłe niedokrwienie kończyn (lekkiego i umiarkowanego stopnia), otyłość, unieruchomienie, zaburzenia krzepnięcia (leki). Najważniejszym argumentem przemawiającym za EVLT nadal pozostaje natomiast kwestia ceny.

W latach 2014–2018 w NASMED zoperowano łącznie 166 chorych metodą VenaSeal i 529 chorych metodą EVLT. W ww. grupach ok. 80% operacji wykonano na VSM i ok. 20% na VSP. Obserwacje wskazują, że średnica niewydolnych żył operowanych metodą VenaSeal jest coraz większa (śr. 9,8 mm; śr. max. 25 mm), ze skutecznością zabiegu przekraczają-

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cą 97% w obserwacji 12- i 24-miesięcznej: żyły odpiszczelowej – 78%, żyły odstrzałkowej – 22%, jednoczasowo w obu kończynach – 12%, równocześnie żyły odpiszczelowej i odstrzałkowej (ta sama kończyna) – 5%. Skuteczność zabiegu VenaSeal (brak rekanalizacji): 12 miesięcy (48 chorych skontrolowanych) – 97,92%*; 24 miesiące (112 skontrolowanych) – 97,4%**/*** [*rekanalizacja – 1 chory (BMI 43,2 kg/m2), „krzywa uczenia”; **rekanalizacja częściowa; ***rekanalizacja całkowita].

Postępowanie „hybrydowe” w leczeniu zaawansowanej przewlekłej niewydolności żylnej Naser Dib, Marek Maruszyński Centrum Medyczne NASMED, Warszawa Jak wykazują liczne obserwacje i dane kliniczne, jedynie u względnie niewielkiej liczby chorych możliwe jest usunięcie niewydolnych głównych pni żylnych, perforatorów i żylaków z zastosowaniem wyłącznie jednego z dostępnych sposobów – zwłaszcza jednoczasowo. Postęp techniczny i technologiczny, jaki dokonał się w ostatnim dziesięcioleciu w leczeniu zaawansowanej choroby żylnej, obecnie pozwala jednak na skuteczne jednoczasowe zastosowanie kilku minimalnie inwazyjnych metod w postępowaniu terapeutycznym.

Poza omówieniem ogólnym postępowania „hybrydowego” szczegółowo przedstawiono jednoczasowe połączenie ablacji laserowej z nietermalnymi metodami: miniflebektomią, skleroterapią pianową oraz użyciem kleju cyjanoakrylowego u chorego z bardzo dużą niewydolnością żyły odpiszczelowej, niewydolnym perforatorem i rozległymi żylakami (C2, C4), obciążonego zaawansowaną chorobą wieńcową.

Wpływ różnych metod leczenia na gojenie owrzodzeń żylnych goleni Sławomir Kaczmarek1, Marcin Gabriel1, Maciej Zieliński1, Karolina Stefaniak1, Zbigniew Krasiński1, Katarzyna Pawlaczyk-Gabriel2 Klinika Chirurgii Naczyniowej, Wewnątrznaczyniowej, Angiologii i Flebologii, Uniwersytet Medyczny w Poznaniu 2 Klinika Hipertensjologii, Angiologii i Chorób Wewnętrznych, Uniwersytet Medyczny w Poznaniu 1

Owrzodzenia żylne goleni (VLU) były i są przyczyną wyalienowania społecznego osób, których dotyczą. Taki stan rzeczy wymusza poszukiwanie metod terapeutycznych umożliwiających uzyskanie szybkiego i trwałego wyleczenia, co skutkować będzie uwolnieniem chorych od obciążeń

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ekonomicznych i przywróceniem ich do normalnego funkcjonowania społecznego.

Celem przeprowadzonych badań było określenie: 1. Czy uwzględnienie leczenia zabiegowego niewydolnych żył powierzchownych w procesie terapeutycznym pacjentów z VLU wpływa na zmianę odsetka i czasu uzyskania wyleczenia oraz na częstość występowania nawrotów; 2. Czy uwzględnienie w chirurgicznym postępowaniu terapeutycznym przeszczepu skórnego pośredniej grubości wpływa na proces gojenia owrzodzeń żylnych; 3. Którzy pacjenci mogą odnieść korzyści z wykonania chirurgicznej korekcji niewydolności żylnej na drugim etapie, po wcześniejszym zachowawczym wyleczeniu owrzodzenia.

Do prospektywnego, nierandomizowanego badania zakwalifikowano 120 pacjentów z objawami przewlekłej niewydolności żylnej w stopniu zaawansowania C6 i włączono ich do jednej z 4 grup badanych: I – leczeni operacyjnie jednoetapowo (chirurgiczna korekcja niewydolności żylnej, wycięcie dopowięziowe owrzodzenia, przeszczep skórny pośredniej grubości, kompresjoterapia); II – leczeni operacyjnie dwuetapowo [1. etap: leczenie miejscowe owrzodzenia (TIME) + kompresjoterapia do czasu wygojenia owrzodzenia, 2. etap: chirurgiczna korekcja niewydolności żylnej po wygojeniu owrzodzenia]; III – leczeni operacyjnie trójetapowo [1. etap: chirurgiczna korekcja niewydolności żylnej, 2. etap: leczenie miejscowe owrzodzenia (TIME) + kompresjoterapia, 3. etap: w razie braku wygojenia 25% powierzchni owrzodzenia w ciągu 12 tygodni wycięcie dopowięziowe owrzodzenia + przeszczep skórny pośredniej grubości); oraz IV – leczeni zachowawczo (miejscowe leczenie zgodnie z TIME + kompresjoterapia).

W czasie 24 miesięcy obserwacji odsetek wyleczonych owrzodzeń wynosił w poszczególnych grupach odpowiednio: 96,67%, 100%, 83,33% oraz 56,67%. Średni czas potrzebny do wyleczenia owrzodzeń wyniósł odpowiednio: 7,97, 17,23, 13,03 oraz 23,2 tygodnia (p < 0,01). Nawroty owrzodzeń obserwowano odpowiednio u: 10%, 6,67%, 10% i 30% pacjentów z poszczególnych grup. Średni czas rozwoju nawrotu wynosił odpowiednio: 31,33, 23,25, 11,67 i 15,05 tygodnia (p = 0,03).

Uzyskane wyniki umożliwiły wyciągnięcie następujących wniosków: 1. Uwzględnienie zabiegowego leczenia żył układu powierzchownego w procesie terapeutycznym pacjentów z VLU pozwala na istotnie skrócenie czasu potrzebnego do wyleczenia owrzodzeń, zwiększenie odsetka wyleczonych zmian oraz zmniejszenie częstości występowania nawrotów; 2. Położenie przeszczepu skórnego jako części postępowania chirurgicznego ma neutralny wpływ na obiektywne wskaźniki gojenia owrzodzeń. Jednakże w części przypadków może być skutecznym narzędziem wspomagającym leczenie owrzodzeń o większej powierzchni, przyczyniając się do pozytywnego nastawienia pacjentów do kompleksowej terapii m.in. poprzez szybkie zmniejszenie nasilenia bólu; 3. Postępowanie dwuetapowe, uwzględniające wdrożenie chirurgicznej korekty niewydolnych żył powierzchownych po wcześniejszym wyleczeniu owrzodze-

Phlebological Review 2018

nia, należy stosować u pacjentów z owrzodzeniami o mniejszej powierzchni i skrupulatnie przestrzegających zasad kompresjoterapii. Pomimo wydłużenia czasu gojenia duży zakres poprawy jakości życia uzyskuje się z pominięciem przeszczepu skórnego pośredniej grubości.

Analiza porównawcza skuteczności kompleksowej terapii obrzękowej vs bandażowanie wielowarstwowe w leczeniu obrzęków limfatycznych kończyn dolnych Paulina Kajzer1, Marcin Gabriel2, Piotr Kostrzębski3, Maria Naglak4, Karolina Piskorz-Kryk4, Alicja Hazy4, Maria Kleczewska4, Klaudia Skwarska4, Katarzyna Pawlaczyk-Gabriel5 Akademia Wychowania Fizycznego im. Eugeniusza Piaseckiego w Poznaniu 2 Klinika Chirurgii Naczyniowej, Wewnątrznaczyniowej, Angiologii i Flebologii, Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu 3 Strefa Osteopatii, Warszawa 4 Szpital Kliniczny Przemienienia Pańskiego, Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu 5 Klinika Hipertensjologii, Angiologii i Chorób Wewnętrznych Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu 1

W Polsce pacjenci z obrzękiem limfatycznym kończyn dolnych napotykają duże problemy z wdrożeniem kompleksowej terapii przeciwobrzękowej. W wielu przypadkach leczenie jest ograniczone do kompresjoterapii. Celem badania było porównanie skuteczności samej kompresjoterapii wielowarstwowej z kompleksową terapią przeciwobrzękową.

Leczeniu poddano 51 kobiet w wieku 50–80 lat z pierwotnym obrzękiem limfatycznym w II–IV stopniu zaawansowania, które włączono do trzech grup: leczonych z użyciem samej kompresjoterapii wielowarstwowej prowadzonej przez 2 tygodnie (1. grupa) oraz kompleksowej terapii przeciwobrzękowej prowadzonej przez 2 tygodnie (2. grupa) i 3 tygodnie (3. grupa). Analizie podlegały rozmiary leczonych kończyn oraz jakość życia leczonych pacjentów.

We wszystkich trzech grupach badawczych zaobserwowano istotne zmniejszenie rozległości obrzęków limfatycznych na kończynach poddanych leczeniu. Zakres zmian był porównywalny w grupach 1. i 2. Zakres zmniejszenia obrzęków był największy w grupie 3.

Z przeprowadzonych badań wynika, że zastosowanie 2-tygodniowej terapii kompresyjnej pozwala na uzyskanie podobnych wyników jak w przypadku kompleksowej terapii przeciwobrzękowej. Wyniki te budzą wątpliwości dotyczące przydatności drenażu limfatycznego w prowadzonej terapii.

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Instructions for authors Phlebological Review is the official journal of the Polish Phlebological Society and an international journal that features peer-reviewed articles on research related to venous and lymphatic diseases. The journal also publishes papers on related topics such as molecular biology, biochemistry, genetics, biophysics, medical technology and imaging dealing with disorders of the veins and lymphatic vessels.

All of the articles in Phlebological Review are published on an open access basis.

Published articles are available (full text) in PDF and HTML format.

Papers should be submitted to the Editorial Office on-line by the Editorial System: www.editorialsystem.com/pr

Preparation of manuscripts

Articles must be written in English with American or British spelling used consistently throughout. Authors not entirely familiar with English are advised to have their style corrected by professional language editors or native English speakers.

• The length of original articles should not exceed 20 printed pages including text, illustrations, tables, and references.

• Each article should contain a structured abstract (200-250 words).

• The manuscript body should be organized in a standard form with separate sections: Introduction, Material and methods, Results, Discussion, and References. Review articles should be divided into sections and subsections as appropriate without numbering.

• All dimensions and measurements must be given in the metric system.

• The source of any drug and special reagent should be identified.

• Particular attention needs to be paid to the selection of appropriate analysis of data and the results of statistical tests should be incorporated in the Results section.

• The nomenclature used should conform to the current edition of the Nomina Anatomica or Nomina Anatomica Veterinaria.

• Acknowledgements should be made in a separate sheet following Discussion and before References. These should contain a list of dedications, acknowledgements, and funding sources.

• Legends of figures and tables should be prepared as a separate file.

• The editor reserves the right to make corrections.

Tables

• Tables numbered in Roman numerals require a brief but descriptive heading.

• The major divisions of the table should be indicated by horizontal rules.

• Explanatory matter should be included in footnotes, indicated in the body of the table in order of their appearance.

• Tables must not duplicate material in the text or in illustrations.

• Tables must be prepared as a separate file.

Illustrations

All figures should be supplied electronically at a resolution of 300dpi in all standard formats (tiff, jpg, Adobe Photoshop, Corel Draw, and EPS). Name your figure files with “Fig” and the figure number, e.g., Fig1.tif • The maximum figure size is 84 mm or 174 mm for use in a single or double column width, respectively.

• When possible, group several illustrations in one block for reproduction. Like all other figures, the block should be prepared within a rectangular frame to fit within a single or double column width of 84 and 174 mm, respectively, and a maximum page height of 226 mm.

• Each figure should include the scale magnification bar; do not use magnification factors in the figure legends.

• All figures, whether photographs, graphs or diagrams, should be numbered using Arabic numerals and cited in the text in consecutive numerical order.

References

The list of references (written on a separate page) should include only those publications that are cited in the text. Avoid citation of aca-

demic books, manuals and atlases. References must be numbered consecutively. References should be given in square brackets and the consecutive number, e.g. [3, 4, 6-12].

References should be written as follows: Journal papers: initials and names of all authors, full title of the paper, journal abbreviation (according to Index Medicus), year of publication, volume (in Arabic numerals), first and last page (examples below): 1. Valverde F. The organization of area 18 in the monkey. Anat Embryol 1978; 154: 305-334.

2. Uray N.J., Gona A.G. Calbindin immunoreactivity in the auricular lobe and interauricular granular band of the cerebellum in bullfrogs. Brain Behav Evol 1999; 53: 10-19.

Book and monographs: initials and names of all authors, full title, edition, publisher, place, year (examples below): 1. Pollack R.S. Tumor surgery of the head and neck. Karger, Basel 1975.

2. Amaral D.G., Price J.L., Pitkänen A., Carmichael S.T. Anatomical organization of the primate amygdaloid complex. In: Aggleton JP (ed.).

The amygdala. Wiley-Liss, New York 1992; 1-66.

Reference to articles that are accepted for publication may be cited as “in press” or Epub.

Ethical requirements

When reporting experiments on human subjects, authors should indicate whether the procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2000 (concerning the ethical principles for the medical community and forbidding releasing the name of the patient, initials or the hospital evidence number) and with the ethical standards of the responsible committee on human experimentation (institutional and national). Information regarding the ethical committee approval for conducting the research and the informed consent of patients to participating in the studies should be included in the Methods section of those articles, in which the diagnostic intervention or the treatment result from non-routine procedures. The authors presenting case studies are obligated not to disclose patients’ personal data. Regarding photographs, in case of any doubt that the picture inadequately protects the patient’s anonymity his consent is required for publication.

Conflict of interest

Authors are expected to describe sources of the research funding, a role of the potential sponsor in planning, executing and analysis of the study, and the influence (bias) the funding organization had on the content of the article. Other relationships (such as employment, consultancies, stock ownership, honoraria, paid expert testimony) providing potential sources of conflict of interest in relation to the submitted article should also be revealed.

Review process

Received manuscripts are first examined by the Phlebological Review editors. Manuscripts with insufficient priority for publication are rejected promptly. Incomplete submissions or manuscripts not prepared in the advised style will not be sent for a peer review until the correct and complete submission has been provided. The registered manuscripts are sent to 2-3 independent experts for scientific evaluation. We encourage authors to suggest the names of possible reviewers in the Editorial System, but we reserve the right of final selection. Submitted papers are accepted for publication after a positive opinion of the independent reviewers.

The Polish Phlebological Society acquires all copyrights, on an exclusive basis, to manuscripts published, including the right to publish in print, using electronic carriers or others, and on the Internet.

Abstracts may be published without the Publisher’s permission.

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