CONTRIBUTORS
Ranjana H. Advani, MD [96] Division of Oncology Department of Medicine Stanford University Stanford, California
Gheath Alatrash, DO, PhD [25] Associate Professor Department of Stem Cell Transplantation and Cellular Therapy Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center Houston, Texas
Doru T. Alexandrescu, MD [121] Department of Medicine Division of Dermatology
University of California, San Diego VA San Diego Health Care System San Diego, California
Carl E. Allen, MD, PhD [71] Department of Pediatrics
Baylor College of Medicine
Texas Children’s Cancer and Hematology Centers
Texas Children’s Hospital Houston, Texas
Karl E. Anderson, MD [59] Professor of Medicine Division of Gastroenterology
The University of Texas Medical Branch at Galveston Galveston, Texas
Kenneth Anderson, MD [104, 106] Director, Lipper Myeloma Center
Dana-Farber Cancer Institute
Kraft Family Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Daniel A. Arber, MD [66]
Donald West and Mary Elizabeth King Professor and Chair of Pathology University of Chicago Chicago, Illinois
David Avigan, MD [24]
Beth Israel Deaconess Medical Center
Harvard Medical School
Boston, Massachusetts
Farrukh T. Awan, MD, MS [91] Associate Professor of Medicine
The University of Texas, Southwestern Medical Center Dallas, Texas
Jennifer Babik, MD, PhD [31] Division of Infectious Diseases Department of Medicine
University of California, San Francisco San Francisco, California
Lina Badimon, PhD, FESC, FAHA [134] Professor
Cardiovascular Science Program-ICCC CiberCV
Hospital de la Santa Creu I Sant Pau Barcelona, Spain
Robert A. Baiocchi, MD, PhD [89] Professor
Division of Hematology Department of Internal Medicine
Wexner Medical Center and James Cancer Center
The Ohio State University Columbus, Ohio
Kelty R. Baker, MD, FACP [52] President
Kelty R. Baker, M.D. P.A. Houston, Texas
Jacques Banchereau, PhD [21] Director of Immunological Sciences
Jackson Laboratory for Genomic Medicine Farmington, Connecticut
Marije Bartels, MD, PhD [48] Pediatric Hematologist Van Creveldkliniek
University Medical Center Utrecht Utrecht University Utrecht, The Netherlands
Rafael Bejar, MD, PhD [86] Associate Professor of Medicine Moores Cancer Center
University of California, San Diego La Jolla, California
Annelise Bennaceur-Griscelli, MD, PhD [27] Professor of Hematology
Assistance Publique-Hôpitaux de Paris–Paris Saclay Division of Hematology
Université Paris Saclay
INSERM U935-INGESTEM National iPSC Infrastructure Villejuif, France
Bruce Beutler, MD [19] Center for the Genetics of Host Defense
University of Texas, Southwestern Medical Center Dallas, Texas
Giada Bianchi, MD [104, 106]
Instructor in Medicine
Harvard Medical School
Associate Director, Amyloidosis Program
Brigham and Women’s Hospital/Dana Farber Cancer Institute
Associate Physician
Division of Hematology, Department of Medicine
Brigham and Women’s Hospital Boston, Massachusetts
David A. Bond, MD [89]
Division of Hematology
Department of Internal Medicine
Wexner Medical Center and James Cancer Center
The Ohio State University Columbus, Ohio
Niels Borregaard,* MD, PhD [64]
The Granulocyte Research Laboratory Department of Hematology
National University Hospital Copenhagen, Denmark
Mettine H. A. Bos, PhD [112]
Assistant Professor
Division of Thrombosis and Hemostasis
Einthoven Laboratory for Vascular and Regenerative Medicine
Leiden University Medical Center
Leiden, The Netherlands
Jonathan E. Brammer, MD [93]
Assistant Professor
Division of Hematology
James Cancer Center
The Ohio State University Columbus, Ohio
Paul F. Bray, MD [111]
Professor of Internal Medicine
Division of Hematology and Hematologic Malignancies
Program in Molecular Medicine
University of Utah Salt Lake City, Utah
Alessandro Broccoli, MD, PhD [100]
Institute of Hematology “Seràgnoli” University of Bologna Bologna, Italy
Virginia C. Broudy, MD [80]
Scripps Professor of Hematology Department of Medicine (Hematology) University of Washington (Hematology) Seattle, Washington
Francis K. Buadi, MD [107]
Division of Hematology
Mayo Clinic Rochester, Minnesota
*Deceased
Harry R. Buller, MD, PhD [133]
Professor of Vascular Medicine
Department of Vascular Medicine
Amsterdam UMC
Amsterdam Medical Centers
University of Amsterdam Amsterdam, The Netherlands
Linda J. Burns, MD [1, 3]
Consultant and Senior Scientific Director
Center for International Blood and Marrow Transplant Research Milwaukee, Wisconsin
John C. Byrd, MD [91]
Warren Brown Chair of Leukemia Research
Distinguished University Professor
The Ohio State University Columbus, Ohio
Brad R. Cairns, PhD [10]
Howard Hughes Medical Institute
Department of Oncological Sciences
Huntsman Cancer Institute
University of Utah School of Medicine
Salt Lake City, Utah
Michael A. Caligiuri, MD [5, 73, 77, 78]
Department of Hematology and Hematopoietic Cell Transplantation
Deana and Steve Campbell Physician-in-Chief Distinguished Chair President, City of Hope National Medical Center
Los Angeles, California
Elias Campo, MD, PhD [95]
Hematopathopathology Section Department of Anatomic Pathology
Hospital Clinic of Barcelona University of Barcelona Barcelona, Spain
Jaime Caro, MD [57]
Professor of Medicine, Emeritus Division of Hematology
Cardeza Foundation for Hematological Research
Sidney Kimmel Medical College Philadelphia, Pennsylvania
Martin P. Carroll, MD [13]
Associate Professor of Medicine Division of Hematology and Oncology
Department of Medicine
Perelman School of Medicine
University of Pennsylvania Philadelphia, Pennsylvania
Guillaume Cartron, MD, PhD [98]
Professor
Hematology Department
University Hospital of Montpellier Montpellier, France
Alessandro Casini, MD, PD [124]
Staff Physician
Division of Angiology and Hemostasis
Faculty of Medicine
University Hospitals of Geneva Geneva, Switzerland
Jorge J. Castillo, MD [108]
Clinical Director
Bing Center for Waldenstrom Macroglobulinemia
Division of Hematological Malignancies
Dana-Farber Cancer Institute;
Associate Professor
Harvard Medical School Boston, Massachusetts
Carla Casulo, MD [101]
Associate Professor of Medicine, Oncology Program Director, Hematology/Oncology Fellowship
Lymphoma Service
Wilmot Cancer Institute
University of Rochester Rochester, New York
Bruce A. Chabner, MD [28]
Professor Medicine
Massachusetts General Hospital
Harvard Medical School Boston, Massachusetts
Richard W. Childs, MD [20]
Clinical Director
Chief, Laboratory of Transplantation Immunotherapy
National Heart, Lung, and Blood Institute
National Institutes of Health
Bethesda, Maryland
Theresa L. Coetzer, PhD [47]
Department of Molecular Medicine and Haematology
School of Pathology
Faculty of Health Sciences
University of the Witwatersrand Johannesburg, South Africa
Claudia S. Cohn, MD [138]
Associate Professor
Laboratory Medicine and Pathology
University of Minnesota Minneapolis, Minnesota
Barry S. Coller, MD [111]
David Rockefeller Professor of Medicine
Head, Allen and Frances Adler Laboratory of Blood and Vascular Biology
Physician-in Chief, Rockefeller University Hospital
Vice President for Medical Affairs
Rockefeller University New York, New York
Michiel Coppens, MD, PhD [131]
Associate Professor of Medicine
Amsterdam UMC
University of Amsterdam Department of Vascular Medicine
Amsterdam Cardiovascular Sciences Amsterdam, The Netherlands
Gay M. Crooks, MB, BS [74]
Professor
Departments of Pathology and Lab Medicine and Pediatrics Division of Pediatric Hematology/Oncology
David Geffen School of Medicine
University of California, Los Angeles Los Angeles, California
David C. Dale, MD [63] Professor of Medicine University of Washington School of Medicine Seattle, Washington
Chi V. Dang, MD, PhD [13]
Scientific Director
Ludwig Institute for Cancer Research New York, New York Professor, The Wistar Institute Philadelphia, Pennsylvania
Utpal P. Davé, MD [4]
Co-Director, Hematopoiesis and Hematologic Malignancies Program
Indiana University Melvin and Bren Simon Comprehensive Cancer Center;
Associate Professor of Medicine and Microbiology and Immunology Division of Hematology and Oncology
R.L. Roudebush VA Medical Center Indiana University School of Medicine Indianapolis, Indiana
Madhav V. Dhodapkar, MD [21]
Brock Chair and Professor of Hematology Oncology Director, Winship Center for Cancer Immunology Emory University Atlanta, Georgia
Michael Dickinson, MBBS (Hons), DMedSci, FRACP, FRCPA [97]
Peter MacCallum Cancer Centre
Royal Melbourne Hospital
Sir Peter MacCallum Department of Oncology
University of Melbourne Melbourne, Australia
Angela Dispenzieri, MD [107] Division of Hematology
Mayo Clinic Rochester, Minnesota
May Dong, BA [13]
Medical Student
University of Massachusetts Medical School Worcester, Massachusetts
Anne G. Douglas, MD [67, 68]
Resident, Department of Neurology Perelman School of Medicine
University of Pennsylvania Philadelphia, Pennsylvania
Steven D. Douglas, MD [67, 68]
Professor of Pediatrics
Chief Section of Immunology
Senior Vice Chair, Pediatrics
Committee on Appointments and Promotions Chair, Pediatrics
Committee on Prestigious Awards and Honors Perelman School of Medicine
University of Pennsylvania Philadelphia, Pennsylvania
Martin Dreyling, MD, PhD [99] Professor of Medicine
Department of Medicine III LMU Hospital Munich, Germany
Connie J. Eaves, PhD, FRS(C) [27]
Distinguished Scientist
Terry Fox Laboratory
British Columbia Cancer Research Institute
Professor
Department of Medical Genetics & School of Biomedical Engineering
University of British Columbia Vancouver, Canada
Yvonne A. Efebera, MD, MPH [77]
Professor Department of Internal Medicine
Division of Hematology, Blood and Marrow Transplant Director and Founder, Comprehensive Amyloidosis Clinic Director, Careers in Internal Medicine
The Ohio State University Columbus, Ohio
William B. Ershler, MD [8]
Director
Division of Benign Hematology
Inova Schar Cancer Institute
Inova Fairfax Hospital Falls Church, Virginia
Miguel A. Escobar, MD [122] Professor of Medicine and Pediatrics
Director, Gulf States Hemophilia and Thrombophilia Center
University of Texas Health Science Center McGovern Medical School Houston, Texas
Andrew G. Evans, MD, PhD [101]
Director of Hematopathology
Associate Professor of Pathology and Laboratory Medicine
University of Rochester School of Medicine and Dentistry
Rochester, New York
Ross M. Fasano, MD [56]
Center for Transfusion and Cellular Therapies
Department of Pathology and Laboratory Medicine
Emory University School of Medicine
Atlanta, Georgia
Amir T. Fathi, MD [28]
Associate Professor of Medicine
Massachusetts General Hospital
Harvard Medical School Boston, Massachusetts
Brian J. Franz, PhD [137] Vitalant
Phoenix, Arizona
Kathleen Freson, PhD [119]
Director of Center for Molecular and Vascular Biology
Professor
Department of Cardiovascular Sciences
Katholieke Universiteit Leuven Leuven, Belgium
Aharon G. Freud, MD, PhD [93] Associate Professor
Department of Pathology
The Ohio State University Columbus, Ohio
Jonathan W. Friedberg, MD, MMSc [101] Director, Wilmot Cancer Institute
Samuel Durand Professor of Medicine and Oncology University of Rochester Rochester, New York
Monica Fung, MD, MPH [31] Division of Infectious Diseases Department of Medicine
University of California, San Francisco San Francisco, California
Stephen J. Galli, MD [66] Professor of Pathology and of Microbiology and Immunology
Stanford University School of Medicine
Stanford University Medical Center Stanford, California
Tomas Ganz, PhD, MD [38, 43, 44] Departments of Medicine and Pathology
David Geffen School of Medicine
University of California, Los Angeles Los Angeles, California
Terry B. Gernsheimer, MD [139] Department of Medicine
University of Washington
Seattle Cancer Care Alliance Seattle, Washington
Stanton L. Gerson, MD [26]
Case Comprehensive Cancer Center
Case Western Reserve University University Hospital of Cleveland Cleveland, Ohio
Morie A. Gertz, MD, MACP [107] Division of Hematology Mayo Clinic Rochester, Minnesota
Larisa J. Geskin, MD, FAAD [102] Department of Dermatology Columbia University Irving Medical Center New York, New York
David Ginsburg, MD [125]
James V. Neel Distinguished University Professor Departments of Internal Medicine, Human Genetics, and Pediatrics
Howard Hughes Medical Institute
University of Michigan Medical School Ann Arbor, Michigan
Elizabeth K.K. Glennon, PhD [14] Postdoctoral Scientist
Center for Global Infectious Disease Research Seattle Children’s Research Institute Seattle, Washington
Lucy A. Godley, MD, PhD [11] Section of Hematology/Oncology Department of Medicine
The Comprehensive Cancer Center
The University of Chicago Chicago, Illinois
Kandace Gollomp, MD [117] Assistant Professor of Pediatrics
The Children’s Hospital of Philadelphia University of Pennsylvania School of Medicine Philadelphia, Pennsylvania
Blanca Gonzalez, MD, PhD [95] Hematopathopathology Section Department of Anatomic Pathology Hospital Clinic of Barcelona University of Barcelona Barcelona, Spain
Victor R. Gordeuk, MD [50] Professor of Medicine University of Illinois Chicago, Illinois
Jason Gotlib, MD, MS [65] Professor of Medicine Division of Hematology
Stanford Cancer Institute
Stanford University School of Medicine Stanford, California
Steven Grant, MD [15] Professor of Medicine
Shirley Carter and Sture Gordon Olsson
Professor of Oncology
Virginia Commonwealth University Richmond, Virginia
Ralph Green, MD, PhD, FRCPath [42, 45]
Professor of Pathology and Medicine Department of Pathology and Laboratory Medicine University of California, Davis Sacramento, California
Xylina T. Gregg, MD [39]
Utah Cancer Specialists Salt Lake City, Utah
Michael R. Grever, MD [92] Professor Emeritus Division of Hematology Department of Internal Medicine
The Ohio State University Columbus, Ohio
John Gribben, MD, DSc, FRCP, FRCPath, FMedSci [76]
Barts Cancer Institute Centre for Haemato-Oncology
Queen Mary University of London London, United Kingdom
Emma M. Groarke, MD [8] Fellow, Hematology Branch National Heart, Lung, and Blood Institute
National Institutes of Health
Mark Hatfield Clinical Research Center Bethesda, Maryland
Katherine A. Hajjar, MD [114, 135]
Brine Family Professor of Cell and Developmental Biology Professor and Vice Chair for Research Department of Pediatrics; Professor of Pediatrics in Medicine
Senior Associate Dean for Faculty Weill Cornell Medicine New York, New York
Amel Hamdi, PhD [60] Department of Physiology Lady Davis Institute McGill University Montreal, Quebec, Canada
Robert D. Harrington, MD [80] Professor Department of Medicine (Infectious Diseases) University of Washington; Chief of Medicine
Section Chief, Infectious Diseases Harborview Medical Center Seattle, Washington
Xiangrong He, MD [138]
Clinical Fellow
Laboratory Medicine and Pathology
Mayo Clinic Rochester, Minnesota
Jeanne E. Hendrickson, MD [56]
Professor
Departments of Laboratory Medicine and Pediatrics
Yale University School of Medicine
New Haven, Connecticut
Paul C. Herrmann, MD, PhD [53]
Professor and Chair
Department of Pathology and Human Anatomy
Loma Linda University School of Medicine Loma Linda, California
Gabriela S. Hobbs, MD [28]
Instructor in Medicine
Massachusetts General Hospital Harvard Medical School Boston, Massachusetts
Steven Horwitz, MD [103]
Associate Attending Lymphoma Service, Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
Chi-Joan How, MD [28]
Fellow in Medical Oncology
Massachusetts General Hospital Boston, Massachusetts
Russell D. Hull, MBBS, MSc [133]
Emeritus Professor of Medicine
Foothills Medical Centre and University of Calgary, Calgary, Canada
Achille Iolascon, MD, PhD [40] Professor of Medical Genetics
Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II Naples, Italy
Joseph E. Italiano, Jr., PhD [111]
Associate Professor of Medicine
Division of Hematology
Brigham and Women’s Hospital
Vascular Biology Program
Boston Children’s Hospital
Harvard Medical School Boston, Massachusetts
Jill M. Johnsen, MD [125]
Associate Member
Bloodworks
Associate Professor of Medicine
University of Washington
Seattle, Washington
Patrick Connor Johnson, MD [28]
Fellow in Medical Oncology
Massachusetts General Hospital Boston, Massachusetts
Lynn B. Jorde, PhD [9]
Mark and Kathie Miller Presidential Professor and Chair Department of Human Genetics
University of Utah School of Medicine
Salt Lake City, Utah
Alexis Kaushansky, PhD [14]
Associate Professor
Department of Pediatrics
School of Medicine
University of Washington; Center for Global Infectious Disease Research
Seattle Children’s Hospital Seattle, Washington
Kenneth Kaushansky, MD, MACP [3, 16, 17, 84, 110, 115, 116, 118]
Senior Vice President, Health Sciences
Dean, Renaissance School of Medicine
Stony Brook University
Stony Brook, New York
Rami Khoriaty, MD [40]
Assistant Professor, Department of Internal Medicine
Assistant Professor, Department of Cell and Developmental Biology
Section Head, Classical Hematology
Core Member, Rogel Cancer Center University of Michigan
Ann Arbor, Michigan
Thomas J. Kipps, MD, PhD [75] Director, Hematology Malignancy Program Director, Center for Novel Therapeutics
Distinguished Professor of Medicine
Moores Cancer Center
University of California, San Diego San Diego, California
Adam S. Kittai, MD [91]
Assistant Professor of Medicine
The Ohio State University Columbus, Ohio
Mark J. Koury, MD [4] Professor of Medicine, Emeritus Division of Hematology/Oncology
Vanderbilt University School of Medicine Nashville, Tennessee
Taco Kuijpers, MD, PhD [61, 64]
Professor of Immunology
Consultant Pediatric Infectious Diseases and Clinical Immunology
Amsterdam University Medical Center
University of Amsterdam Amsterdam, The Netherlands
Abdullah Kutlar, MD [50] Professor of Medicine
Augusta University
Augusta, Georgia
Robert A. Kyle, MD, MACP [109] Professor of Medicine Laboratory Medicine and Pathology
Mayo Clinic College of Medicine Rochester, Minnesota
Geoffrey A. Land, PhD, HCLD, F(AAM) [137] Vitalant
Phoenix, Arizona
Angela M. Lager [11]
Section of Hematology/Oncology Department of Medicine
The Comprehensive Cancer Center
The University of Chicago Chicago, Illinois
Lewis L. Lanier, PhD [20] Professor Department of Microbiology and Immunology University of California, San Francisco San Francisco, California
Richard A. Larson, MD [90] Professor of Medicine
Section of Hematology/Oncology Department of Medicine
The Comprehensive Cancer Center
The University of Chicago Chicago, Illinois
Michelle M. Le Beau, PhD [11] Section of Hematology/Oncology Department of Medicine
The Comprehensive Cancer Center
The University of Chicago Chicago, Illinois
Houry Leblebjian, Pharm D [28] Department of Pharmacy Dana Farber Cancer Institute Boston, Massachusetts
Frank W.G. Leebeek, MD, PhD [130] Professor of Hematology Department of Hematology
Erasmus University Medical Center Rotterdam, The Netherlands
Matthew M. Lei, Pharm D [28] Department of Pharmacy
Massachusetts General Hospital Boston, Massachusetts
Marcel Levi, MD, PhD, FRCP [3, 18, 32, 113, 115, 120, 121, 127]
Professor of Medicine
University College London Hospitals
London, United Kingdom; Professor of Medicine
University of Amsterdam Amsterdam, The Netherlands
Jerrold H. Levy, MD, FAHA, FCCM [140]
Professor of Anesthesiology
Cardiothoracic Anesthesiology, Critical Care, and Surgery (Cardiothoracic)
Duke University School of Medicine Durham, North Carolina
Zhenyu Li, MD, PhD [111]
Cardiovascular Research Center University of Kentucky Lexington, Kentucky
Marshall A. Lichtman, MD, MACP [1, 3, 36, 54, 62, 69, 70, 82, 85, 87, 88, 105]
Professor Emeritus of Medicine and of Biochemistry and Biophysics
Dean Emeritus, School of Medicine and Dentistry
James P. Wilmot Cancer Institute
University of Rochester Medical Center Rochester, New York
Jane L. Liesveld, MD [87, 88]
Professor of Medicine (Hematology-Oncology)
James P. Wilmot Cancer Institute
University of Rochester Medical Center Rochester, New York
David C. Linch, FRCP, FRCPath, FMed Sci [3, 94]
Professor of Haematology Cancer Program Director UCL and UCL Hospitals Biomedical Research Centre University College London London, United Kingdom
Ton Lisman, PhD [130]
Professor of Experimental Surgery Surgical Research Laboratory Section of Hepatobiliary Surgery and Liver Transplantation Department of Surgery
University Medical Center, Groningen Groningen, The Netherlands
Pete Lollar, MD [126]
Aflac Cancer and Blood Disorders Center Department of Pediatrics
Emory University Atlanta, Georgia
Christine Lomas-Francis, MSc, FIBMS [136]
Immunohematology and Genomics
New York Blood Center Long Island City, New York
Gerard Lozanski, MD [92]
Professor of Pathology Clinical Department of Pathology
The Ohio State University Columbus, Ohio
Naomi L.C. Luban, MD [56] Professor of Pediatrics and Pathology School of Medicine and Health Sciences
George Washington University; Medical Director, Office of Human Subjects Protection Senior Hematologist Children’s National Hospital Washington, DC
Fabienne Lucas, MD, PhD [76] Department of Pathology Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts
Nicola C. Maciocia, MBChB, BSc, FRCPath [23] Department of Haematology Cancer Institute
London, United Kingdom
Paul M. Maciocia, MBChB, PhD, FRCPath [23] Department of Haematology Cancer Institute
London, United Kingdom
Anthony G. Mansour, MD [78] Department of Hematology and Hematopoietic Cell Transplantation
City of Hope National Medical Center Los Angeles, California
Elaine R. Mardis, PhD [10]
The Steve and Cindy Rasmussen Institute for Genomic Medicine Nationwide Children’s Hospital Columbus, Ohio
Kenneth L. McClain, MD, PhD [71] Department of Pediatrics
Baylor College of Medicine
Texas Children’s Cancer and Hematology Centers
Texas Children’s Hospital Houston, Texas
Jeffrey McCullough, MD [138] Global Blood Advisor
Edina, Minnesota; Emeritus Professor
Laboratory Medicine and Pathology
University of Minnesota Minneapolis, Minnesota
Neha Mehta-Shah, MD, MSCI [103]
Assistant Professor Department of Medicine
Division of Oncology
Washington University School of Medicine in St. Louis St. Louis, Missouri
Guiomar Mendieta, MD, MSc [134]
Cardiovascular Institute, Cardiology Department
Hospital Clinic
University of Barcelona
Cardiovascular Science Program, ICCC
Hospital de la Santa Creu I Sant Pau Barcelona, Spain
Marzia Menegatti, BSc, PhD [123]
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and Fondazione Luigi Villa Milan, Italy
Manoj P. Menon, MD, MPH [80]
Associate Professor
Department of Medicine (Hematology)
University of Washington; Section Chief
Hematology and Medical Oncology
Harborview Medical Center; Assistant Professor
Vaccine and Infectious Disease
Clinical Research Divisions
Fred Hutchinson Cancer Research Center
Seattle, Washington
Dean D. Metcalfe, MD [66]
Chief, Mast Cell Biology Section
Laboratory of Allergic Diseases
National Institute of Allergy and Infectious Diseases
National Institutes of Health Bethesda, Maryland
Saskia Middeldorp, MD, PhD [131]
Professor
Department of Vascular Medicine
Amsterdam Cardiovascular Sciences
Amsterdam UMC
University of Amsterdam Amsterdam, The Netherlands
Martha P. Mims, MD, PhD [7]
Professor of Medicine and Chief Hematology/Oncology
Baylor College of Medicine Houston, Texas
Anjali Mishra, PhD [93]
Assistant Professor
Sidney Kimmel Cancer Center
Thomas Jefferson University Philadelphia, Pennsylvania
Ananya Datta Mitra, MD [42, 45]
Section of Hematopathology
Department of Pathology and Laboratory Medicine
University of California, Davis Health, School of Medicine
Sacramento, California
Joel Moake, MD [52]
Professor of Medicine Emeritus
Baylor College of Medicine
Senior Research Scientist
Department of Bioengineering
Rice University
Houston, Texas
Narla Mohandas, DSc [33]
Laboratory of Red Cell Physiology
New York Blood Center
New York, New York
Jeffrey J. Molldrem, MD [25] Professor and Chair, ad interim Division of Cancer Medicine
Department of Hematopoietic Biology and Malignancy
The University of Texas MD Anderson Cancer Center Houston, Texas
Eva Marie Y. Moresco, PhD [19]
Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas, Texas
Diana Morlote, MD [2, 46]
Assistant Professor
Hematopathology and Molecular Genetic Pathology Division of Genomics and Bioinformatics
Department of Pathology
The University of Alabama at Birmingham Birmingham, Alabama
Alison Moskowitz, MD [103]
Associate Attending Lymphoma Service Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
Eric Mou, MD [96] Division of Oncology Department of Medicine
Stanford University Stanford, California
William A. Muller, MD, PhD [114]
Janardan K. Reddy Professor of Pathology Feinberg School of Medicine
Northwestern University Chicago, Illinois
Natarajan Muthusamy, DVM, PhD [73] Professor, Hematology
The Ohio State University Columbus, Ohio
Christopher S. Nabel, MD, PhD [28] Fellow in Medical Oncology
Massachusetts General Hospital Boston, Massachusetts
Srikanth Nagalla, MBBS, MS [57]
Associate Professor of Medicine
Program Director, Hematology/Oncology Fellowship Division of Hematology/Oncology
University of Texas, Southwestern Medical Center
Dallas, Texas
Marguerite Neerman-Arbez, PhD [124] Professor
Department of Genetic Medicine and Development University of Geneva Faculty of Medicine Geneva, Switzerland
Robert S. Negrin, MD [29] Professor of Medicine
Chief, Division of Blood and Marrow Transplantation
Stanford University School of Medicine Stanford, California
Luigi D. Notarangelo, MD [79]
Laboratory of Clinical Immunology and Microbiology
National Institute of Allergy and Infectious Diseases
National Institutes of Health Bethesda, Maryland
Hans D. Ochs, MD [79]
Professor of Pediatrics
Jeffrey Modell Chair of Pediatric Immunology Research Center for Immunity and Immunotherapies
Seattle Children’s Research Institute University of Washington Seattle, Washington
Elizabeth K. O’Donnell, MD [104, 106] Assistant Professor of Medicine
Massachusetts General Hospital Harvard Medical School Boston, Massachusetts
Willem Ouwehand, MD, PhD, FMedSci [119]
Professor of Experimental Haematology Honorary Consultant of Haematology
National Health Service Blood Transfusion Honorary Faculty Member Wellcome Trust Sanger Institute; Department of Haematology University of Cambridge NHS Blood and Transplant Building
Cambridge Biomedical Campus Cambridge, United Kingdom
Charles H. Packman, MD [55] Professor of Medicine
Department of Hematologic Oncology and Blood Disorders
Levine Cancer Institute
University of North Carolina School of Medicine
Charlotte, North Carolina
Teresa Padró, PhD, FESC [134] Cardiovascular Science Program-ICCC CiberCV
Hospital de la Santa Creu I Sant Pau Barcelona, Spain
James Palis, MD [6] Professor of Pediatrics
Director, Center for Pediatric Biomedical Research University of Rochester Medical Center Rochester, New York
Charles J. Parker, MD [41]
Professor of Medicine
Department of Medicine
Division of Hematology and Hematologic Malignancies
University of Utah School of Medicine
Salt Lake City, Utah
Karl S. Peggs, MB BCh, MA, MRCP, FRCPath [22]
Senior Lecturer in Stem Cell Transplantation and Immunotherapy
Director
Adult Stem Cell Transplantation Services
University College London Cancer Institute London, United Kingdom
Flora Peyvandi, MD, PhD [123]
Director, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Vice Director, Department of Pathophysiology and Transplantation
Università degli Studi di Milano
Milan, Italy
John D. Phillips, PhD [59]
Division of Hematology
Department of Medicine
University of Utah School of Medicine
Salt Lake City, Utah
Mortimer Poncz, MD [117]
University of Pennsylvania School of Medicine
The Children’s Hospital of Philadelphia
Professor of Pediatrics
Chief, Pediatric Hematology
Philadelphia, Pennsylvania
Prem Ponka,* MD, PhD, FCMA [60]
Department of Physiology
McGill University and Lady Davis Institute
Montreal, Quebec, Canada
Pierluigi Porcu, MD [93]
Professor of Medical Oncology, Dermatology, and Cutaneous Biology
Director, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation
Department of Medical Oncology
Sidney Kimmel Cancer Center
Thomas Jefferson University
Philadelphia, Pennsylvania
Jacqueline N. Poston, MD [139]
Department of Medicine
University of Washington
Seattle Cancer Care Alliance
Fred Hutchinson Cancer Research Center
Bloodworks NW Research Institute Seattle, Washington
Jaroslav F. Prchal, MD, FRCPC [83]
Director
Department of Oncology
St. Mary’s Hospital Center
Montreal, Quebec, Canada
Josef T. Prchal, MD [3, 34, 35, 51, 58, 60, 83, 85]
Professor of Hematology and Malignant Hematology
Adjunct in Genetics and Pathology
University of Utah & Huntsman Cancer Institute
Salt Lake City, Utah
1. interní klinika VFN a Ústav patologické fyziologie, 1. LF School of Medicine
Universita Karlova, Prague, Czech Republic
Martin A. Pule, MRCP, FRCPath [23]
Department of Haematology
Senior Lecturer in Haematology
Clinical Haematologist Consultant
UCL Cancer Institute
London, United Kingdom
Sergio A. Quezada, PhD [22]
Department of Haematology
University College London Cancer Institute
London, United Kingdom
Noopur S. Raje, MD, PhD [28]
Professor of Medicine
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts
Jacob H. Rand, MD [132]
Professor of Pathology and Laboratory Medicine
New York Presbyterian Weill Cornell New York, New York
A. Koneti Rao, MD, FACP, FAHA [119]
Sol Sherry Professor of Medicine
Director, Benign Hematology, Hemostasis and Thrombosis
Co-Director, Sol Sherry Thrombosis Research Center
Professor of Thrombosis Research and Pharmacology
Professor of Clinical Pathology and Laboratory Medicine
Lewis Katz School of Medicine
Temple University Philadelphia, Pennsylvania
Gary E. Raskob, PhD [133]
Dean, Hudson College of Public Health
Regents Professor, Epidemiology and Medicine
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma
Lubica Rauova, PhD [117]
University of Pennsylvania School of Medicine
Research Associate Professor of Pediatrics
The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania
*Deceased
Vishnu V.B. Reddy, MD [2, 46]
Section Head, UAB Hospital Hematology Bone Marrow Lab Director, Hematopathology Fellowship Program
Division of Laboratory Medicine
Professor, Department of Pathology
The University of Alabama at Birmingham Birmingham, Alabama
Mark T. Reding, MD [122]
Associate Professor of Medicine
Director, Center for Bleeding and Clotting Disorders University of Minnesota Medical Center Minneapolis, Minnesota
Pieter H. Reitsma, PhD [112]
Professor of Experimental Medicine
Einthoven Laboratory for Experimental Vascular and Regenerative Medicine
Leiden University Medical Center
Leiden, The Netherlands
Shoshana Revel-Vilk, MD, MCs [72]
Associate Professor of Pediatrics
Gaucher Unit and Pediatric Hematology/Oncology Unit
Shaare Zedek Medical Center
Hebrew University Medical School Jerusalem, Israel
Andrew R. Rezvani, MD [29]
Assistant Professor of Medicine
Associate Clinical Chief, Division of Blood and Marrow Transplantation
Stanford University School of Medicine Stanford, California
Paul G. Richardson, MD [28]
R.J. Corman Professor of Medicine
Dana Farber Cancer Institute
Harvard Medical School
Boston, Massachusetts
Jia Ruan, MD, PhD [135]
Associate Professor of Clinical Medicine
Lymphoma Program
Division of Hematology and Medical Oncology
Weill Cornell Medicine
New York, New York
Roberta Russo, PhD [40]
Assistant Professor of Medical Genetics
Department of Molecular Medicine and Medical Biotechnology
CEINGE
Biotecnologie Avanzate
University of Naples Federico II Naples, Italy
Joel Saltz, MD, PhD [12]
Founding Chair and Professor of Biomedical Informatics
Renaissance School of Medicine
Stony Brook University
Stony Brook, New York
Clémentine Sarkozy, MD, PhD [98]
Department of Therapeutic Innovation
Gustave Roussy
Université Paris-Saclay Villejuif, France
Sam Schulman, MD, PhD, FRCPS [32] Professor, Department of Medicine
Director, Thrombosis Service
Hamilton Health Sciences General Hospital
McMaster University Hamilton, Ontario, Canada
Steven Scoville, MD, PhD [5]
General Surgery
The Ohio State University Columbus, Ohio
Marie Scully, MB BS, MRCP, FRCPath, MD [128]
Professor
Department of Haematology
Cardiometabolic Programme
National Institute of Health Research
University College London/University College London Hospitals
Biomedical research Centre
University College London Hospital London, United Kingdom
Christopher S. Seet, MD, PhD [74]
Assistant Professor
Department of Medicine
Division of Hematology-Oncology
David Geffen School of Medicine
University of California, Los Angeles Los Angeles, California
George B. Segel, MD [6, 36]
Emeritus Professor of Pediatric Professor of Medicine
James P. Wilmot Cancer Institute
University of Rochester Medical Center Rochester, New York
Uri Seligsohn, MD [127]
Professor and Director
Amalia Biron Research Institute of Thrombosis and Hemostasis Department of Hematology
Chaim Sheba Medical Center
Tel-Hashomer and Sackler Faculty of Medicine
Tel Aviv University
Tel Aviv, Israel
John F. Seymour, FAHMS, MB, BS, PhD, FRACP [97]
Peter MacCallum Cancer Centre
Royal Melbourne Hospital; Professor
Sir Peter MacCallum Department of Oncology
University of Melbourne Melbourne, Australia
Beth Shaz, MD [140]
New York Blood Center
New York, New York
Vivien A. Sheehan, MD, PhD [50]
Assistant Professor of Pediatrics
Baylor College of Medicine
Houston, Texas
Taimur Sher, MD [107] Division of Hematology/Oncology
Mayo Clinic Jacksonville, Florida
Sujit Sheth, MD [49] Department of Pediatrics
Weill Cornell Medicine
New York, New York
William Shomali, MD [65] Division of Hematology
Stanford Cancer Institute
Stanford University School of Medicine Stanford, California
Suthesh Sivapalaratnam, MD, PhD, MRCP (London) [119]
Senior Lecturer Department of Haematology
Royal London Hospital London, United Kingdom
Sarah J. Skuli, MD [13] Fellow
Division of Hematology and Oncology Department of Medicine
Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania
Susan S. Smyth, MD, PhD [111] Professor and Chief Division of Cardiovascular Medicine
Physician Investigator
Lexington Veterans Affairs Medical Center University of Kentucky Lexington, Kentucky
Philippe Solal-Céligny, MD, PhD [98] Professor of Haematology Institut de Cancérologie de l’Ouest Saint-Herblain, France
Michael A. Spinner, MD [96] Division of Oncology Department of Medicine
Stanford University Stanford, California
David P. Steensma, MD [86]
Associate Professor of Medicine
Edward P. Evans Chair of Myelodysplastic Syndromes Research Dana-Farber Cancer Institute
Harvard Medical School
Boston, Massachusetts
Sean R. Stowell, MD, PhD [126]
Center for Transfusion and Cellular Therapies Department of Pathology and Laboratory Medicine
Emory University Atlanta, Georgia
Sankar Swaminathan, MD [81]
Don Merril Rees Presidential Endowed Chair Professor and Division Chief Division of Infectious Diseases
University of Utah School of Medicine
Salt Lake City, Utah
Jeff Szer, MB BS, FRACP [72] Professor of Medicine
Peter MacCallum Cancer Centre
The Royal Melbourne Hospital University of Melbourne and Clinical Haematology Melbourne, Victoria, Australia
Tsewang Tashi, MD [83]
Huntsman Cancer Center University of Utah Salt Lake City, Utah
Swee Lay Thein, MD [49]
National Heart, Lung, and Blood Institute
The National Institutes of Health Bethesda, Maryland
Perumal Thiagarajan, MD [34] Professor of Medicine and Pathology
Baylor College of Medicine
Director of Transfusion Medicine and Hematology Laboratory
Michael E. DeBakey VA Medical Center Houston, Texas
Megan Trager, MD [102] Department of Dermatology
Columbia University Irving Medical Center New York, New York
Steven P. Treon, MD, PHD, FACP, FRCP [108] Professor of Medicine
Harvard Medical School; Director
Bing Center for Waldenstrom’s Macroglobulinemia
Dana Farber Cancer Institute Boston, Massachusetts
Giorgio Trinchieri, MD [20]
National Institutes of Health Distinguished Investigator Chief, Laboratory of Integrative Cancer Immunology
Center for Cancer Research
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
Ali G. Turhan, MD, PhD [27]
Professor of Hematology
Assistance Publique-Hôpitaux de Paris–Paris Saclay
Division of Hematology
Université Paris Saclay
INSERM U935-INGESTEM National iPSC Infrastructure Villejuif, France
Eduard J. van Beers, MD, PhD [48] Hematologist
Van Creveldkliniek
University Medical Center Utrecht Utrecht University Utrecht, The Netherlands
Cornelis van’t Veer, PhD [112] Associate Professor Center for Experimental and Molecular Medicine
Amsterdam University Medical Centres University of Amsterdam Amsterdam, The Netherlands
Richard van Wijk, PhD [48] Associate Professor
Central Diagnostic Laboratory
University Medical Center Utrecht Utrecht University Utrecht, The Netherlands
Ralph R. Vassallo, MD, FACP [137] Vitalant
Scottsdale, Arizona; Clinical Professor
Department of Pathology University of New Mexico Albuquerque, New Mexico
Kamalakannan Vijayan, PhD [14] Fellow PhD
Seattle Children’s Research Institute Seattle, Washington
Gemma Vilahur, PhD, FESC [134] Cardiovascular Science Program-ICCC CiberCV
Hospital de la Santa Creu I Sant Pau Barcelona, Spain
Dietlind L. Wahner-Roedler, MD, MS, FACP [109] Professor of Medicine Department of Medicine Mayo Clinic College of Medicine Rochester, Minnesota
Luojun Wang, MD [95] Pathology Fellow
Hematopathopathology Section Department of Anatomic Pathology Hospital Clinic of Barcelona University of Barcelona Barcelona, Spain
Robert Weinstein, MD [30] Professor of Medicine and Pathology
University of Massachusetts Medical School Chief, Division of Transfusion Medicine
University of Massachusetts Memorial Medical Center Worcester, Massachusetts
Matthew Weinstock, MD [24]
Beth Israel Deaconess Medical Center
Harvard Medical School Boston, Massachusetts
Karl Welte, MD [63] Professor of Hematology University to Tubingen Tubingen, Germany
Sidney W. Whiteheart, PhD, FAHA [111] George Schwert Endowed Professor of Biochemistry University Research Professor University of Kentucky College of Medicine Lexington, Kentucky
Lucia R. Wolgast, MD [132] Director, Clinical Laboratories Montefiore Moses Hospital Associate Professor, Albert Einstein College of Medicine Montefiore Medical Center Albert Einstein College of Medicine Bronx, New York
Neal S. Young, MD [8, 37] Chief, Hematology Branch National Heart, Lung, and Blood Institute Mark Hatfield Clinical Research Center National Institutes of Health Bethesda, Maryland
X. Long Zheng, MD, PhD [129] Professor and Russell J. Eilers, MD Endowed Chair Chair of Department of Pathology and Laboratory Medicine The University of Kansas Medical Center Kansas City, Kansas
Liang Zhou, MD, PhD [15] Instructor, Hematology/Oncology Medical College of Virginia Virginia Commonwealth University Richmond, Virginia
Pier Luigi Zinzani, MD, PhD [100] Chief of Lymphoma and CLL Unit Institute of Hematology “Seràgnoli” University of Bologna Bologna, Italy
Ari Zimran, MD [72]
Associate Professor of Medicine Gaucher Unit, Shaare Zedek Medical Center Hebrew University Medical School Jerusalem, Israel
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INITIAL APPROACH TO THE PATIENT: HISTORY AND PHYSICAL EXAMINATION
Marshall A. Lichtman and Linda J. Burns
SUMMARY
The care of a patient with a suspected hematologic abnormality begins with a systematic attempt to determine the nature of the illness by eliciting an in-depth medical history and performing a thorough physical examination. The physician should identify the patient’s symptoms systematically and obtain as much relevant information as possible about their origin and evolution and about the general health of the patient by appropriate questions designed to explore the patient’s recent and remote experience. Reviewing previous records may add important data for understanding the onset or progression of illness. Hereditary and environmental factors should be carefully sought and evaluated. The use of drugs and medications, nutritional patterns, and sexual behavior should be considered. The physician should follow the medical history with a physical examination to obtain evidence for tissue and organ abnormalities that can be assessed through bedside observation to permit a careful search for signs of the illnesses suggested by the history. Skin changes and hepatic, splenic, or lymph nodal enlargement are a few findings that may be of considerable help in pointing toward a diagnosis. Additional history should be obtained during the physical examination, as findings suggest an additional or alternative consideration. Thus, the history and physical examination should be considered as a unit, providing the basic information with which further diagnostic information is integrated, with blood and marrow studies, imaging studies and tissue examination .
Primary hematologic diseases are common in the aggregate, but hematologic manifestations secondary to other diseases occur even more frequently. For example, the signs and symptoms of anemia and the presence of enlarged lymph nodes are common clinical findings that may be related to a hematologic disease, but which also occur frequently as secondary manifestations of disorders not considered primarily hematologic. A wide variety of diseases may produce signs or symptoms of hematologic illness. Thus, in patients with a connective tissue disease, all the signs and symptoms of anemia may be elicited and lymphadenopathy may be notable, but additional findings are usually present that indicate primary involvement of some system besides the hematopoietic (marrow) or lymphopoietic (lymph nodes or other lymphatic sites). In this discussion, emphasis is placed on the clinical findings resulting from either primary hematologic disease or the complications of hematologic disorders so as to avoid presenting an extensive catalog of signs and symptoms encountered in general clinical medicine.
In each discussion of specific diseases in subsequent chapters, the signs and symptoms that accompany the particular disorder are presented, and the clinical findings are covered in detail. This chapter takes a more general systematic approach.
THE HEMATOLOGY CONSULTATION
Table 1–1 lists the major abnormalities that result in the evaluation of the patient by the hematologist. The signs indicated in Table 1–1 may reflect a primary or secondary hematologic problem. For example, immature granulocytes in the blood may be signs of myeloid diseases such as myelogenous leukemia, or, depending on the frequency of these cells and the level of immaturity, the dislodgment of cells resulting from marrow metastases of a carcinoma. Nucleated red cells in the blood may reflect the breakdown in the marrow–blood interface seen in primary myelofibrosis or the hypoxia of congestive heart failure. Certain disorders have a propensity for secondary hematologic abnormalities; kidney, liver, and chronic inflammatory diseases are prominent among such abnormalities. Chronic alcoholism, nutritional fetishes, and the use of certain medications may be causal factors in blood cell or coagulation protein disorders. Pregnant women and persons of older age are prone to certain hematologic disorders: anemia, thrombocytopenia, or intravascular coagulation in the former case, and hematologic malignancies, pernicious anemia, and clonal hematopoiesis with mild cytopenias in the latter. The history and physical examination can provide vital clues to the possible diagnosis and also to the rationale choice of laboratory tests.
THE HISTORY
In today’s technology- and procedure-driven medical environment, the importance of carefully gathering information from patient inquiry and examination is at risk of losing its primacy. The history (and physical examination) remains the vital starting point for the evaluation of any clinical problem.1–3
GENERAL SYMPTOMS AND SIGNS
Performance status (PS) is used to establish semiquantitatively the extent of a patient’s disability. This status is important in evaluating patient comparability in clinical trials, in determining the likely tolerance to cytotoxic therapy, and in evaluating the effects of therapy. Table 1–2 presents well-founded criteria for measuring PS for adults (Karnofsky Score) and children (Lansky Score).4,5 An abbreviated version, as proposed by the Eastern Cooperative Oncology Group (Table 1–3), sometimes is used.6
Weight loss is a frequent accompaniment of many serious diseases, including primary hematologic malignancies, but it is not a prominent accompaniment of most hematologic diseases. Many “wasting” diseases, such as disseminated carcinoma and tuberculosis, cause anemia, and pronounced emaciation should suggest one of these diseases rather than anemia as the primary disorder.
Fever is a common early manifestation of the aggressive lymphomas or acute leukemias as a result of pyrogenic cytokines (eg, interleukin [IL]-1, IL-6, and IL-8) released as a reflection of the disease itself. After chemotherapy-induced cytopenias or in the face of accompanying immunodeficiency, infection is usually the cause of fever. In patients with “fever of unknown origin,” lymphoma, particularly Hodgkin lymphoma, should be considered. Occasionally, primary myelofibrosis, acute leukemia, advanced myelodysplastic syndrome, and other lymphomas may also cause fever. In rare patients with severe pernicious anemia or hemolytic anemia, fever may be present. Pel-Ebstein fever is a prolonged cyclic fever, first associated with Hodgkin lymphoma (it occurs rarely), but may occur, also, in some infections (cytomegalovirus or Mycobacterium tuberculosis infection in an immunocompromised host). Chills may accompany severe hemolytic processes and the bacteremia that may complicate the immunocompromised or neutropenic
TABLE 1–1. Findings That May Lead to a Hematology Consultation
Decreased hemoglobin concentration (anemia)
Leukopenia or neutropenia
Thrombocytopenia
Pancytopenia
Increased hemoglobin concentration (polycythemia)
Leukocytosis or neutrophilia
Eosinophilia
Basophilia or mastocytosis
Monocytosis
Lymphocytosis
Thrombocytosis
Immature granulocytes or nucleated red cells in the blood
Lymphadenopathy
Splenomegaly
Hypergammaglobulinemia: monoclonal or polyclonal
Purpura
Exaggerated bleeding: spontaneous or trauma related
Prolonged partial thromboplastin or prothrombin coagulation times
Venous thromboembolism
Thrombophilia
Elevated serum ferritin level
Obstetrical adverse events (eg, recurrent fetal loss, stillbirth, and HELLP syndrome)
HELLP, hemolytic anemia, elevated liver enzymes, and low platelet count.
TABLE 1–2. Performance Status Criteria in Adults and Children
Karnofsky Scale (age ≥16 years)a
Percentage (%)
patient. Night sweats suggest the presence of low-grade fever and may occur in patients with lymphoma or leukemia.
Fatigue, malaise, and lassitude are such common accompaniments of both physical and emotional disorders that their evaluation is complex and often difficult. In patients with serious disease, these symptoms may be readily explained by fever, muscle wasting, or other associated findings. Patients with moderate or severe anemia frequently complain of fatigue, malaise, or lassitude and these symptoms may accompany the hematologic malignancies. Fatigue or lassitude may occur also with iron deficiency even in the absence of sufficient anemia to account for the symptom. In slowly developing chronic anemias, the patient may not recognize reduced exercise tolerance, or other loss of physical capabilities except in retrospect, after a remission or a cure has been induced by appropriate therapy. Anemia may be responsible for more symptoms than has been traditionally recognized, as suggested by the remarkable improvement in quality of life of most uremic patients treated with erythropoietin.
Weakness may accompany anemia or the wasting of malignant processes, in which cases it is manifest as a general loss of strength or reduced capacity for exercise. The weakness may be localized as a result of neurologic complications of hematologic disease. In vitamin B12 deficiency (eg, pernicious anemia), there may be weakness of the lower extremities, accompanied by numbness, tingling, and unsteadiness of gait. Peripheral neuropathy also occurs with monoclonal immunoglobulinemias. Weakness of one or more extremities in patients with leukemia, myeloma, or lymphoma may signify central or peripheral nervous system invasion or compression as a result of vertebral collapse, a paraneoplastic syndrome (eg, encephalitis), or brain or meningeal involvement. Myopathy secondary to malignancy occurs with the hematologic malignancies and is usually manifest as weakness of proximal muscle groups. Footdrop or wristdrop may occur in lead poisoning, amyloidosis, systemic autoimmune diseases, or as a complication of vincristine therapy. Paralysis may occur in acute intermittent porphyria.
Able to carry on normal activity; no special care is needed
100 Normal; no complaints, no evidence of disease
90 Able to carry on normal activity
80 Normal activity with effort
Unable to work; able to live at home, cares for most personal needs; a varying amount of assistance is needed
70 Cares for self; unable to carry on normal activity or to do active work
60 Requires occasional assistance but is able to care for most needs
50 Requires considerable assistance and frequent medical care
Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly
40 Disabled; requires special care and assistance
30 Severely disabled; hospitalization indicated, although death not imminent
20 Very sick, hospitalization necessary
10 Moribund, fatal process progressing rapidly
Lansky Scale (age ≥1 year and <16 years)b
Able to carry on normal activity; no special care is needed
Fully active
Minor restriction in physically strenuous play
Restricted in strenuous play, tires more easily, otherwise active
Mild to moderate restriction
Both greater restrictions of, and less time spent in active play
Ambulatory up to 50% of time, limited active play with assistance/supervision
Considerable assistance required for any active play; fully able to engage in quiet play
Moderate to severe restriction
Able to initiate quiet activities
Needs considerable assistance for quiet activity
Limited to very passive activity initiated by others
Completely disabled, not even passive play
0 Dead Dead
aThe Karnofsky Scale data is adapted with permission from V Mor, L Laliberte, JN Morris, and M Wiemann.4
bThe Lansky Scale data is adapted with permission from SB Lansky, MA List, LL Lansky, et al.5
Ears
TABLE 1–3. Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade Activity
0 Fully active, able to carry on all predisease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg, light housework, office work
2 Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5 Dead
Reproduced with permission from Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. Dec;5(6):649-655.
SPECIFIC SYMPTOMS OR SIGNS
Nervous System
Headache may be the result of a number of causes related to hematologic diseases. Anemia or polycythemia may cause mild to severe headache. Invasion or compression of the brain by leukemia or lymphoma, or opportunistic infection of the CNS by Cryptococcus or Mycobacterium species, may also cause headache in patients with hematologic malignancies. Hemorrhage into the brain or subarachnoid space in patients with thrombocytopenia or other bleeding disorders may cause sudden, severe headache.
Paresthesias may occur because of peripheral neuropathy in pernicious anemia or secondary to hematologic malignancy or amyloidosis. They may also result from therapy with several chemotherapeutic agents (eg, vincristine, cisplatin, and others).
Confusion may accompany malignant or infectious processes involving the brain, sometimes as a result of the accompanying fever. Confusion may also occur with severe anemia, hypercalcemia (eg, myeloma), thrombotic thrombocytopenic purpura, or high-dose glucocorticoid therapy. Confusion or apparent senility may be a manifestation of pernicious anemia. Frank psychosis may develop in acute intermittent porphyria or with high-dose glucocorticoid therapy.
Impairment of consciousness may be a result of increased intracranial pressure secondary to hemorrhage or leukemia or lymphoma in the CNS. It may also accompany severe anemia, polycythemia, hyperviscosity secondary, usually, to an immunoglobulin (Ig) M monoclonal protein (uncommonly IgA or IgG) in the plasma, or a leukemic hyperleukocytosis syndrome, especially in chronic myelogenous leukemia.
Eyes
Conjunctival plethora is a feature of polycythemia and pallor a result of anemia. Occasionally blindness may result from retinal hemorrhages secondary to severe anemia and thrombocytopenia or blurred vision resulting from severe hyperviscosity resulting from macroglobulinemia or extreme hyperleukocytosis of leukemia. Partial or complete visual loss can stem from retinal vein or artery thrombosis. Diplopia or disturbances of ocular movement may occur with orbital tumors or paralysis of the third, fourth, or sixth cranial nerve because of compression by tumor, especially extranodal lymphoma, extramedullary myeloma, or myeloid (granulocytic) sarcoma.
Vertigo, tinnitus, and “roaring” in the ears may occur with marked anemia, polycythemia, hyperleukocytic leukemia, or macroglobulinemiainduced hyperviscosity. Ménière disease was first described in a patient with acute leukemia and inner ear hemorrhage.
Nasopharynx, Oropharynx, and Oral Cavity
Epistaxis may occur in patients with thrombocytopenia, acquired or inherited platelet function disorders, and von Willebrand disease. Anosmia or olfactory hallucinations occur in pernicious anemia. The nasopharynx may be invaded by a granulocytic sarcoma or extranodal lymphoma; the symptoms are dependent on the structures invaded. The paranasal sinuses may be involved by opportunistic organisms, such as fungus in patients with severe, prolonged neutropenia. Pain or tingling in the tongue occurs in pernicious anemia and may accompany a vitamin deficiency or severe iron deficiency. Macroglossia occurs in amyloidosis. Bleeding gums may occur with bleeding disorders. Infiltration of the gingiva with leukemic cells occurs notably in acute monocytic leukemia. Ulceration of the tongue or oral mucosa may be severe in the acute leukemias or in patients with severe neutropenia. Dryness of the mouth may be caused by hypercalcemia, secondary, for example, to myeloma. Dysphagia may be seen in patients with severe mucous membrane atrophy associated with chronic iron-deficiency anemia.
Neck
Painless swelling in the neck is characteristic of lymphoma but also may be caused by a number of other diseases. Occasionally, the enlarged lymph nodes of lymphomas may be tender or painful because of secondary infection or rapid growth. Painful or tender lymphadenopathy is usually associated with inflammatory reactions, such as infectious mononucleosis or suppurative adenitis. Diffuse swelling of the neck and face may occur with obstruction of the superior vena cava as a result of lymphomatous compression.
Chest and Heart
Both dyspnea and palpitations, usually on effort but occasionally at rest, may occur because of anemia or pulmonary embolism. Congestive heart failure may supervene, and angina pectoris may become manifest in anemic patients. The impact of anemia on the circulatory system depends in part on the rapidity with which it develops, and chronic anemia may become severe without producing major symptoms; with severe acute blood loss, the patient may develop shock with a nearly normal hemoglobin level, prior to compensatory hemodilution. Cough may result from enlarged mediastinal nodes compressing the trachea or bronchi. Chest pain may arise from involvement of the ribs or sternum with lymphoma or multiple myeloma, nerve-root invasion or compression, or herpes zoster; the pain of herpes zoster usually precedes the skin lesions by several days. Chest pain with inspiration suggests a pulmonary infarct, as does hemoptysis. Tenderness of the sternum may be quite pronounced in chronic myelogenous or acute leukemia, and occasionally in primary myelofibrosis, or if intramedullary lymphoma or myeloma proliferation is rapidly progressive.
Gastrointestinal System
Dysphagia is discussed under “Nasopharynx, Oropharynx, and Oral Cavity” above. Anorexia frequently occurs but usually has no specific diagnostic significance. Hypercalcemia and azotemia cause anorexia, nausea, and vomiting. A variety of ill-defined gastrointestinal complaints grouped under the heading “indigestion” may occur with hematologic diseases. Abdominal fullness, premature satiety, belching, or discomfort may occur because of a greatly enlarged spleen, but such splenomegaly may also be entirely asymptomatic. Abdominal pain may
arise from intestinal obstruction by lymphoma, retroperitoneal bleeding, lead poisoning, ileus secondary to therapy with the vinca alkaloids, acute hemolysis, allergic purpura, the abdominal crises of sickle cell disease, or acute intermittent porphyria. Diarrhea may occur in pernicious anemia. It also may be prominent in the various forms of intestinal malabsorption, although significant malabsorption may occur without diarrhea. In small-bowel malabsorption, steatorrhea may be a notable feature. Malabsorption may be a manifestation of small-bowel lymphoma. Gastrointestinal bleeding related to thrombocytopenia or other bleeding disorder may be occult but often is manifest as hematemesis or melena. Hematochezia can occur if a bleeding disorder is associated with a colonic lesion. Constipation may occur in the patient with hypercalcemia or in one receiving treatment with the vinca alkaloids.
Genitourinary and Reproductive Systems
Impotence or bladder dysfunction may occur with spinal cord or peripheral nerve damage caused by one of the hematologic malignancies or with pernicious anemia. Priapism may occur in hyperleukocytic leukemia, essential thrombocythemia, or sickle cell disease. Hematuria may be a manifestation of hemophilia A or B. Red urine may also occur with intravascular hemolysis (hemoglobinuria), myoglobinuria, or porphyrinuria. Injection of anthracycline drugs or ingestion of drugs such as phenazopyridine (Pyridium) regularly causes the urine to turn red. The use of deferoxamine mesylate (Desferal) may result in rust colored urine. Amenorrhea may also be induced by drugs, such as antimetabolites or alkylating agents. Menorrhagia is a common cause of iron deficiency, and care must be taken to obtain a history of the number of prior pregnancies and an accurate assessment of the extent of menstrual blood loss. Semiquantification can be obtained from estimates of the number of days of heavy bleeding (usually <3), the number of days of any bleeding (usually <7), number of tampons or pads used (requirement for double pads suggests excessive bleeding), degree of blood soaking, and clots formed, and from inquiries such as, “Have you experienced a gush of blood when a tampon is removed?” However, an objective distinction between menorrhagia (loss of more than 80 mL blood per period) and normal blood loss can best be made by a visual assessment technique using pictorial charts of towels or tampons.7 Menorrhagia may occur in patients with bleeding disorders.
Back and Extremities
Back pain may accompany acute hemolytic reactions or be a result of involvement of bone or the nervous system in acute leukemia or aggressive lymphoma. It is one of the most common manifestations of myeloma.
Arthritis or arthralgia may occur with gout secondary to increased uric acid production in patients with hematologic malignancies, especially acute lymphocytic leukemia in childhood, myelofibrosis, myelodysplastic syndrome, and hemolytic anemia. They also occur in the plasma cell dyscrasias, acute leukemias, and sickle cell disease without evidence of gout, and in allergic purpura. Arthritis may accompany hemochromatosis, although the association has not been carefully established. In the latter case the arthritis starts typically in the small joints of the hand (second and third metacarpal joints), and episodes of acute synovitis may be related to deposition of calcium pyrophosphate dehydrate crystals. Hemarthroses in patients with severe bleeding disorders cause marked joint pain. Autoimmune diseases may present as anemia and/or thrombocytopenia, and arthritis appears as a later manifestation. Shoulder pain on the left may be a result of infarction of the spleen and on the right of gall bladder disease associated with chronic hemolytic anemia such as hereditary spherocytosis. Bone pain may occur with bone involvement by the hematologic malignancies; it is common in the congenital hemolytic anemias, such as sickle cell anemia, and may occur in myelofibrosis. Administration of granulocyte- or
granulocyte-monocyte colony-stimulating factor may induce bone pain. In patients with Hodgkin lymphoma, ingestion of alcohol may induce pain at the site of any lesion, including those in bone. Edema of the lower extremities, sometimes unilateral, may occur because of obstruction to veins or lymphatics by lymphomatous masses or from deep venous thrombosis. The latter can also cause edema of the upper extremities.
Skin
Skin manifestations of hematologic disease, including changes in texture or color, itching, and the presence of specific or nonspecific lesions, may be of great importance. The skin in iron-deficient patients may become dry, the hair dry and fine, and the nails brittle. In hypothyroidism, which may cause anemia, the skin is dry, coarse, and scaly. Jaundice may be apparent with pernicious anemia or congenital or acquired hemolytic anemia. The skin of patients with pernicious anemia is said to be “lemon yellow” because of the simultaneous appearance of jaundice and pallor. Jaundice may also occur in patients with hematologic malignancies, especially lymphomas, as a result of liver involvement or biliary tract obstruction. Pallor is a common accompaniment of anemia, although some severely anemic patients may not appear pale. Erythromelalgia may be a troublesome complication of polycythemia vera. Patchy plaques or widespread erythroderma occur in cutaneous T-cell lymphoma (especially Sézary syndrome) and in some cases of chronic lymphocytic leukemia or lymphocytic lymphoma. The skin is often involved, sometimes severely, in graft-versus-host disease following hematopoietic cell transplantation. Patients with hemochromatosis may have bronze or grayish pigmentation of the skin. Cyanosis occurs with methemoglobinemia, either hereditary or acquired; sulfhemoglobinemia; abnormal hemoglobins with low oxygen affinity; and primary and secondary polycythemia. Cyanosis of the ears or the fingertips may occur after exposure to cold in individuals with cryoglobulins or cold agglutinins.
Itching may occur in the absence of any visible skin lesions in Hodgkin lymphoma and may be extreme. Mycosis fungoides or other lymphomas with skin involvement may also present as itching. A significant number of patients with polycythemia vera will complain of itching after bathing.
Petechiae and ecchymoses are most often seen in the extremities in patients with thrombocytopenia, nonthrombocytopenic purpura, or acquired or inherited platelet function abnormalities and von Willebrand disease. Unless secondary to trauma, these lesions usually are painless; the lesions of psychogenic purpura and erythema nodosum are painful. Easy bruising is a common complaint, especially among women, and when no other hemorrhagic symptoms are present, usually no abnormalities are found after detailed study. This symptom may, however, indicate a mild hereditary bleeding disorder, such as von Willebrand disease or one of the platelet disorders. Infiltrative lesions may occur in the leukemias (leukemia cutis) and lymphomas (lymphoma cutis) and are sometimes the presenting complaint. Monocytic leukemia has a higher frequency of skin infiltration than other forms of leukemia. Necrotic lesions may occur with intravascular coagulation, purpura fulminans, and warfarin-induced skin necrosis, or, rarely, with exposure to cold in patients with circulating cryoproteins or cold agglutinins.
Leg ulcers are a common complaint in sickle cell anemia and occur rarely in other hereditary anemias. They also are associated with longterm hydroxyurea therapy in myeloproliferative neoplasms.
DRUGS AND CHEMICALS
Drugs
Drug therapy, either self-prescribed or ordered by a physician, is extremely common in our society. Drugs often induce or aggravate
