Williams Manual of Hematology Tenth Edition Marshall A Lichtman 2 All Chapter

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Williams
Hematology
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Williams
Hematology Tenth Edition
Kenneth Kaushansky, MD, MACP Marshall A. Lichtman, MD, MACP
Senior Vice President, Health Sciences Professor Emeritus of Medicine and of Biochemistry
Dean, Renaissance School of Medicine and Biophysics
Stony Brook University Dean Emeritus, School of Medicine and Dentistry
Stony Brook, New York James P. Wilmot Cancer Institute
University of Rochester Medical Center
Josef T. Prchal, MD Rochester, New York
Professor of Hematology and Malignant Hematology
Adjunct in Genetics and Pathology Marcel Levi, MD, PhD, FRCP
University of Utah & Huntsman Cancer Institute Professor of Medicine
Salt Lake City, Utah University College London Hospitals
1. interní klinika VFN a Ústav patologické fyziologie London, United Kingdom
1. LF School of Medicine Professor of Medicine
Universita Karlova, Prague, Czech Republic University of Amsterdam
Amsterdam, The Netherlands
Linda J. Burns, MD
Consultant and Senior Scientific Director David C. Linch, FRCP, FRCPath, FMed Sci
Center for International Blood and Marrow Transplant Research Professor of Haematology
Milwaukee, Wisconsin Cancer Program Director
UCL/UCLH Biomedical Research Centre
University College London
London, United Kingdom
New York Chicago San Francisco Athens London Madrid Mexico City
Milan New Delhi Singapore Sydney Toronto

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ix
ix
CONTRIBUTORS
Ranjana H. Advani, MD [96] Jennifer Babik, MD, PhD [31]
Division of Oncology Division of Infectious Diseases
Department of Medicine Department of Medicine
Stanford University University of California, San Francisco
Stanford, California San Francisco, California
Gheath Alatrash, DO, PhD [25] Lina Badimon, PhD, FESC, FAHA [134]
Associate Professor Professor
Department of Stem Cell Transplantation and Cellular Therapy Cardiovascular Science Program-ICCC
Division of Cancer Medicine CiberCV
The University of Texas MD Anderson Cancer Center Hospital de la Santa Creu I Sant Pau
Houston, Texas Barcelona, Spain
Doru T. Alexandrescu, MD [121] Robert A. Baiocchi, MD, PhD [89]

Department of Medicine Professor
Division of Dermatology Division of Hematology
University of California, San Diego Department of Internal Medicine
VA San Diego Health Care System Wexner Medical Center and James Cancer Center
San Diego, California The Ohio State University
Columbus, Ohio
Carl E. Allen, MD, PhD [71]
Kelty R. Baker, MD, FACP [52]
Department of Pediatrics
President
Baylor College of Medicine
Kelty R. Baker, M.D. P.A.
Texas Children’s Cancer and Hematology Centers
Houston, Texas
Texas Children’s Hospital
Houston, Texas Jacques Banchereau, PhD [21]
Director of Immunological Sciences
Karl E. Anderson, MD [59] Jackson Laboratory for Genomic Medicine
Professor of Medicine Farmington, Connecticut
Division of Gastroenterology
The University of Texas Medical Branch at Galveston Marije Bartels, MD, PhD [48]
Galveston, Texas Pediatric Hematologist
Van Creveldkliniek
Kenneth Anderson, MD [104, 106] University Medical Center Utrecht
Director, Lipper Myeloma Center Utrecht University
Dana-Farber Cancer Institute Utrecht, The Netherlands
Kraft Family Professor of Medicine
Harvard Medical School Rafael Bejar, MD, PhD [86]
Boston, Massachusetts Associate Professor of Medicine
Moores Cancer Center
Daniel A. Arber, MD [66] University of California, San Diego
Donald West and Mary Elizabeth King Professor and La Jolla, California
Chair of Pathology
University of Chicago Annelise Bennaceur-Griscelli, MD, PhD [27]
Chicago, Illinois Professor of Hematology
Assistance Publique-Hôpitaux de Paris–Paris Saclay
David Avigan, MD [24] Division of Hematology
Beth Israel Deaconess Medical Center Université Paris Saclay
Harvard Medical School INSERM U935-INGESTEM National iPSC Infrastructure
Boston, Massachusetts Villejuif, France
Farrukh T. Awan, MD, MS [91] Bruce Beutler, MD [19]

Associate Professor of Medicine Center for the Genetics of Host Defense
The University of Texas, Southwestern Medical Center University of Texas, Southwestern Medical Center
Dallas, Texas Dallas, Texas

x Contributors
Giada Bianchi, MD [104, 106] Harry R. Buller, MD, PhD [133]

Instructor in Medicine Professor of Vascular Medicine
Harvard Medical School Department of Vascular Medicine
Associate Director, Amyloidosis Program Amsterdam UMC
Brigham and Women’s Hospital/Dana Farber Cancer Institute Amsterdam Medical Centers
Associate Physician University of Amsterdam
Division of Hematology, Department of Medicine Amsterdam, The Netherlands
Brigham and Women’s Hospital
Boston, Massachusetts Linda J. Burns, MD [1, 3]
Consultant and Senior Scientific Director
David A. Bond, MD [89] Center for International Blood and Marrow Transplant Research
Division of Hematology Milwaukee, Wisconsin
Department of Internal Medicine
Wexner Medical Center and James Cancer Center John C. Byrd, MD [91]
The Ohio State University Warren Brown Chair of Leukemia Research
Columbus, Ohio Distinguished University Professor
The Ohio State University
Niels Borregaard,* MD, PhD [64] Columbus, Ohio
The Granulocyte Research Laboratory
Department of Hematology Brad R. Cairns, PhD [10]
National University Hospital Howard Hughes Medical Institute
Copenhagen, Denmark Department of Oncological Sciences
Huntsman Cancer Institute
Mettine H. A. Bos, PhD [112] University of Utah School of Medicine
Assistant Professor Salt Lake City, Utah
Division of Thrombosis and Hemostasis
Einthoven Laboratory for Vascular and Regenerative Medicine Michael A. Caligiuri, MD [5, 73, 77, 78]
Leiden University Medical Center Department of Hematology and Hematopoietic Cell Transplantation
Leiden, The Netherlands Deana and Steve Campbell Physician-in-Chief Distinguished Chair
President, City of Hope National Medical Center
Jonathan E. Brammer, MD [93] Los Angeles, California
Assistant Professor
Division of Hematology Elias Campo, MD, PhD [95]
James Cancer Center Hematopathopathology Section
The Ohio State University Department of Anatomic Pathology
Columbus, Ohio Hospital Clinic of Barcelona
University of Barcelona
Paul F. Bray, MD [111] Barcelona, Spain
Professor of Internal Medicine
Division of Hematology and Hematologic Malignancies Jaime Caro, MD [57]
Program in Molecular Medicine Professor of Medicine, Emeritus
University of Utah Division of Hematology
Salt Lake City, Utah Cardeza Foundation for Hematological Research
Sidney Kimmel Medical College
Alessandro Broccoli, MD, PhD [100] Philadelphia, Pennsylvania
Institute of Hematology “Seràgnoli”
University of Bologna Martin P. Carroll, MD [13]
Bologna, Italy Associate Professor of Medicine
Division of Hematology and Oncology
Virginia C. Broudy, MD [80] Department of Medicine
Scripps Professor of Hematology Perelman School of Medicine
Department of Medicine (Hematology) University of Pennsylvania
University of Washington (Hematology) Philadelphia, Pennsylvania
Seattle, Washington
Guillaume Cartron, MD, PhD [98]
Francis K. Buadi, MD [107] Professor
Division of Hematology Hematology Department
Mayo Clinic University Hospital of Montpellier
Rochester, Minnesota Montpellier, France
*
Deceased

Contributors xi
Alessandro Casini, MD, PD [124] Michiel Coppens, MD, PhD [131]

Staff Physician Associate Professor of Medicine
Division of Angiology and Hemostasis Amsterdam UMC
Faculty of Medicine University of Amsterdam
University Hospitals of Geneva Department of Vascular Medicine
Geneva, Switzerland Amsterdam Cardiovascular Sciences
Amsterdam, The Netherlands
Jorge J. Castillo, MD [108]
Clinical Director Gay M. Crooks, MB, BS [74]
Bing Center for Waldenstrom Macroglobulinemia Professor
Division of Hematological Malignancies Departments of Pathology and Lab Medicine and Pediatrics
Dana-Farber Cancer Institute; Division of Pediatric Hematology/Oncology
Associate Professor David Geffen School of Medicine
Harvard Medical School University of California, Los Angeles
Boston, Massachusetts Los Angeles, California
Carla Casulo, MD [101] David C. Dale, MD [63]

Associate Professor of Medicine, Oncology Professor of Medicine
Program Director, Hematology/Oncology Fellowship University of Washington School of Medicine
Lymphoma Service Seattle, Washington
Wilmot Cancer Institute
University of Rochester Chi V. Dang, MD, PhD [13]
Rochester, New York Scientific Director
Ludwig Institute for Cancer Research
Bruce A. Chabner, MD [28] New York, New York
Professor Medicine Professor, The Wistar Institute
Massachusetts General Hospital Philadelphia, Pennsylvania
Harvard Medical School
Boston, Massachusetts Utpal P. Davé, MD [4]
Co-Director, Hematopoiesis and Hematologic Malignancies Program
Richard W. Childs, MD [20] Indiana University Melvin and Bren Simon Comprehensive
Clinical Director Cancer Center;
Chief, Laboratory of Transplantation Immunotherapy Associate Professor of Medicine and Microbiology and Immunology
National Heart, Lung, and Blood Institute Division of Hematology and Oncology
National Institutes of Health R.L. Roudebush VA Medical Center
Bethesda, Maryland Indiana University School of Medicine
Indianapolis, Indiana
Theresa L. Coetzer, PhD [47]
Madhav V. Dhodapkar, MD [21]
Department of Molecular Medicine and Haematology
Brock Chair and Professor of Hematology Oncology
School of Pathology
Director, Winship Center for Cancer Immunology
Faculty of Health Sciences
Emory University
University of the Witwatersrand
Atlanta, Georgia
Johannesburg, South Africa
Michael Dickinson, MBBS (Hons),
Claudia S. Cohn, MD [138] DMedSci, FRACP, FRCPA [97]
Associate Professor
Peter MacCallum Cancer Centre
Laboratory Medicine and Pathology
Royal Melbourne Hospital
University of Minnesota
Sir Peter MacCallum Department of Oncology
Minneapolis, Minnesota
University of Melbourne
Melbourne, Australia
Barry S. Coller, MD [111]
David Rockefeller Professor of Medicine Angela Dispenzieri, MD [107]
Head, Allen and Frances Adler Laboratory of Blood Division of Hematology
and Vascular Biology Mayo Clinic
Physician-in Chief, Rockefeller University Hospital Rochester, Minnesota
Vice President for Medical Affairs
Rockefeller University May Dong, BA [13]
New York, New York Medical Student
University of Massachusetts Medical School
Worcester, Massachusetts

xii Contributors
Anne G. Douglas, MD [67, 68] Ross M. Fasano, MD [56]

Resident, Department of Neurology Center for Transfusion and Cellular Therapies
Perelman School of Medicine Department of Pathology and Laboratory Medicine
University of Pennsylvania Emory University School of Medicine
Philadelphia, Pennsylvania Atlanta, Georgia
Steven D. Douglas, MD [67, 68] Amir T. Fathi, MD [28]

Professor of Pediatrics Associate Professor of Medicine
Chief Section of Immunology Massachusetts General Hospital
Senior Vice Chair, Pediatrics Harvard Medical School
Committee on Appointments and Promotions Boston, Massachusetts
Chair, Pediatrics
Committee on Prestigious Awards and Honors Brian J. Franz, PhD [137]
Perelman School of Medicine Vitalant
University of Pennsylvania Phoenix, Arizona
Philadelphia, Pennsylvania
Kathleen Freson, PhD [119]
Martin Dreyling, MD, PhD [99] Director of Center for Molecular and Vascular Biology
Professor of Medicine Professor
Department of Medicine III Department of Cardiovascular Sciences
LMU Hospital Katholieke Universiteit Leuven
Munich, Germany Leuven, Belgium
Connie J. Eaves, PhD, FRS(C) [27] Aharon G. Freud, MD, PhD [93]
Distinguished Scientist Associate Professor
Terry Fox Laboratory Department of Pathology
British Columbia Cancer Research Institute The Ohio State University
Professor Columbus, Ohio
Department of Medical Genetics & School of Biomedical Engineering
University of British Columbia Jonathan W. Friedberg, MD, MMSc [101]
Vancouver, Canada Director, Wilmot Cancer Institute
Samuel Durand Professor of Medicine and Oncology
Yvonne A. Efebera, MD, MPH [77] University of Rochester
Professor Rochester, New York
Department of Internal Medicine
Division of Hematology, Blood and Marrow Transplant Monica Fung, MD, MPH [31]
Director and Founder, Comprehensive Amyloidosis Clinic Division of Infectious Diseases
Director, Careers in Internal Medicine Department of Medicine
The Ohio State University University of California, San Francisco
Columbus, Ohio San Francisco, California
William B. Ershler, MD [8] Stephen J. Galli, MD [66]

Director Professor of Pathology and of Microbiology and Immunology
Division of Benign Hematology Stanford University School of Medicine
Inova Schar Cancer Institute Stanford University Medical Center
Inova Fairfax Hospital Stanford, California
Falls Church, Virginia
Tomas Ganz, PhD, MD [38, 43, 44]
Miguel A. Escobar, MD [122] Departments of Medicine and Pathology
Professor of Medicine and Pediatrics David Geffen School of Medicine
Director, Gulf States Hemophilia and Thrombophilia Center University of California, Los Angeles
University of Texas Health Science Center Los Angeles, California
McGovern Medical School
Houston, Texas Terry B. Gernsheimer, MD [139]
Department of Medicine
Andrew G. Evans, MD, PhD [101] University of Washington
Director of Hematopathology Seattle Cancer Care Alliance
Associate Professor of Pathology and Laboratory Medicine Seattle, Washington
University of Rochester School of Medicine and Dentistry
Rochester, New York

Contributors xiii
Stanton L. Gerson, MD [26] Steven Grant, MD [15]

Case Comprehensive Cancer Center Professor of Medicine
Case Western Reserve University Shirley Carter and Sture Gordon Olsson
University Hospital of Cleveland Professor of Oncology
Cleveland, Ohio Virginia Commonwealth University
Richmond, Virginia
Morie A. Gertz, MD, MACP [107]
Division of Hematology Ralph Green, MD, PhD, FRCPath [42, 45]
Mayo Clinic Professor of Pathology and Medicine
Rochester, Minnesota Department of Pathology and Laboratory Medicine
University of California, Davis
Larisa J. Geskin, MD, FAAD [102] Sacramento, California
Department of Dermatology
Columbia University Irving Medical Center Xylina T. Gregg, MD [39]
New York, New York Utah Cancer Specialists
Salt Lake City, Utah
David Ginsburg, MD [125]
James V. Neel Distinguished University Professor Michael R. Grever, MD [92]
Departments of Internal Medicine, Human Genetics, and Pediatrics Professor Emeritus
Howard Hughes Medical Institute Division of Hematology
University of Michigan Medical School Department of Internal Medicine
Ann Arbor, Michigan The Ohio State University
Columbus, Ohio
Elizabeth K.K. Glennon, PhD [14]
Postdoctoral Scientist John Gribben, MD, DSc, FRCP, FRCPath, FMedSci [76]
Center for Global Infectious Disease Research Barts Cancer Institute
Seattle Children’s Research Institute Centre for Haemato-Oncology
Seattle, Washington Queen Mary University of London
Lucy A. Godley, MD, PhD [11]
Section of Hematology/Oncology Emma M. Groarke, MD [8]
Department of Medicine Fellow, Hematology Branch
The Comprehensive Cancer Center National Heart, Lung, and Blood Institute
The University of Chicago National Institutes of Health
Chicago, Illinois Mark Hatfield Clinical Research Center
Bethesda, Maryland
Kandace Gollomp, MD [117]
Assistant Professor of Pediatrics Katherine A. Hajjar, MD [114, 135]
The Children’s Hospital of Philadelphia Brine Family Professor of Cell and Developmental Biology
University of Pennsylvania School of Medicine Professor and Vice Chair for Research
Philadelphia, Pennsylvania Department of Pediatrics;
Professor of Pediatrics in Medicine
Blanca Gonzalez, MD, PhD [95] Senior Associate Dean for Faculty
Hematopathopathology Section Weill Cornell Medicine
Department of Anatomic Pathology New York, New York
Hospital Clinic of Barcelona
University of Barcelona Amel Hamdi, PhD [60]
Barcelona, Spain Department of Physiology
Lady Davis Institute
Victor R. Gordeuk, MD [50] McGill University
Professor of Medicine Montreal, Quebec, Canada
University of Illinois
Chicago, Illinois Robert D. Harrington, MD [80]
Professor
Jason Gotlib, MD, MS [65] Department of Medicine (Infectious Diseases)
Professor of Medicine University of Washington;
Division of Hematology Chief of Medicine
Stanford Cancer Institute Section Chief, Infectious Diseases
Stanford University School of Medicine Harborview Medical Center
Stanford, California Seattle, Washington

xiv Contributors
Xiangrong He, MD [138] Patrick Connor Johnson, MD [28]

Clinical Fellow Fellow in Medical Oncology
Laboratory Medicine and Pathology Massachusetts General Hospital
Mayo Clinic Boston, Massachusetts
Rochester, Minnesota
Lynn B. Jorde, PhD [9]
Jeanne E. Hendrickson, MD [56] Mark and Kathie Miller Presidential Professor and Chair
Professor Department of Human Genetics
Departments of Laboratory Medicine and Pediatrics University of Utah School of Medicine
Yale University School of Medicine Salt Lake City, Utah
New Haven, Connecticut
Alexis Kaushansky, PhD [14]
Paul C. Herrmann, MD, PhD [53] Associate Professor
Professor and Chair Department of Pediatrics
Department of Pathology and Human Anatomy School of Medicine
Loma Linda University School of Medicine University of Washington;
Loma Linda, California Center for Global Infectious Disease Research
Seattle Children’s Hospital
Gabriela S. Hobbs, MD [28] Seattle, Washington
Instructor in Medicine
Massachusetts General Hospital Kenneth Kaushansky, MD, MACP
Harvard Medical School [3, 16, 17, 84, 110, 115, 116, 118]
Boston, Massachusetts Senior Vice President, Health Sciences
Dean, Renaissance School of Medicine
Steven Horwitz, MD [103] Stony Brook University
Associate Attending Stony Brook, New York
Lymphoma Service, Department of Medicine
Memorial Sloan Kettering Cancer Center Rami Khoriaty, MD [40]
New York, New York Assistant Professor, Department of Internal Medicine
Assistant Professor, Department of Cell and Developmental Biology
Chi-Joan How, MD [28] Section Head, Classical Hematology
Fellow in Medical Oncology Core Member, Rogel Cancer Center
Massachusetts General Hospital University of Michigan
Boston, Massachusetts Ann Arbor, Michigan
Russell D. Hull, MBBS, MSc [133] Thomas J. Kipps, MD, PhD [75]
Emeritus Professor of Medicine Director, Hematology Malignancy Program
Foothills Medical Centre and University of Calgary, Director, Center for Novel Therapeutics
Calgary, Canada Distinguished Professor of Medicine
Moores Cancer Center
Achille Iolascon, MD, PhD [40] University of California, San Diego
Professor of Medical Genetics San Diego, California
Department of Molecular Medicine and Medical Biotechnology
University of Naples Federico II Adam S. Kittai, MD [91]
Naples, Italy Assistant Professor of Medicine
The Ohio State University
Joseph E. Italiano, Jr., PhD [111] Columbus, Ohio
Associate Professor of Medicine
Division of Hematology Mark J. Koury, MD [4]
Brigham and Women’s Hospital Professor of Medicine, Emeritus
Vascular Biology Program Division of Hematology/Oncology
Boston Children’s Hospital Vanderbilt University School of Medicine
Harvard Medical School Nashville, Tennessee
Boston, Massachusetts
Taco Kuijpers, MD, PhD [61, 64]
Jill M. Johnsen, MD [125] Professor of Immunology
Associate Member Consultant Pediatric Infectious Diseases and Clinical Immunology
Bloodworks Amsterdam University Medical Center
Associate Professor of Medicine University of Amsterdam
University of Washington Amsterdam, The Netherlands
Seattle, Washington

Contributors xv
Abdullah Kutlar, MD [50] Marcel Levi, MD, PhD, FRCP [3, 18, 32, 113, 115, 120, 121, 127]
Professor of Medicine Professor of Medicine
Augusta University University College London Hospitals
Augusta, Georgia London, United Kingdom;
Professor of Medicine
Robert A. Kyle, MD, MACP [109] University of Amsterdam
Professor of Medicine Amsterdam, The Netherlands
Laboratory Medicine and Pathology
Mayo Clinic College of Medicine Jerrold H. Levy, MD, FAHA, FCCM [140]
Rochester, Minnesota Professor of Anesthesiology
Cardiothoracic Anesthesiology, Critical Care,
Geoffrey A. Land, PhD, HCLD, F(AAM) [137] and Surgery (Cardiothoracic)
Vitalant Duke University School of Medicine
Phoenix, Arizona Durham, North Carolina
Angela M. Lager [11] Zhenyu Li, MD, PhD [111]

Section of Hematology/Oncology Cardiovascular Research Center
Department of Medicine University of Kentucky
The Comprehensive Cancer Center Lexington, Kentucky
The University of Chicago
Chicago, Illinois Marshall A. Lichtman, MD, MACP [1, 3, 36, 54, 62, 69, 70, 82,
85, 87, 88, 105]
Lewis L. Lanier, PhD [20] Professor Emeritus of Medicine and of Biochemistry and Biophysics
Professor Dean Emeritus, School of Medicine and Dentistry
Department of Microbiology and Immunology James P. Wilmot Cancer Institute
University of California, San Francisco University of Rochester Medical Center
San Francisco, California Rochester, New York
Richard A. Larson, MD [90] Jane L. Liesveld, MD [87, 88]

Professor of Medicine Professor of Medicine (Hematology-Oncology)
Section of Hematology/Oncology James P. Wilmot Cancer Institute
Department of Medicine University of Rochester Medical Center
The Comprehensive Cancer Center Rochester, New York
Chicago, Illinois David C. Linch, FRCP, FRCPath, FMed Sci [3, 94]
Professor of Haematology
Michelle M. Le Beau, PhD [11] Cancer Program Director
Section of Hematology/Oncology UCL and UCL Hospitals Biomedical Research Centre
Department of Medicine University College London
The Comprehensive Cancer Center London, United Kingdom
Chicago, Illinois Ton Lisman, PhD [130]
Professor of Experimental Surgery
Houry Leblebjian, Pharm D [28] Surgical Research Laboratory
Department of Pharmacy Section of Hepatobiliary Surgery and Liver Transplantation
Dana Farber Cancer Institute Department of Surgery
Boston, Massachusetts University Medical Center, Groningen
Groningen, The Netherlands
Frank W.G. Leebeek, MD, PhD [130]
Professor of Hematology Pete Lollar, MD [126]
Department of Hematology Aflac Cancer and Blood Disorders Center
Erasmus University Medical Center Department of Pediatrics
Rotterdam, The Netherlands Emory University
Atlanta, Georgia
Matthew M. Lei, Pharm D [28]
Department of Pharmacy Christine Lomas-Francis, MSc, FIBMS [136]
Massachusetts General Hospital Immunohematology and Genomics
Boston, Massachusetts New York Blood Center
Long Island City, New York

xvi Contributors
Gerard Lozanski, MD [92] Guiomar Mendieta, MD, MSc [134]

Professor of Pathology Clinical Cardiovascular Institute, Cardiology Department
Department of Pathology Hospital Clinic
The Ohio State University University of Barcelona
Columbus, Ohio Cardiovascular Science Program, ICCC
Hospital de la Santa Creu I Sant Pau
Naomi L.C. Luban, MD [56] Barcelona, Spain
Professor of Pediatrics and Pathology
School of Medicine and Health Sciences Marzia Menegatti, BSc, PhD [123]
George Washington University; Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Medical Director, Office of Human Subjects Protection Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and
Senior Hematologist Fondazione Luigi Villa
Children’s National Hospital Milan, Italy
Washington, DC
Manoj P. Menon, MD, MPH [80]
Associate Professor
Fabienne Lucas, MD, PhD [76]
Department of Medicine (Hematology)
Department of Pathology
University of Washington;
Brigham and Women’s Hospital
Section Chief
Hematology and Medical Oncology
Harborview Medical Center;
Assistant Professor
Nicola C. Maciocia, MBChB, BSc, FRCPath [23]
Vaccine and Infectious Disease
Department of Haematology
Clinical Research Divisions
Cancer Institute
Fred Hutchinson Cancer Research Center
Seattle, Washington
Paul M. Maciocia, MBChB, PhD, FRCPath [23] Dean D. Metcalfe, MD [66]
Department of Haematology Chief, Mast Cell Biology Section
Cancer Institute Laboratory of Allergic Diseases
London, United Kingdom National Institute of Allergy and Infectious Diseases
National Institutes of Health
Anthony G. Mansour, MD [78] Bethesda, Maryland
Department of Hematology and Hematopoietic
Cell Transplantation Saskia Middeldorp, MD, PhD [131]
City of Hope National Medical Center Professor
Los Angeles, California Department of Vascular Medicine
Amsterdam Cardiovascular Sciences
Elaine R. Mardis, PhD [10] Amsterdam UMC
The Steve and Cindy Rasmussen Institute for Genomic Medicine University of Amsterdam
Nationwide Children’s Hospital Amsterdam, The Netherlands
Columbus, Ohio
Martha P. Mims, MD, PhD [7]
Professor of Medicine and Chief Hematology/Oncology
Kenneth L. McClain, MD, PhD [71]
Department of Pediatrics
Houston, Texas
Texas Children’s Cancer and Hematology Centers Anjali Mishra, PhD [93]
Texas Children’s Hospital Assistant Professor
Houston, Texas Sidney Kimmel Cancer Center
Thomas Jefferson University
Jeffrey McCullough, MD [138] Philadelphia, Pennsylvania
Global Blood Advisor
Edina, Minnesota; Ananya Datta Mitra, MD [42, 45]
Emeritus Professor Section of Hematopathology
Laboratory Medicine and Pathology Department of Pathology and Laboratory Medicine
University of Minnesota University of California, Davis Health, School of Medicine
Minneapolis, Minnesota Sacramento, California
Joel Moake, MD [52]

Neha Mehta-Shah, MD, MSCI [103] Professor of Medicine Emeritus
Assistant Professor Baylor College of Medicine
Department of Medicine Senior Research Scientist
Division of Oncology Department of Bioengineering
Washington University School of Medicine in St. Louis Rice University
St. Louis, Missouri Houston, Texas

Contributors xvii
Narla Mohandas, DSc [33] Marguerite Neerman-Arbez, PhD [124]

Laboratory of Red Cell Physiology Professor
New York Blood Center Department of Genetic Medicine and Development
New York, New York University of Geneva Faculty of Medicine
Geneva, Switzerland
Jeffrey J. Molldrem, MD [25]
Professor and Chair, ad interim Robert S. Negrin, MD [29]
Division of Cancer Medicine Professor of Medicine
Department of Hematopoietic Biology and Malignancy Chief, Division of Blood and Marrow Transplantation
The University of Texas MD Anderson Cancer Center Stanford University School of Medicine
Houston, Texas Stanford, California
Eva Marie Y. Moresco, PhD [19] Luigi D. Notarangelo, MD [79]

Center for the Genetics of Host Defense Laboratory of Clinical Immunology and Microbiology
University of Texas Southwestern Medical Center National Institute of Allergy and Infectious Diseases
Dallas, Texas National Institutes of Health
Bethesda, Maryland
Diana Morlote, MD [2, 46]
Assistant Professor Hans D. Ochs, MD [79]
Hematopathology and Molecular Genetic Pathology Professor of Pediatrics
Division of Genomics and Bioinformatics Jeffrey Modell Chair of Pediatric Immunology Research
Department of Pathology Center for Immunity and Immunotherapies
The University of Alabama at Birmingham Seattle Children’s Research Institute
Birmingham, Alabama University of Washington
Seattle, Washington
Alison Moskowitz, MD [103]
Associate Attending Elizabeth K. O’Donnell, MD [104, 106]
Lymphoma Service Assistant Professor of Medicine
Department of Medicine Massachusetts General Hospital
Memorial Sloan Kettering Cancer Center Harvard Medical School
New York, New York Boston, Massachusetts
Eric Mou, MD [96] Willem Ouwehand, MD, PhD, FMedSci [119]

Division of Oncology Professor of Experimental Haematology
Department of Medicine Honorary Consultant of Haematology
Stanford University National Health Service Blood Transfusion
Stanford, California Honorary Faculty Member
Wellcome Trust Sanger Institute;
William A. Muller, MD, PhD [114] Department of Haematology
Janardan K. Reddy Professor of Pathology University of Cambridge
Feinberg School of Medicine NHS Blood and Transplant Building
Northwestern University Cambridge Biomedical Campus
Chicago, Illinois Cambridge, United Kingdom
Natarajan Muthusamy, DVM, PhD [73] Charles H. Packman, MD [55]

Professor, Hematology Professor of Medicine
The Ohio State University Department of Hematologic Oncology and Blood Disorders
Columbus, Ohio Levine Cancer Institute
University of North Carolina School of Medicine
Christopher S. Nabel, MD, PhD [28] Charlotte, North Carolina
Fellow in Medical Oncology
Massachusetts General Hospital Teresa Padró, PhD, FESC [134]
Boston, Massachusetts Cardiovascular Science Program-ICCC
CiberCV
Srikanth Nagalla, MBBS, MS [57] Hospital de la Santa Creu I Sant Pau
Associate Professor of Medicine Barcelona, Spain
Program Director, Hematology/Oncology Fellowship
Division of Hematology/Oncology James Palis, MD [6]
University of Texas, Southwestern Medical Center Professor of Pediatrics
Dallas, Texas Director, Center for Pediatric Biomedical Research
Rochester, New York

xviii Contributors
Charles J. Parker, MD [41] Jaroslav F. Prchal, MD, FRCPC [83]

Professor of Medicine Director
Department of Medicine Department of Oncology
Division of Hematology and Hematologic Malignancies St. Mary’s Hospital Center
University of Utah School of Medicine Montreal, Quebec, Canada
Josef T. Prchal, MD [3, 34, 35, 51, 58, 60, 83, 85]
Karl S. Peggs, MB BCh, MA, MRCP, FRCPath [22] Professor of Hematology and Malignant Hematology
Senior Lecturer in Stem Cell Transplantation and Immunotherapy Adjunct in Genetics and Pathology
Director University of Utah & Huntsman Cancer Institute
Adult Stem Cell Transplantation Services Salt Lake City, Utah
University College London Cancer Institute 1. interní klinika VFN a Ústav patologické fyziologie, 1. LF
London, United Kingdom School of Medicine
Universita Karlova, Prague, Czech Republic
Flora Peyvandi, MD, PhD [123]
Director, Angelo Bianchi Bonomi Hemophilia and Thrombosis Martin A. Pule, MRCP, FRCPath [23]
Center Department of Haematology
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Senior Lecturer in Haematology
Vice Director, Department of Pathophysiology and Transplantation Clinical Haematologist Consultant
Università degli Studi di Milano UCL Cancer Institute
Milan, Italy London, United Kingdom
John D. Phillips, PhD [59] Sergio A. Quezada, PhD [22]

Division of Hematology Department of Haematology
Department of Medicine University College London Cancer Institute
University of Utah School of Medicine London, United Kingdom
Noopur S. Raje, MD, PhD [28]
Mortimer Poncz, MD [117] Massachusetts General Hospital
University of Pennsylvania School of Medicine
The Children’s Hospital of Philadelphia
Professor of Pediatrics
Chief, Pediatric Hematology
Jacob H. Rand, MD [132]
Professor of Pathology and Laboratory Medicine
New York Presbyterian Weill Cornell
Prem Ponka,* MD, PhD, FCMA [60] New York, New York
Department of Physiology
McGill University and Lady Davis Institute A. Koneti Rao, MD, FACP, FAHA [119]
Montreal, Quebec, Canada Sol Sherry Professor of Medicine
Director, Benign Hematology, Hemostasis and Thrombosis
Pierluigi Porcu, MD [93] Co-Director, Sol Sherry Thrombosis Research Center
Professor of Medical Oncology, Dermatology, and Cutaneous Professor of Thrombosis Research and Pharmacology
Biology Professor of Clinical Pathology and Laboratory Medicine
Director, Division of Hematologic Malignancies and Hematopoietic Lewis Katz School of Medicine
Stem Cell Transplantation Temple University
Department of Medical Oncology Philadelphia, Pennsylvania
Sidney Kimmel Cancer Center
Thomas Jefferson University Gary E. Raskob, PhD [133]
Philadelphia, Pennsylvania Dean, Hudson College of Public Health
Regents Professor, Epidemiology and Medicine
Jacqueline N. Poston, MD [139] University of Oklahoma Health Sciences Center
Department of Medicine Oklahoma City, Oklahoma
University of Washington
Seattle Cancer Care Alliance Lubica Rauova, PhD [117]
Fred Hutchinson Cancer Research Center University of Pennsylvania School of Medicine
Bloodworks NW Research Institute Research Associate Professor of Pediatrics
Seattle, Washington The Children’s Hospital of Philadelphia
*
Deceased

Contributors xix
Vishnu V.B. Reddy, MD [2, 46] Clémentine Sarkozy, MD, PhD [98]
Section Head, UAB Hospital Hematology Bone Marrow Lab Department of Therapeutic Innovation
Director, Hematopathology Fellowship Program Gustave Roussy
Division of Laboratory Medicine Université Paris-Saclay
Professor, Department of Pathology Villejuif, France
The University of Alabama at Birmingham
Birmingham, Alabama Sam Schulman, MD, PhD, FRCPS [32]
Professor, Department of Medicine
Mark T. Reding, MD [122] Director, Thrombosis Service
Associate Professor of Medicine Hamilton Health Sciences General Hospital
Director, Center for Bleeding and Clotting Disorders McMaster University
University of Minnesota Medical Center Hamilton, Ontario, Canada
Minneapolis, Minnesota
Steven Scoville, MD, PhD [5]
Pieter H. Reitsma, PhD [112] General Surgery
Professor of Experimental Medicine The Ohio State University
Einthoven Laboratory for Experimental Vascular and Columbus, Ohio
Regenerative Medicine
Leiden University Medical Center Marie Scully, MB BS, MRCP, FRCPath, MD [128]
Leiden, The Netherlands Professor
Department of Haematology
Shoshana Revel-Vilk, MD, MCs [72] Cardiometabolic Programme
Associate Professor of Pediatrics National Institute of Health Research
Gaucher Unit and Pediatric Hematology/Oncology Unit University College London/University College London Hospitals
Shaare Zedek Medical Center Biomedical research Centre
Hebrew University Medical School University College London Hospital
Jerusalem, Israel London, United Kingdom
Andrew R. Rezvani, MD [29] Christopher S. Seet, MD, PhD [74]

Assistant Professor of Medicine Assistant Professor
Associate Clinical Chief, Division of Blood and Marrow Department of Medicine
Transplantation Division of Hematology-Oncology
Stanford University School of Medicine David Geffen School of Medicine
Stanford, California University of California, Los Angeles
Los Angeles, California
Paul G. Richardson, MD [28]
R.J. Corman Professor of Medicine George B. Segel, MD [6, 36]
Dana Farber Cancer Institute Emeritus Professor of Pediatric
Harvard Medical School Professor of Medicine
Boston, Massachusetts James P. Wilmot Cancer Institute
Jia Ruan, MD, PhD [135] Rochester, New York
Associate Professor of Clinical Medicine
Lymphoma Program Uri Seligsohn, MD [127]
Division of Hematology and Medical Oncology Professor and Director
Weill Cornell Medicine Amalia Biron Research Institute of Thrombosis and Hemostasis
New York, New York Department of Hematology
Chaim Sheba Medical Center
Roberta Russo, PhD [40] Tel-Hashomer and Sackler Faculty of Medicine
Assistant Professor of Medical Genetics Tel Aviv University
Department of Molecular Medicine and Medical Biotechnology Tel Aviv, Israel
CEINGE
Biotecnologie Avanzate John F. Seymour, FAHMS, MB, BS, PhD, FRACP [97]
University of Naples Federico II Peter MacCallum Cancer Centre
Naples, Italy Royal Melbourne Hospital;
Professor
Joel Saltz, MD, PhD [12] Sir Peter MacCallum Department of Oncology
Founding Chair and Professor of Biomedical Informatics University of Melbourne
Renaissance School of Medicine Melbourne, Australia
Stony Brook University
Stony Brook, New York Beth Shaz, MD [140]
New York Blood Center
New York, New York

xx Contributors
Vivien A. Sheehan, MD, PhD [50] Sean R. Stowell, MD, PhD [126]
Assistant Professor of Pediatrics Center for Transfusion and Cellular Therapies
Baylor College of Medicine Department of Pathology and Laboratory Medicine
Houston, Texas Emory University
Atlanta, Georgia
Taimur Sher, MD [107]
Division of Hematology/Oncology Sankar Swaminathan, MD [81]
Mayo Clinic Don Merril Rees Presidential Endowed Chair
Jacksonville, Florida Professor and Division Chief
Division of Infectious Diseases
Sujit Sheth, MD [49] University of Utah School of Medicine
Department of Pediatrics Salt Lake City, Utah
Weill Cornell Medicine
New York, New York Jeff Szer, MB BS, FRACP [72]
William Shomali, MD [65] Peter MacCallum Cancer Centre
Division of Hematology The Royal Melbourne Hospital
Stanford Cancer Institute University of Melbourne and Clinical Haematology
Stanford University School of Medicine Melbourne, Victoria, Australia
Stanford, California
Tsewang Tashi, MD [83]
Suthesh Sivapalaratnam, MD, PhD, MRCP (London) [119] Huntsman Cancer Center
Senior Lecturer University of Utah
Department of Haematology Salt Lake City, Utah
Royal London Hospital
London, United Kingdom Swee Lay Thein, MD [49]
National Heart, Lung, and Blood Institute
Sarah J. Skuli, MD [13] The National Institutes of Health
Fellow Bethesda, Maryland
Division of Hematology and Oncology
Department of Medicine Perumal Thiagarajan, MD [34]
Perelman School of Medicine Professor of Medicine and Pathology
University of Pennsylvania Baylor College of Medicine
Philadelphia, Pennsylvania Director of Transfusion Medicine and Hematology Laboratory
Michael E. DeBakey VA Medical Center
Susan S. Smyth, MD, PhD [111] Houston, Texas
Professor and Chief
Division of Cardiovascular Medicine Megan Trager, MD [102]
Physician Investigator Department of Dermatology
Lexington Veterans Affairs Medical Center Columbia University Irving Medical Center
University of Kentucky New York, New York
Lexington, Kentucky
Steven P. Treon, MD, PHD, FACP, FRCP [108]
Philippe Solal-Céligny, MD, PhD [98] Professor of Medicine
Professor of Haematology Harvard Medical School;
Institut de Cancérologie de l’Ouest Director
Saint-Herblain, France Bing Center for Waldenstrom’s Macroglobulinemia
Dana Farber Cancer Institute
Michael A. Spinner, MD [96] Boston, Massachusetts
Division of Oncology
Department of Medicine Giorgio Trinchieri, MD [20]
Stanford University National Institutes of Health Distinguished Investigator
Stanford, California Chief, Laboratory of Integrative Cancer Immunology
Center for Cancer Research
David P. Steensma, MD [86] National Cancer Institute
Associate Professor of Medicine National Institutes of Health
Edward P. Evans Chair of Myelodysplastic Syndromes Research Bethesda, Maryland
Dana-Farber Cancer Institute

Contributors xxi
Ali G. Turhan, MD, PhD [27] Robert Weinstein, MD [30]

Professor of Hematology Professor of Medicine and Pathology
Assistance Publique-Hôpitaux de Paris–Paris Saclay University of Massachusetts Medical School
Division of Hematology Chief, Division of Transfusion Medicine
Université Paris Saclay University of Massachusetts Memorial Medical Center
INSERM U935-INGESTEM National iPSC Infrastructure Worcester, Massachusetts
Villejuif, France
Matthew Weinstock, MD [24]
Eduard J. van Beers, MD, PhD [48] Beth Israel Deaconess Medical Center
Hematologist Harvard Medical School
Van Creveldkliniek Boston, Massachusetts
University Medical Center Utrecht
Utrecht University Karl Welte, MD [63]
Utrecht, The Netherlands Professor of Hematology
University to Tubingen
Cornelis van’t Veer, PhD [112] Tubingen, Germany
Associate Professor
Center for Experimental and Molecular Medicine Sidney W. Whiteheart, PhD, FAHA [111]
Amsterdam University Medical Centres George Schwert Endowed Professor of Biochemistry
University of Amsterdam University Research Professor
Amsterdam, The Netherlands University of Kentucky College of Medicine
Lexington, Kentucky
Richard van Wijk, PhD [48]
Associate Professor Lucia R. Wolgast, MD [132]
Central Diagnostic Laboratory Director, Clinical Laboratories Montefiore Moses Hospital
University Medical Center Utrecht Associate Professor, Albert Einstein College of Medicine
Utrecht University Montefiore Medical Center
Utrecht, The Netherlands Albert Einstein College of Medicine
Bronx, New York
Ralph R. Vassallo, MD, FACP [137]
Vitalant Neal S. Young, MD [8, 37]
Scottsdale, Arizona; Chief, Hematology Branch
Clinical Professor National Heart, Lung, and Blood Institute
Department of Pathology Mark Hatfield Clinical Research Center
University of New Mexico National Institutes of Health
Albuquerque, New Mexico Bethesda, Maryland
Kamalakannan Vijayan, PhD [14] X. Long Zheng, MD, PhD [129]

Fellow PhD Professor and Russell J. Eilers, MD Endowed Chair
Seattle Children’s Research Institute Chair of Department of Pathology and Laboratory Medicine
Seattle, Washington The University of Kansas Medical Center
Kansas City, Kansas
Gemma Vilahur, PhD, FESC [134]
Cardiovascular Science Program-ICCC Liang Zhou, MD, PhD [15]
CiberCV Instructor, Hematology/Oncology
Hospital de la Santa Creu I Sant Pau Medical College of Virginia
Barcelona, Spain Virginia Commonwealth University
Richmond, Virginia
Dietlind L. Wahner-Roedler, MD, MS, FACP [109]
Professor of Medicine Pier Luigi Zinzani, MD, PhD [100]
Department of Medicine Chief of Lymphoma and CLL Unit
Mayo Clinic College of Medicine Institute of Hematology “Seràgnoli”
Rochester, Minnesota University of Bologna
Bologna, Italy
Luojun Wang, MD [95]
Pathology Fellow Ari Zimran, MD [72]
Hematopathopathology Section Associate Professor of Medicine
Department of Anatomic Pathology Gaucher Unit, Shaare Zedek Medical Center
Hospital Clinic of Barcelona Hebrew University Medical School
University of Barcelona Jerusalem, Israel
Barcelona, Spain

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xxiii
xxiii
PREFACE
The first edition of Williams Hematology (né Hematology) was pub- into the 10th edition of Williams Hematology. The Manual features
lished in 1972. This, our 10th edition, represents our continued efforts the most salient clinical content from the parent text and is useful in
over one-half century to provide the most current concepts of the time-restricted clinical situations. The Manual will be available for the
genetic basis, pathophysiology, diagnosis, and treatment of hematologic iPhone and other mobile formats. It has been particularly useful for
diseases. physicians studying for the American Board of Internal Medicine
The rate of growth in our understanding of diseases of blood cells Certification in Hematology and comparable other examinations in
and coagulation pathways has justified, indeed mandated, the effort other jurisdictions.
of the editors to publish periodic major revisions in this comprehen- The production of this book required the timely cooperation of
sive textbook of hematology. The sequencing of patient genomes and 233 contributors for the writing or revising of 140 chapters. We are
advances in knowledge in epigenetics, proteomics, and metabolomics, grateful for their insight and work in providing this comprehensive and
as applied to hematologic disorders, have accelerated the understanding up-to-date text. Despite the growth of both basic and clinical knowl-
of the pathogenesis of the diseases of our interest and provided new edge and the passion that each of our contributors brings to the topic of
pathways to treatment. Advances in our dissection of molecular and cel- their chapter, we have been able to maintain the text in a single volume
lular biology and immunology have translated into improved diagnostic through attention to chapter length.
and therapeutic methods. Customizing immunotherapy to attack tumor The editorial board has lost the experience and intellect of Oliver
cell antigens and identifying specific molecular targets for therapy in W. Press, who died from a malignant brain tumor in 2017 and who had
several hematologic disorders have, as anticipated, become reality. Gene joined the board as the expert in lymphopoiesis and lymphoma for the
therapy is being implemented to cure selected, monogenic, inherited 9th edition. His contributions to the field and to his institution, The
hematologic diseases, such as hemophilia A and B. Sickle cell anemia Fred Hutchinson Cancer Center, were singular.
is a disease about which we have known more than almost any other The readers of the 10th edition of Williams Hematology will note
genetic disorder, yet we have been unable to modulate, significantly, its the expanding international participation in the text with the addition
horrific impact on patients. Finally, we may be edging toward a dramatic of Professor David Linch, University College, London, who is the edi-
improvement in therapy by preventing the suppression of F hemoglobin tor for the biology and diseases of lymphocytes and the lymphoma
synthesis after birth, minimizing the fraction of hemoglobin S in post- sections. Thus, the 10th edition has two of its six editors from the
natal blood. Other promising approaches to gene therapy are also being United Kingdom and chapter authors from Belgium, Canada, France,
studied in sickle cell anemia and thalassemia. CRISPR-Cas9 method- Germany, Israel, Italy, Netherlands, South Africa, Spain, Switzerland,
ology has been a singular application in several of these gene-editing and the United Kingdom in addition to the United States. The prep-
approaches. Hematology continues to be the poster child for the ratio- aration of this edition of Williams Hematology required our authors
nal design of therapeutics applicable to other fields of medicine. throughout Europe, other international sites, and the United States to
This edition of Williams Hematology endeavors to facilitate access remain dedicated to their task despite the impact of the new strain of
to information, both within the book and its associated links. Each coronavirus (SARS-CoV-2) infection and its dissemination as coro-
chapter has been revised or rewritten to provide current information. navirus disease, first identified in late 2019 (COVID-19) and thereafter
To reflect the increased application of immunotherapy, chapters on became a pandemic, a contagion of historic consequences. The editors
this important topic have been added, including Chapter 22, “Immune are grateful for their dedication despite the hardships endured by many
Checkpoint Inhibitors”; Chapter 23, “Immune Cell Therapy: Chimeric of our contributors.
Antigen Receptor T-Cell Therapy”; and Chapter 24, “Immune Cell The editors have had expert administrative assistance in the man-
Therapy: Dendritic Cell and Natural Killer Cell Therapy,” along with agement of the manuscripts for which they were primarily responsible.
the revised and updated Chapter 25, “Vaccine Therapy.” A new Chapter We thank Susan Daley in Rochester, New York; Teresa MacDonald in
12, “Application of Big Data and Deep Learning in Hematology” has London, United Kingdom; and Shelly Saxton in Salt Lake City, Utah,
been introduced. for their very helpful participation in the production of the book. Spe-
At the center of diagnostic hematology is blood and marrow cell cial acknowledgment goes to Marie Brito in Stony Brook, New York,
morphology. Thus, we have continued the incorporation of informative who was responsible for coordinating the management of 140 chapters,
color images representing the relevant diseases in each chapter, allowing including many new figures, tables, and clinical cases, and managing
easy access to illustrations of cell morphology important to diagnosis. other administrative matters, a challenging task that Ms. Brito per-
The 10th edition of Williams Hematology is also available online formed with skill and good humor. The editors also acknowledge the
as part of the excellent www.accessmedicine.com website. With direct interest and support of our colleagues at McGraw Hill, including James
links to a comprehensive drug therapy database and to other impor- F. Shanahan, Vice President and Group Publisher; Karen G. Edmonson,
tant medical texts, including Harrison’s Principles of Internal Medicine Senior Content Acquisitions Editor; Kim Davis, Developmental
and Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Director; Leah Carton, Editorial Coordinator; and Revathi Viswanathan,
Williams Hematology Online is part of a comprehensive resource cov- Client Services Manager for Williams Hematology.
ering all disciplines within medical education and practice. The online
edition of Williams Hematology also includes PubMed links to journal Kenneth Kaushansky
articles cited in the references. New in this online edition is the presen- Marshall A. Lichtman
tation of clinical cases for readers to explore, each linked to the relevant Josef T. Prchal
disease-oriented chapter. Marcel Levi
The companion handbook, Williams Manual of Hematology, will Linda J. Burns
be revised to reflect the diagnostic and therapeutic advances entered David C. Linch

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Part I Clinical Evaluation
of the Patient
1. Initial Approach to the Patient: History and 3. Consultative Hematology . . . . . . . . . . . . . . . . 31
Physical Examination . . . . . . . . . . . . . . . . . . . . . 3
2. Examination of Blood and
Marrow Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Kaushansky-Ch01_p0001-0010.indd 1 16/10/20 5:46 PM

3
CHAPTER 1 THE HEMATOLOGY CONSULTATION
INITIAL APPROACH TO THE 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,
PATIENT: HISTORY AND immature granulocytes in the blood may be signs of myeloid diseases
such as myelogenous leukemia, or, depending on the frequency of these
PHYSICAL EXAMINATION 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 pri-
mary myelofibrosis or the hypoxia of congestive heart failure. Certain
Marshall A. Lichtman and Linda J. Burns 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
SUMMARY use of certain medications may be causal factors in blood cell or coag-
ulation protein disorders. Pregnant women and persons of older age
The care of a patient with a suspected hematologic abnormality begins are prone to certain hematologic disorders: anemia, thrombocytope-
with a systematic attempt to determine the nature of the illness by elic- nia, or intravascular coagulation in the former case, and hematologic
malignancies, pernicious anemia, and clonal hematopoiesis with mild
iting an in-depth medical history and performing a thorough physical
cytopenias in the latter. The history and physical examination can pro-
examination. The physician should identify the patient’s symptoms sys-
vide vital clues to the possible diagnosis and also to the rationale choice
tematically and obtain as much relevant information as possible about of laboratory tests.
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 THE HISTORY
for understanding the onset or progression of illness. Hereditary and envi-
ronmental factors should be carefully sought and evaluated. The use of In today’s technology- and procedure-driven medical environment, the
drugs and medications, nutritional patterns, and sexual behavior should importance of carefully gathering information from patient inquiry and
examination is at risk of losing its primacy. The history (and physical
be considered. The physician should follow the medical history with a
examination) remains the vital starting point for the evaluation of any
physical examination to obtain evidence for tissue and organ abnormal-
clinical problem.1–3
ities 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 GENERAL SYMPTOMS AND SIGNS
be of considerable help in pointing toward a diagnosis. Additional history Performance status (PS) is used to establish semiquantitatively the
should be obtained during the physical examination, as findings suggest extent of a patient’s disability. This status is important in evaluating
an additional or alternative consideration. Thus, the history and physical patient comparability in clinical trials, in determining the likely tol-
examination should be considered as a unit, providing the basic informa- erance to cytotoxic therapy, and in evaluating the effects of therapy.
tion with which further diagnostic information is integrated, with blood Table 1–2 presents well-founded criteria for measuring PS for adults
and marrow studies, imaging studies and tissue examination. (Karnofsky Score) and children (Lansky Score).4,5 An abbreviated
version, as proposed by the Eastern Cooperative Oncology Group
Primary hematologic diseases are common in the aggregate, but hema-
(Table 1–3), sometimes is used.6
tologic manifestations secondary to other diseases occur even more fre- Weight loss is a frequent accompaniment of many serious diseases,
quently. For example, the signs and symptoms of anemia and the presence including primary hematologic malignancies, but it is not a prominent
of enlarged lymph nodes are common clinical findings that may be related accompaniment of most hematologic diseases. Many “wasting” dis-
to a hematologic disease, but which also occur frequently as secondary eases, such as disseminated carcinoma and tuberculosis, cause anemia,
manifestations of disorders not considered primarily hematologic. A wide and pronounced emaciation should suggest one of these diseases rather
variety of diseases may produce signs or symptoms of hematologic illness. than anemia as the primary disorder.
Thus, in patients with a connective tissue disease, all the signs and symp- Fever is a common early manifestation of the aggressive lympho-
toms of anemia may be elicited and lymphadenopathy may be notable, but mas or acute leukemias as a result of pyrogenic cytokines (eg, interleu-
additional findings are usually present that indicate primary involvement of kin [IL]-1, IL-6, and IL-8) released as a reflection of the disease itself.
some system besides the hematopoietic (marrow) or lymphopoietic (lymph After chemotherapy-induced cytopenias or in the face of accompanying
immunodeficiency, infection is usually the cause of fever. In patients
nodes or other lymphatic sites). In this discussion, emphasis is placed on
with “fever of unknown origin,” lymphoma, particularly Hodgkin lym-
the clinical findings resulting from either primary hematologic disease or phoma, should be considered. Occasionally, primary myelofibrosis,
the complications of hematologic disorders so as to avoid presenting an acute leukemia, advanced myelodysplastic syndrome, and other lym-
extensive catalog of signs and symptoms encountered in general clinical phomas may also cause fever. In rare patients with severe pernicious
medicine. anemia or hemolytic anemia, fever may be present. Pel-Ebstein fever
In each discussion of specific diseases in subsequent chapters, the signs is a prolonged cyclic fever, first associated with Hodgkin lymphoma (it
and symptoms that accompany the particular disorder are presented, and the occurs rarely), but may occur, also, in some infections (cytomegalovirus
clinical findings are covered in detail. This chapter takes a more general sys- or Mycobacterium tuberculosis infection in an immunocompromised
tematic approach. host). Chills may accompany severe hemolytic processes and the bac-
teremia that may complicate the immunocompromised or neutropenic

4 Part I: Clinical Evaluation of the Patient
patient. Night sweats suggest the presence of low-grade fever and may
TABLE 1–1. Findings That May Lead to a Hematology
occur in patients with lymphoma or leukemia.
Consultation
Fatigue, malaise, and lassitude are such common accompani-
Decreased hemoglobin concentration (anemia) ments of both physical and emotional disorders that their evaluation
Leukopenia or neutropenia is complex and often difficult. In patients with serious disease, these
Thrombocytopenia symptoms may be readily explained by fever, muscle wasting, or other
Pancytopenia associated findings. Patients with moderate or severe anemia fre-
quently complain of fatigue, malaise, or lassitude and these symptoms
Increased hemoglobin concentration (polycythemia)
may accompany the hematologic malignancies. Fatigue or lassitude
Leukocytosis or neutrophilia may occur also with iron deficiency even in the absence of sufficient
Eosinophilia anemia to account for the symptom. In slowly developing chronic
Basophilia or mastocytosis anemias, the patient may not recognize reduced exercise tolerance, or
Monocytosis other loss of physical capabilities except in retrospect, after a remission
or a cure has been induced by appropriate therapy. Anemia may be
Lymphocytosis
responsible for more symptoms than has been traditionally recognized,
Thrombocytosis as suggested by the remarkable improvement in quality of life of most
Immature granulocytes or nucleated red cells in the blood uremic patients treated with erythropoietin.
Lymphadenopathy Weakness may accompany anemia or the wasting of malignant
Splenomegaly processes, in which cases it is manifest as a general loss of strength or
Hypergammaglobulinemia: monoclonal or polyclonal reduced capacity for exercise. The weakness may be localized as a result
of neurologic complications of hematologic disease. In vitamin B12 defi-
Purpura
ciency (eg, pernicious anemia), there may be weakness of the lower
Exaggerated bleeding: spontaneous or trauma related extremities, accompanied by numbness, tingling, and unsteadiness of
Prolonged partial thromboplastin or prothrombin coagulation times gait. Peripheral neuropathy also occurs with monoclonal immunoglob-
Venous thromboembolism ulinemias. Weakness of one or more extremities in patients with leuke-
Thrombophilia mia, myeloma, or lymphoma may signify central or peripheral nervous
system invasion or compression as a result of vertebral collapse, a para-
Elevated serum ferritin level
neoplastic syndrome (eg, encephalitis), or brain or meningeal involve-
Obstetrical adverse events (eg, recurrent fetal loss, stillbirth, and ment. Myopathy secondary to malignancy occurs with the hematologic
HELLP syndrome)
malignancies and is usually manifest as weakness of proximal muscle
HELLP, hemolytic anemia, elevated liver enzymes, and low platelet groups. Footdrop or wristdrop may occur in lead poisoning, amyloido-
count. sis, systemic autoimmune diseases, or as a complication of vincristine
therapy. Paralysis may occur in acute intermittent porphyria.
TABLE 1–2. Performance Status Criteria in Adults and Children

Karnofsky Scale (age ≥16 years)a Lansky Scale (age ≥1 year and <16 years)b
Percentage Able to carry on normal activity; no special care is needed Able to carry on normal activity; no special care is needed
(%)
100 Normal; no complaints, no evidence of disease Fully active
90 Able to carry on normal activity Minor restriction in physically strenuous play
80 Normal activity with effort Restricted in strenuous play, tires more easily, otherwise active
Unable to work; able to live at home, cares for most personal Mild to moderate restriction
needs; a varying amount of assistance is needed
70 Cares for self; unable to carry on normal activity or to do active work Both greater restrictions of, and less time spent in active play
60 Requires occasional assistance but is able to care for most Ambulatory up to 50% of time, limited active play with
needs assistance/supervision
50 Requires considerable assistance and frequent medical care Considerable assistance required for any active play; fully
able to engage in quiet play
Unable to care for self; requires equivalent of institutional or Moderate to severe restriction
hospital care; disease may be progressing rapidly
40 Disabled; requires special care and assistance Able to initiate quiet activities
30 Severely disabled; hospitalization indicated, although death Needs considerable assistance for quiet activity
not imminent
20 Very sick, hospitalization necessary Limited to very passive activity initiated by others
10 Moribund, fatal process progressing rapidly Completely disabled, not even passive play
0 Dead Dead
a
The Karnofsky Scale data is adapted with permission from V Mor, L Laliberte, JN Morris, and M Wiemann.4
b
The Lansky Scale data is adapted with permission from SB Lansky, MA List, LL Lansky, et al.5

Chapter 1: Initial Approach to the Patient: History and Physical Examination 5
TABLE 1–3. Eastern Cooperative Oncology Group (ECOG) Ears

Performance Status Vertigo, tinnitus, and “roaring” in the ears may occur with marked
anemia, polycythemia, hyperleukocytic leukemia, or macroglobulinemia-
Grade Activity induced hyperviscosity. Ménière disease was first described in a patient
0 Fully active, able to carry on all predisease perfor- with acute leukemia and inner ear hemorrhage.
mance without restriction
1 Restricted in physically strenuous activity but Nasopharynx, Oropharynx, and Oral Cavity
ambulatory and able to carry out work of a light Epistaxis may occur in patients with thrombocytopenia, acquired or
or sedentary nature, eg, light housework, office inherited platelet function disorders, and von Willebrand disease.
work Anosmia or olfactory hallucinations occur in pernicious anemia. The
2 Ambulatory and capable of all self-care but unable nasopharynx may be invaded by a granulocytic sarcoma or extranodal
to carry out any work activities; up and about more lymphoma; the symptoms are dependent on the structures invaded. The
than 50% of waking hours paranasal sinuses may be involved by opportunistic organisms, such as
3 Capable of only limited self-care, confined to bed fungus in patients with severe, prolonged neutropenia. Pain or tingling
or chair more than 50% of waking hours in the tongue occurs in pernicious anemia and may accompany a vitamin
deficiency or severe iron deficiency. Macroglossia occurs in amyloidosis.
4 Completely disabled; cannot carry on any self-care;
Bleeding gums may occur with bleeding disorders. Infiltration of the
totally confined to bed or chair
gingiva with leukemic cells occurs notably in acute monocytic leuke-
5 Dead mia. Ulceration of the tongue or oral mucosa may be severe in the acute
leukemias or in patients with severe neutropenia. Dryness of the mouth
Reproduced with permission from Oken MM, Creech RH, Tormey DC,
et al. Toxicity and response criteria of the Eastern Cooperative Oncology may be caused by hypercalcemia, secondary, for example, to myeloma.
Group. Am J Clin Oncol. Dec;5(6):649-655. Dysphagia may be seen in patients with severe mucous membrane atrophy
associated with chronic iron-deficiency anemia.
SPECIFIC SYMPTOMS OR SIGNS
Neck
Nervous System Painless swelling in the neck is characteristic of lymphoma but also may
Headache may be the result of a number of causes related to hematologic be caused by a number of other diseases. Occasionally, the enlarged
diseases. Anemia or polycythemia may cause mild to severe headache. lymph nodes of lymphomas may be tender or painful because of sec-
Invasion or compression of the brain by leukemia or lymphoma, or ondary infection or rapid growth. Painful or tender lymphadenopathy
opportunistic infection of the CNS by Cryptococcus or Mycobacterium is usually associated with inflammatory reactions, such as infectious
species, may also cause headache in patients with hematologic malig- mononucleosis or suppurative adenitis. Diffuse swelling of the neck and
nancies. Hemorrhage into the brain or subarachnoid space in patients face may occur with obstruction of the superior vena cava as a result of
with thrombocytopenia or other bleeding disorders may cause sudden, lymphomatous compression.
severe headache.
Paresthesias may occur because of peripheral neuropathy in per-
Chest and Heart
nicious anemia or secondary to hematologic malignancy or amyloido-
Both dyspnea and palpitations, usually on effort but occasionally at
sis. They may also result from therapy with several chemotherapeutic
rest, may occur because of anemia or pulmonary embolism. Congestive
agents (eg, vincristine, cisplatin, and others).
heart failure may supervene, and angina pectoris may become manifest
Confusion may accompany malignant or infectious processes
in anemic patients. The impact of anemia on the circulatory system
involving the brain, sometimes as a result of the accompanying fever.
depends in part on the rapidity with which it develops, and chronic
Confusion may also occur with severe anemia, hypercalcemia (eg, mye-
anemia may become severe without producing major symptoms; with
loma), thrombotic thrombocytopenic purpura, or high-dose glucocor-
severe acute blood loss, the patient may develop shock with a nearly
ticoid therapy. Confusion or apparent senility may be a manifestation of
normal hemoglobin level, prior to compensatory hemodilution. Cough
pernicious anemia. Frank psychosis may develop in acute intermittent
may result from enlarged mediastinal nodes compressing the trachea
porphyria or with high-dose glucocorticoid therapy.
or bronchi. Chest pain may arise from involvement of the ribs or ster-
Impairment of consciousness may be a result of increased intracra-
num with lymphoma or multiple myeloma, nerve-root invasion or com-
nial pressure secondary to hemorrhage or leukemia or lymphoma in
pression, or herpes zoster; the pain of herpes zoster usually precedes
the CNS. It may also accompany severe anemia, polycythemia, hyper-
the skin lesions by several days. Chest pain with inspiration suggests a
viscosity secondary, usually, to an immunoglobulin (Ig) M monoclonal
pulmonary infarct, as does hemoptysis. Tenderness of the sternum may
protein (uncommonly IgA or IgG) in the plasma, or a leukemic hyper-
be quite pronounced in chronic myelogenous or acute leukemia, and
leukocytosis syndrome, especially in chronic myelogenous leukemia.
occasionally in primary myelofibrosis, or if intramedullary lymphoma
Eyes or myeloma proliferation is rapidly progressive.
Conjunctival plethora is a feature of polycythemia and pallor a result of
anemia. Occasionally blindness may result from retinal hemorrhages Gastrointestinal System
secondary to severe anemia and thrombocytopenia or blurred vision Dysphagia is discussed under “Nasopharynx, Oropharynx, and Oral
resulting from severe hyperviscosity resulting from macroglobulinemia Cavity” above. Anorexia frequently occurs but usually has no specific
or extreme hyperleukocytosis of leukemia. Partial or complete visual diagnostic significance. Hypercalcemia and azotemia cause anorexia,
loss can stem from retinal vein or artery thrombosis. Diplopia or distur- nausea, and vomiting. A variety of ill-defined gastrointestinal com-
bances of ocular movement may occur with orbital tumors or paralysis plaints grouped under the heading “indigestion” may occur with
of the third, fourth, or sixth cranial nerve because of compression by hematologic diseases. Abdominal fullness, premature satiety, belching,
tumor, especially extranodal lymphoma, extramedullary myeloma, or or discomfort may occur because of a greatly enlarged spleen, but such
myeloid (granulocytic) sarcoma. splenomegaly may also be entirely asymptomatic. Abdominal pain may

arise from intestinal obstruction by lymphoma, retroperitoneal bleed- granulocyte-monocyte colony-stimulating factor may induce bone
ing, lead poisoning, ileus secondary to therapy with the vinca alkaloids, pain. In patients with Hodgkin lymphoma, ingestion of alcohol may
acute hemolysis, allergic purpura, the abdominal crises of sickle cell dis- induce pain at the site of any lesion, including those in bone. Edema
ease, or acute intermittent porphyria. Diarrhea may occur in pernicious of the lower extremities, sometimes unilateral, may occur because of
anemia. It also may be prominent in the various forms of intestinal obstruction to veins or lymphatics by lymphomatous masses or from
malabsorption, although significant malabsorption may occur without deep venous thrombosis. The latter can also cause edema of the upper
diarrhea. In small-bowel malabsorption, steatorrhea may be a notable extremities.
feature. Malabsorption may be a manifestation of small-bowel lym-
phoma. Gastrointestinal bleeding related to thrombocytopenia or other Skin
bleeding disorder may be occult but often is manifest as hematemesis Skin manifestations of hematologic disease, including changes in tex-
or melena. Hematochezia can occur if a bleeding disorder is associated ture or color, itching, and the presence of specific or nonspecific lesions,
with a colonic lesion. Constipation may occur in the patient with hyper- may be of great importance. The skin in iron-deficient patients may
calcemia or in one receiving treatment with the vinca alkaloids. become dry, the hair dry and fine, and the nails brittle. In hypothyroid-
ism, which may cause anemia, the skin is dry, coarse, and scaly. Jaundice
Genitourinary and Reproductive Systems may be apparent with pernicious anemia or congenital or acquired
Impotence or bladder dysfunction may occur with spinal cord or periph- hemolytic anemia. The skin of patients with pernicious anemia is said
eral nerve damage caused by one of the hematologic malignancies or to be “lemon yellow” because of the simultaneous appearance of jaun-
with pernicious anemia. Priapism may occur in hyperleukocytic leuke- dice and pallor. Jaundice may also occur in patients with hematologic
mia, essential thrombocythemia, or sickle cell disease. Hematuria may malignancies, especially lymphomas, as a result of liver involvement or
be a manifestation of hemophilia A or B. Red urine may also occur with biliary tract obstruction. Pallor is a common accompaniment of ane-
intravascular hemolysis (hemoglobinuria), myoglobinuria, or porphy- mia, although some severely anemic patients may not appear pale.
rinuria. Injection of anthracycline drugs or ingestion of drugs such as Erythromelalgia may be a troublesome complication of polycythemia
phenazopyridine (Pyridium) regularly causes the urine to turn red. The vera. Patchy plaques or widespread erythroderma occur in cutaneous
use of deferoxamine mesylate (Desferal) may result in rust colored urine. T-cell lymphoma (especially Sézary syndrome) and in some cases of
Amenorrhea may also be induced by drugs, such as antimetabolites or chronic lymphocytic leukemia or lymphocytic lymphoma. The skin is
alkylating agents. Menorrhagia is a common cause of iron deficiency, often involved, sometimes severely, in graft-versus-host disease follow-
and care must be taken to obtain a history of the number of prior preg- ing hematopoietic cell transplantation. Patients with hemochromatosis
nancies and an accurate assessment of the extent of menstrual blood may have bronze or grayish pigmentation of the skin. Cyanosis occurs
loss. Semiquantification can be obtained from estimates of the number with methemoglobinemia, either hereditary or acquired; sulfhemoglo-
of days of heavy bleeding (usually <3), the number of days of any bleed- binemia; abnormal hemoglobins with low oxygen affinity; and primary
ing (usually <7), number of tampons or pads used (requirement for and secondary polycythemia. Cyanosis of the ears or the fingertips may
double pads suggests excessive bleeding), degree of blood soaking, and occur after exposure to cold in individuals with cryoglobulins or cold
clots formed, and from inquiries such as, “Have you experienced a gush agglutinins.
of blood when a tampon is removed?” However, an objective distinction Itching may occur in the absence of any visible skin lesions in
between menorrhagia (loss of more than 80 mL blood per period) and Hodgkin lymphoma and may be extreme. Mycosis fungoides or other
normal blood loss can best be made by a visual assessment technique lymphomas with skin involvement may also present as itching. A sig-
using pictorial charts of towels or tampons.7 Menorrhagia may occur in nificant number of patients with polycythemia vera will complain of
patients with bleeding disorders. itching after bathing.
Petechiae and ecchymoses are most often seen in the extremities in
Back and Extremities patients with thrombocytopenia, nonthrombocytopenic purpura, or
Back pain may accompany acute hemolytic reactions or be a result acquired or inherited platelet function abnormalities and von Willebrand
of involvement of bone or the nervous system in acute leukemia or disease. Unless secondary to trauma, these lesions usually are painless; the
aggressive lymphoma. It is one of the most common manifestations of lesions of psychogenic purpura and erythema nodosum are painful. Easy
myeloma. bruising is a common complaint, especially among women, and when no
Arthritis or arthralgia may occur with gout secondary to increased other hemorrhagic symptoms are present, usually no abnormalities are
uric acid production in patients with hematologic malignancies, espe- found after detailed study. This symptom may, however, indicate a mild
cially acute lymphocytic leukemia in childhood, myelofibrosis, myel- hereditary bleeding disorder, such as von Willebrand disease or one of
odysplastic syndrome, and hemolytic anemia. They also occur in the the platelet disorders. Infiltrative lesions may occur in the leukemias
plasma cell dyscrasias, acute leukemias, and sickle cell disease without (leukemia cutis) and lymphomas (lymphoma cutis) and are sometimes
evidence of gout, and in allergic purpura. Arthritis may accompany the presenting complaint. Monocytic leukemia has a higher frequency of
hemochromatosis, although the association has not been carefully skin infiltration than other forms of leukemia. Necrotic lesions may occur
established. In the latter case the arthritis starts typically in the small with intravascular coagulation, purpura fulminans, and warfarin-induced
joints of the hand (second and third metacarpal joints), and episodes skin necrosis, or, rarely, with exposure to cold in patients with circulating
of acute synovitis may be related to deposition of calcium pyrophos- cryoproteins or cold agglutinins.
phate dehydrate crystals. Hemarthroses in patients with severe bleeding Leg ulcers are a common complaint in sickle cell anemia and occur
disorders cause marked joint pain. Autoimmune diseases may present rarely in other hereditary anemias. They also are associated with long-
as anemia and/or thrombocytopenia, and arthritis appears as a later term hydroxyurea therapy in myeloproliferative neoplasms.
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 DRUGS AND CHEMICALS
may occur with bone involvement by the hematologic malignancies; it Drugs
is common in the congenital hemolytic anemias, such as sickle cell anemia, Drug therapy, either self-prescribed or ordered by a physician, is
and may occur in myelofibrosis. Administration of granulocyte- or extremely common in our society. Drugs often induce or aggravate

hematologic disease, making it essential that a careful history of drug anemia, and gallstones in relatives. In patients with disorders of hemo-
ingestion, including beneficial and adverse reactions, be obtained from stasis or venous thrombosis, particular attention must be given to bleed-
all patients. Drugs taken regularly, including nonprescription medica- ing manifestations or venous thromboembolism in family members.
tions, often become a part of the patient’s way of life and are forgotten In the case of autosomal recessive disorders such as pyruvate kinase
or are not recognized as “drugs.” deficiency, the parents are usually not affected, but a similar clinical
Agents such as aspirin, laxatives, tranquilizers, medicinal iron, syndrome may have occurred in siblings. It is particularly important
vitamins, other nutritional supplements, and sedatives are often not to inquire about siblings who may have died in infancy, as these may
immediately volunteered when asked if the patient is taking any med- be forgotten, especially by older patients. When sex-linked inheritance
ications. Furthermore, drugs may be ingested in unrecognized form, is suspected, it is necessary to inquire about symptoms in the maternal
such as antibiotics in food or quinine in tonic water. Specific, persis- grandfather, maternal uncles, male siblings, and nephews. In patients
tent questioning, often on several occasions, may be necessary before a with disorders with dominant inheritance, such as hereditary spherocy-
complete history of drug use is obtained. It is very important to obtain tosis, one may expect to find that one parent, and possibly siblings and
detailed information on alcohol consumption from every patient. The children of the patient, has stigmata of the disease. Ethnic background
four “CAGE” questions—about needing to cut down, being annoyed may be important in the consideration of certain diseases such as α- and
by criticism, having guilt feelings, and requiring a drink as a morning β-thalassemia, sickle cell anemia, glucose-6-phosphate dehydrogenase
eye-opener—provide an effective approach to the history of alcohol use. deficiency, hemoglobin E, and other inherited disorders that are prev-
Patients should also be asked about the use of recreational drugs. The alent in specific geographic areas, such as the Mediterranean basin or
use of “alternative medicines” and herbal medicines is common, and Southeast Asia.
many patients will not consider these medications or may actively with-
hold information about their use. Nonjudgmental questioning may be SEXUAL HISTORY
successful in identifying agents in this category that the patient is tak-
ing. Some patients equate the term “drugs,” as opposed to “medicines,” Because of the frequency of infection with HIV, it is important to ascer-
with illicit drugs. Establishing that the examiner is interested in all tain the sexual behavior of the patient, especially risk factors for trans-
forms of ingestants—prescribed drugs, self-remedies, alternative reme- mission of HIV.
dies, etcetera—is important to ensure getting the information required.
PREVENTIVE HEMATOLOGY
Chemicals Ideally, the physician’s goal is to prevent illness, and opportunities exist
In addition to drugs, most people are exposed regularly to a variety of for hematologists to prevent the development of hematologic disor-
chemicals in the environment, some of which may be potentially harmful ders. These opportunities include identification of individual genetic
agents and result in a deleterious hematologic effect, such as anemia or risk factors and avoidance of situations that may make a latent disorder
leukopenia. An occupational history should explore exposure to poten- manifest. Prophylactic therapy, as for example in avoiding venous sta-
tially harmful chemicals. This information should be supplemented sis in patients heterozygous for protein C deficiency or administering
by inquiries about hobbies and other interests that result in work with prophylactic heparin at the time of major surgery, is a more immediate
chemicals, such as glues and solvents. When a toxin is suspected, the aspect of prevention because it depends on the physician’s intervention.
patient’s daily activities and environment should be carefully reviewed, Hematologists may also prevent disease by reinforcing community
as significant exposure to toxic chemicals may occur incidentally. medicine efforts. Examples include fostering the elimination of sources
of environmental lead that may result in childhood anemia. Prenatal
VACCINATION diagnosis can provide information to families as to whether a fetus is
Vaccinations can be complicated by acute immune thrombocytope- affected with a hematologic disorder.
nia. In infants, this is most notable after measles, mumps, and rubella
(MMR) vaccine. The occurrence of acute immune thrombocytopenia is ASSESSMENT OF GERIATRIC PATIENTS
approximately 1 in 25,000 children vaccinated, occurs within 6 weeks The fraction of the population older than age 65 years has increased
of vaccination, and in the majority of occurrences is self-limited. There dramatically since the 1970s. This increase will continue, such that
is no evidence that children with antecedent immune thrombocytope- by 2040 approximately 22% of the U.S. population will be older than
nia are at risk of recurrence after MMR vaccination.8 Analysis, thus far, age 65 years. This trend is evident worldwide.
shows rare cases in following administration of other vaccines (hepatitis A, Frailty is a pathophysiologic syndrome in older adults that predis-
diphtheria-pertussis-tetanus, or varicella) administered to older children poses to a risk for poor health outcomes including falls, disability, hos-
and adolescents and significant risk has not been ascertained.9 pitalization, and mortality.10–12 It also limits tolerance to certain forms
of therapy, including intensive chemotherapy for cancer. The frailty
NUTRITION phenotype’s principal features are: (a) decreased functional reserve,
Children who are breastfed without iron supplementation may develop (b) impairment of physiologic systems, and (c) inability to regain a
iron-deficiency anemia. Nutritional information can be useful in physiologic steady-state after a stressful event (eg, chemotherapy).
deducing the possible role of dietary deficiency in anemia. The avoid- Numerous quantitative and qualitative instruments have been
ance of certain food groups, as might be the case with vegetarians, or reported as useful in determining the presence of frailty in the older
the ingestion of uncooked fish can be clues to the pathogenesis of meg- individual. In essence, the frailty index includes: (a) unintended weight
aloblastic anemia. loss, (b) decreased grip strength, (c) ease of exhaustion, (d) slow gait
speed, and (e) low physical activity.
One group studying patients age 75 years or older with hematologic
FAMILY HISTORY malignancies has found that gait speed measured with a stopwatch over
A carefully obtained family history may be of great importance in 4 meters as a sole measurement is strongly correlated with survival.13
the study of patients with hematologic disease (Chap. 9). In the case For example, patients with a gait speed of >0.80 m/s had threefold overall
of hemolytic disorders, questions should be asked regarding jaundice, survival at 2 years and twice the overall survival at 7 years.

A self-administered questionnaire of 10 questions has been pro- The patient should be examined in daylight rather than under incan-
posed as another approach to assessing frailty and can be accessed at descent or fluorescent light, because the yellow color of the latter masks
https://consultgeri.org/try-this/general-assessment/issue-34.pdf. the yellow color of the patient. Jaundice is a result of actual staining
An increased fraction of older individuals are being given che- of the skin by bile pigment, and bilirubin glucuronide (direct-reacting
motherapy or hematopoietic cell transplantation for hematologic (and or conjugated bilirubin) stains the skin more readily than the unconju-
other system) neoplasms. It has become important to assess frailty in gated form. Jaundice of the skin may not be visible if the bilirubin level
this population as a determinant of the likelihood that intensive therapy is below 2–3 mg/dL. Yellow pigmentation of the skin may also occur
can be administered in an older patient. Selecting a frailty index appro- with carotenemia, especially in young children.
priate to general clinical assessment should be a standard part of the
examination of an older patient. Petechiae and Ecchymoses
Petechiae are small (1–2 mm), round, red or brown lesions resulting
from hemorrhage into the skin and are present primarily in areas with
PHYSICAL EXAMINATION high venous pressure, such as the lower extremities. These lesions do not
A detailed physical examination should be performed on every patient, blanch on pressure, and this can be readily demonstrated by compress-
with sufficient attention paid to all systems so as to obtain a full eval- ing the skin with a glass microscope slide or magnifying lens. Petechiae
uation of the general health of the individual. The skin, eyes, tongue, may occasionally be elevated slightly, that is, palpable; this finding sug-
lymph nodes, skeleton, spleen, liver, and nervous system are especially gests vasculitis. Ecchymoses may be of various sizes and shapes and may
pertinent to hematologic disease and therefore deserve special attention. be red, purple, blue, or yellowish green, depending on the intensity of
the skin hemorrhage and its age. They may be flat or elevated; some are
painful and tender. The lesions of hereditary hemorrhagic telangiectasia
SKIN are small, flat, nonpulsatile, and violaceous. They blanch with pressure.
Pallor and Flushing
The color of the skin is a result of the pigment contained therein and to Excoriation
the blood flowing through the skin capillaries. The component of skin Itching may be intense in some hematologic disorders, such as
color related to the blood may be a useful guide to anemia or polycythe- Hodgkin lymphoma, even in the absence of skin lesions. Excoriation
mia, as pallor may result when the hemoglobin level is reduced and red- of the skin from scratching is the only physical manifestation of this
ness when the hemoglobin level is increased. The amount of pigment in severe symptom.
the skin modifies skin color and can mislead the clinician, as in individ-
uals with pallor resulting from decreased pigment, or make skin color Leg Ulcers
useless as a guide because of the intense pigmentation present. Open ulcers or scars from healed ulcers are often found in the region of
Alterations in blood flow and in hemoglobin content may change the internal or external malleoli in patients with sickle cell anemia, and,
skin color; this, too, can mislead the clinician. Thus emotion may cause rarely, in other hereditary anemias.
either pallor or blushing. Exposure of the skin to cold or heat may sim-
ilarly cause pallor or blushing. Chronic exposure to wind or sun may Nails
lead to permanent redness of the skin, and chronic ingestion of alcohol Detection of pallor or rubor by examining the nails was discussed ear-
to a flushed face. The degree of erythema of the skin can be evaluated by lier (see “Pallor and Flushing” above). The fingernails in chronic, severe
pressing the thumb firmly against the skin, as on the forehead, so that the iron-deficiency anemia may be ridged longitudinally and flattened or
capillaries are emptied, and then comparing the color of the compressed concave rather than convex. The latter change is referred to as koilonychia
spot with the surrounding skin immediately after the thumb is removed. and is uncommon.
The mucous membranes and nail beds are usually more reliable
guides to anemia or polycythemia than the skin. The conjunctivae and Eyes
gums may be inflamed, however, and therefore not reflect the hemoglo- Jaundice, pallor, or plethora may be detected from examination of the
bin level, or the gums may appear pale because of pressure from the lips. eyes. Jaundice is usually more readily detected in the sclerae than in
The gums and the nail beds may also be pigmented and the capillaries the skin. Ophthalmoscopic examination is also essential in patients with
correspondingly obscured. In some individuals, the color of the capil- hematologic disease. Retinal hemorrhages and exudates occur in patients
laries does not become fully visible through the nails unless pressure is with severe anemia and thrombocytopenia. These hemorrhages are
applied to the fingertip, either laterally or on the end of the nail. usually the typical “flame-shaped” hemorrhages, but they may be quite
The palmar creases are useful guides to the hemoglobin level and large and elevate the retina so that they may appear as a darkly col-
appear pink in the fully opened hand unless the hemoglobin is 7 g/dL ored tumor. Round hemorrhages with white centers are also often seen.
or less. Liver disease may induce flushing of the thenar and hypothenar Dilatation of the veins may be seen in polycythemia; in patients with
eminences of the palm, even in patients with anemia. macroglobulinemia, the veins are engorged and segmented, resembling
link sausages.
Cyanosis
The detection of cyanosis, like the detection of pallor, may be made dif- Mouth
ficult by skin pigmentation. Cyanosis is a function of the total amount Pallor of the mucosa has already been discussed (see “Pallor and Flushing”
of reduced hemoglobin, methemoglobin, or sulfhemoglobin present. above). Ulceration of the oral mucosa occurs commonly in neutropenic
The minimum amounts of these pigments that cause detectable cyano- patients. In leukemia, there also may be infiltration of the gums with
sis are approximately 5 g/dL blood of reduced hemoglobin, 1.5–2.0 g/dL swelling, redness, and bleeding. Bleeding from the mucosa may occur
of methemoglobin, and 0.5 g/dL of sulfhemoglobin (Chap. 51). with a hemorrhagic disease. A dark line of lead sulfide may be deposited
in the gums at the base of the teeth in lead poisoning. The tongue may
Jaundice be completely smooth in pernicious anemia and iron-deficiency anemia.
Jaundice may be observed in the skin of individuals who are not oth- Patients with an upper dental prosthesis may also have papillary atro-
erwise deeply pigmented or in the sclerae or the mucous membranes. phy, presumably on a mechanical basis. The tongue may be smooth

and red in patients with nutritional deficiencies. This may be accompa- spleen to descend and be felt by the examiner’s fingers. If nothing is felt,
nied by fissuring at the corners of the mouth, but fissuring may also be the palpation should be performed repeatedly, moving the examining
caused by ill-fitting dentures. An enlarged tongue, abnormally firm to hand approximately 2 cm toward the inguinal ligament each time. It
palpation, may indicate the presence of primary amyloidosis. is often advantageous to carry out the examination initially with the
patient lying on the right side with left knee flexed and to repeat it with
Lymph Nodes the patient supine.
Lymph nodes are widely distributed in the body, and in disease, any It is not always possible to be sure that a left upper quadrant mass
node or group of nodes may be involved. The major concern on phys- is spleen; masses in the stomach, colon, kidney, or pancreas may mimic
ical examination is the detection of enlarged or tender nodes in the splenomegaly on physical examination. When there is uncertainty
cervical, supraclavicular, axillary, epitrochlear, inguinal, or iliofemoral regarding the nature of a mass in the left upper quadrant, imaging pro-
regions. Under normal conditions in adults, the only readily palpa- cedures will usually permit an accurate diagnosis.20,21
ble lymph nodes are in the inguinal region, where several firm nodes The application of handheld ultrasonography can enhance the sen-
0.5–2.0 cm long are normally attached to the dense fascia below sitivity of the bedside evaluation of spleen size and its application can be
the inguinal ligament and in the femoral triangle. In children, multi- readily taught to the examining physician.22
ple small (0.5–1.0 cm) nodes may be palpated in the cervical region as
well. Supraclavicular nodes may sometimes be palpable only when the Liver
patient performs the Valsalva maneuver. Palpation of the edge of the liver in the right upper quadrant of the
Enlarged lymph nodes are ordinarily detected in the superficial abdomen is commonly used to detect hepatic enlargement, although
areas by palpation, although they are sometimes large enough to be the inaccuracies of this method have been demonstrated. To properly
seen. Palpation should be gentle and is best performed with a circu- assess liver size, it is necessary to determine both the upper and lower
lar motion of the fingertips, using slowly increasing pressure. Tender borders of the liver by percussion. The normal liver may be palpable as
lymph nodes usually indicate an inflammatory etiology, although rap- much as 4–5 cm below the right costal margin, but is usually not pal-
idly proliferative lymphoma may be tender to palpation.14–16 pable in the epigastrium. The height of liver dullness is best measured
Nodes too deep to palpate may be detected by specific imaging in a specific line, 8, 10, or 12 cm to the right of the midline. Techniques
procedures, including computerized tomography, magnetic resonance should be standardized so that serial measurements can be made. The
imaging, ultrasound studies, gallium scintography, and positron emis- vertical span of the normal liver determined in this manner will range
sion tomography. approximately 10 cm in an average-size adult male and approximately
2 cm smaller in an adult female. Because of variations introduced by
Chest technique, each physician should determine the normal area of liver
Increased rib or sternal tenderness is an important physical sign often dullness by the physician’s own procedure. Correlation of radioisotope
ignored. Increased bone pain may be generalized, as in leukemia, or imaging data with results from routine physical examinations indicates
spotty, as in plasma cell myeloma or metastatic tumors. The superfi- that often a liver of normal size is considered enlarged on physical
cial surfaces of all bones should be examined thoroughly by applying examination and an enlarged liver is considered normal. Ultrasonogra-
intermittent firm pressure with the fingertips to locate potential areas phy and computed tomography measurements are useful in determin-
of disease. ing size and demonstrating localized infiltrative lesions.23–25
Spleen Nervous System

The normal adult spleen is usually not palpable on physical examina- A thorough evaluation of neurologic function is necessary in many
tion, but occasionally the tip may be felt.17 Palpability of the normal patients with hematologic disease. Vitamin B12 deficiency impairs cere-
spleen may be related to body habitus, but there is disagreement on this bral, olfactory, spinal cord, and peripheral nerve function, and severe
point. Percussion, palpation, or a combination of these 2 methods may chronic deficiency may lead to irreversible neurologic degeneration.
detect enlarged spleens.18 Some enlarged spleens may be visible by pro- Leukemic meningitis is often manifested by headache, visual impair-
trusion of the abdominal wall. ment, or cranial nerve dysfunction. Tumor growth in the brain or spinal
The normal spleen weighs approximately 150 g and lies in the peri- cord compression may be caused by malignant lymphoma or plasma cell
toneal cavity against the diaphragm and the posterolateral abdominal myeloma. A variety of neurologic abnormalities may develop in patients
wall at the level of the lower three ribs. As it enlarges it remains close with leukemias, lymphomas, and myeloma as a consequence of tumor
to the abdominal wall, while the lower pole moves downward, anteri- infiltration, bleeding, infection, or a paraneoplastic syndrome. Essen-
orly, and to the right. Spleens enlarged only 40% above normal may be tial monoclonal gammopathy is associated with several types of sen-
palpable, but significant splenic enlargement may occur and the organ sory and motor neuropathies. Polyneuropathy is a feature of POEMS, a
still not be felt on physical examination. A good but imperfect correla- syndrome marked by polyneuropathy, organomegaly, endocrinopathy,
tion has been reported between spleen size estimated from radioisotope monoclonal gammopathy, and skin changes.
scanning or ultrasonography and spleen weight determined after sple-
nectomy or at autopsy.19 Although it is common to fail to palpate an Joints
enlarged spleen on physical examination, palpation of a normal-sized Deformities of the knees, elbows, ankles, shoulders, wrists, or hips may
spleen is unusual, and therefore a palpable spleen is usually a significant be the result of repeated hemorrhage in patients with hemophilia A,
physical finding. hemophilia B, or severe factor VII deficiency. Often, a target joint is
An enlarged spleen lies just beneath the abdominal wall and can be prominently affected.
identified by its movement during respiration. The splenic notch may
be evident if the organ is moderately enlarged. During the examination REFERENCES
the patient lies in a relaxed, supine position. The examiner, standing
1. Bickley LS. Bates Guide to Physical Examination and History Taking. 12th ed. Wolters
on the patient’s right, lightly palpates the left upper abdomen with the Kluwer; 2017.
right hand while exerting pressure forward with the palm of the left 2. Sackett DL. A primer on the precision and accuracy of the clinical examination. JAMA.
hand placed over the lower ribs posterolaterally. This action permits the 1992;267:2638-2644.

3. Williams ME. Geriatric Physical Diagnosis: A Guide to Observation and Assessment. 15. Gaddey HL, Riegel AM. Unexplained lymphadenopathy: evaluation and differential
McFarland & Company; 2009. diagnosis. Am Fam Physician. 2016;94:896-903.
4. Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky performance sta- 16. Lucey BC, Stuhlfaut JW, Soto JA. Mesenteric lymph nodes seen at imaging: causes and
tus scale: an examination of its reliability and validity in a research setting. Cancer. significance. Radiographics. 2005;25:351-365.
1984;53:2002-2007. 17. Arkles LB, Gill GD, Molan MP. A palpable spleen is not necessarily enlarged or patho-
5. Lansky SB, List MA, Lansky LL, et al. The measurement of performance in childhood logical. Med J Aust. 1986;145:15-17.
cancer patients. Cancer. 1987;60:1651-1656. 18. Barkun AN, Camus M, Green L, et al. The bedside assessment of splenic enlargement.
6. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Am J Med. 1991;91:512-518.
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 19. Benter T, Klühs L, Teichgräber U. Sonography of the spleen. J Ultrasound Med.
7. Janssen CA, Scholten PC, Heintz AP. A simple visual assessment technique to dis- 2011;30:1281-1293.
criminate between menorrhagia and normal menstrual blood loss. Obstet Gynecol. 20. Cessford T, Meneilly GS, Arishenkoff S, et al. Comparing physical examination with
1995;85:977-982. sonographic versions of the same examination techniques for splenomegaly. J Ultra-
8. Black C, Kaye JA, Jick H. MMR vaccine and idiopathic thrombocytopaenic purpura. sound Med. 2018;37:1621-1629.
Br J Clin Pharmacol. 2003;55:107-111. 21. Palas J, Matos AP, Ramalho M. The spleen revisited: An overview on magnetic reso-
9. O’Leary ST, Glanz JM, McClure DL, et al. The risk of immune thrombocytopenic pur- nance imaging. Radiol Res Pract. 2013;2013:219297.
pura after vaccination in children and adolescents. Pediatrics. 2012;129:248-255. 22. Arishenkoff S, Eddy C, Roberts JM, et al. Accuracy of spleen measurement by medical
10. Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: evidence for a phenotype. residents using hand-carried ultrasound. J Ultrasound Med. 2015;34:2203-2207.
J Gerontol A Biol Sci Med Sci. 2001;56:M146-M156. 23. Patzak M, Porzner M, Oeztuerk S, et al; EMIL Study Group. Assessment of liver size by
11. Xue QL. The frailty syndrome: definition and natural history. Clin Geriatr Med. ultrasonography. J Clin Ultrasound. 2014;42:399-404.
2011;27:1-15. 24. Barloon TJ, Brown BP, Abu-Yousef MM, et al. Teaching physical examination of the
12. Dent E, Kowal P, Hoogendijk EO. Frailty measurement in research and clinical practice: adult liver with the use of real-time sonography. Acad Radiol. 1998;5:101-103.
a review. Eur J Intern Med. 2016;31:3-10. 25. Elstein D, Hadas-Halpern I, Azuri Y, et al. Accuracy of ultrasonography in assessing
13. Liu M, DuMontier C, Murillo A. Gait speed, grip strength and clinical outcomes in spleen and liver. J Ultrasound Med. 1997;16:209-211.
older patients with hematologic malignancies. Blood. 2019;134:374-382.
14. Grubnic S, Vinnicombe SJ, Norman AR, Husband JE. MR evaluation of normal retro-
peritoneal and pelvic lymph nodes. Clin Radiol. 2002;57:193-200.

11
CHAPTER 2 of the cells of the blood, including new parameters with diagnostic util-
ity. The morphologic and functional complexity of blood cells requires
EXAMINATION OF BLOOD direct microscopic examination of a stained blood film by a trained

observer. However, it is possible to use automated techniques to analyze
and report on the majority of samples, using defined criteria (“flags”) to
AND MARROW CELLS select those that need further microscopic review. Automated hematol-
ogy analyzers typically incorporate multiple proprietary software flags
based on acceptability criteria related to pattern recognition in the mul-
tiparameter displays or comparison of different detection modes for the
Vishnu V.B. Reddy and Diana Morlote same cell type. Instruments flag abnormalities they cannot definitively
identify, so that a skilled morphologist can then visually evaluate that
specimen. Some of these flags can be adjusted or suppressed by the user
SUMMARY to achieve an appropriate balance that minimizes both false positives
and false negatives. Guidelines for manual blood film review based on
Examination of the blood and marrow are mainstays of hematologic diagno- comparative data have been published, based on instruments then in
sis. The decision to perform a marrow examination, and the types of special common use.2 Protocols for evaluating and adjusting flagging criteria
studies required, should follow from a careful analysis of blood cells and the within an individual laboratory have been described.3 The proportion
history and physical examination of the patient. Currently available auto- of samples requiring manual blood film review differs among instru-
mated blood cell analyzers provide an increasing array of novel quantitative ments and the type of patient population tested. Studies show a 10% to
parameters and flag abnormal samples that need manual microscopic review. 30% manual review rate,4,5 with a false negative rate (ie, abnormal sam-
ples that were not flagged for review) varying from approximately 3%2
The marrow should be examined when the clinical history, blood cell counts,
to 10–14%.6 Most of the false negatives with current instrumentation
blood film, or laboratory test results suggest the possibility of a primary or sec- are related to red cell and platelet morphologies with relatively limited
ondary hematologic disorder for which morphologic analysis or special studies diagnostic significance.6
of the marrow would aid in the diagnosis. In addition to determining the cel- The characteristics of automated hematology analyzer systems
lularity and morphology of precursor cells, or infiltration by nonhematopoietic have been reviewed.7 Although detailed descriptions of individual
cells, the marrow aspirate and biopsy provide cells for immunophenotyping by instruments are beyond the scope of this chapter, the general principles
flow cytometry or immunostains, cytogenetic and molecular studies, culture employed by state-of-the-art instrumentation are summarized below.
of infectious organisms, and storage for further analysis. The major analytical challenges are the frequency of the different cell
types, which vary over many orders of magnitude, from red cells (1012/L)
to basophils (106/L), and the complexity of the structure of normal and
abnormal blood cells. Over the past several decades, instruments have
The blood and marrow are examined so as to answer these questions: become increasingly sophisticated with the use of multiple parameters
Is the marrow producing appropriate numbers of mature cells in the to produce more precise results in the great majority of patient samples.
major hematopoietic lineages? Is the development of each hematopoi- In a typical automated hematology analyzer, the blood sample is aspi-
etic lineage qualitatively normal? Are there abnormal (eg, leukemia or rated and separated into different fluidic streams. The streams are mixed
lymphoma) cells present? with various buffers that accomplish specific purposes in the analysis,
When it comes to the blood, quantitative measures available from for instance, using differential lysis to distinguish subsets of leukocytes,
automated cell counters are reliable and provide a rapid and cost-effective reagents to measure hemoglobin or detect myeloperoxidase containing
way to screen for primary or secondary disturbances of hematopoiesis. leukocytes, and various fluorescent dyes. Measurements of each fluidic
Light microscopic observation of the blood film is essential to confirm stream are made in flow as the sample passes through a series of detec-
certain quantitative results and to investigate qualitatively abnormal dif- tors in what are essentially modified flow cytometers. Commonly used
ferentiation of the hematopoietic lineages. Based on examination of the principles include light scatter at various angles, electrical impedance
blood, the physician is directed toward a more focused assessment of mar- and conductivity, and fluorescence or light absorption of cells stained
row function or to systemic disorders that secondarily involve the hemato- in flow. Light scatter yields information about cell size (using scatter
poietic system. At that point, a marrow examination may be pursued in at low-incident angles), nuclear lobulation, and cytoplasmic granularity
order to explore marrow disorders as etiologies for blood abnormalities. (using high-angle light scatter) and refractive index, with polarization of
In 1923, Arinkin devised the marrow aspiration technique,1 which the scattered light as an additional parameter. If red cells are converted
was the prototype for our current aspiration procedure. Regular use to spherocytes by the buffer solution to eliminate the variability of cell
of the posterior iliac crest for aspiration and biopsy and regular use of shape, light scatter at different angles can provide information about
biopsy to complement aspiration did not occur until the 1970s, when hemoglobin content, as well as size of individual red cells. Cell size is
staging of lymphoma made biopsy a frequent procedure and new sim- also estimated by measuring change in electrical resistance, which is
pler biopsy instruments became readily available. proportional to cell size as cells enter a narrow orifice through which
a direct current is maintained, the original Coulter principle, which
was named for Wallace Coulter, the developer of the electronic particle
QUANTITATIVE MEASURES OF counter.8 Radiofrequency capacitance measurement yields additional
intracellular structural information that complements the direct cur-
CELLS IN THE BLOOD rent measurement. Differential lysis with detergents of varying strength
PRINCIPLES OF AUTOMATED or pH is used to separate certain leukocyte types, such as basophils and
immature granulocytic cells, from the major normal blood cell types.
BLOOD CELL ANALYSIS In addition, nucleic-acid-binding fluorescent dyes incorporated into
Automated blood cell analysis is the cornerstone of the modern hema- the lysis buffer measure total RNA plus DNA in the cells and are used
tology laboratory, allowing rapid, cost-effective, and accurate analysis in some analyzers to help differentiate leukocyte types. Fluorescence
Kaushansky-Ch02_p0011-0030.indd 11 16/10/20 7:56 AM

Diff channel WBC/baso channel Figure 2–1. Schematic of multiparameter cell discrimi-
Fluorescence (total nucleic acids)
nation in an automated hematology analyzer. The Sysmex

Atyp lymph XE-2100 is used as an example, in which leukocytes are
discriminated by (A) DNA/RNA fluorescence using a poly-
Forward scatter
Imm gran Basos methine dye versus high-angle (side) light scatter in lysed
Mono
blood; (B) side scatter versus low-angle (forward) light
scatter after acidic lysis in a separate aliquot that preserves
basophil structure; and (C) direct current (DC) impedance
versus radio frequency (RF) capacitance of cells subjected to
Lymph Leukocytes
a lysis reagent that relatively preserves immature cells with
Neut + baso other than basos
lower membrane lipid content. Nucleated red blood cells
Cell ghost (NRBC) are distinguished (D) in a lysed sample stained with
Eos Cell ghost nucleic acid dye where leukocyte nuclei have detectably
Side scatter Side scatter higher DNA/RNA content than red cell nuclei. Atyp Lymph,
A B atypical lymphocytes; Baso, basophils; Blasts, blast cells; Diff
Channel, differential count channel; Eos, eosinophils; HPC,
Immature myeloid channel NRBC channel hematopoietic progenitor cells; Imm Gran, immature gran-
ulocytes; Lymph, lymphocytes; Mono, monocytes; Neut +
Plt clumps Baso, neutrophils + basophils; Plt Clumps, platelet clumps;
WBC, white blood cells.
RF capacitance
Forward scatter
Imm gran
NRBC
Cell ghost
Leukocytes
Blasts
HPC Cell ghost
DC impedance Fluorescence (total nucleic acids)
C D
measurements after staining with RNA binding dyes are commonly some cases of autoimmune hemolytic anemia). This causes red cells to
used to detect and subclassify reticulocytes and platelets. Light absorp- clump and affects the accuracy of both the red blood cell (RBC) count
tion is the principle used for hemoglobin measurement and in some and MCV, as well as the resultant hematocrit.
instruments for identifying peroxidase-positive granulocytes. Instru- The hematocrit may also be determined by subjecting the blood to
ments rely on a combination of techniques for accuracy and precision sufficient centrifugal force to pack the cells while minimizing trapped
(Fig. 2–1).9 There is significant overlap in methodology between auto- extracellular fluid. This approach was traditionally done in capillary
mated hematology analyzers and flow cytometers. The latter are distin- tubes filled with blood and centrifuged at very high speed (referred to
guished by extensive use of fluorochrome tagged antibodies to identify as the “microhematocrit” or, informally, as a “spun crit”). However, this
cell subtypes. is a manual procedure that is not well adapted to routine processing in
Point-of-care “bedside” testing is far more challenging in hema- a high-volume clinical laboratory, and is affected by varying amounts
tology than for typical clinical chemistry analytes for many of the rea- of plasma trapped between red cells in the packed cell volume,12 typi-
sons described above. Instruments have been described for bedside cally approximately 2% to 3% of the packed volume.13 The hemoglobin
measurement of hemoglobin, total leukocytes, 3- and 5-part leukocyte determination now is preferred to the hematocrit, because it is mea-
differential count, malaria parasitemia, and CD4+ T-cell count, mainly sured directly and is the best indicator of the oxygen-carrying capacity
targeting clinical settings with limited access to standard laboratory of the blood (Chap. 35).
testing. More work remains to be done to demonstrate the reliability
and clinical impact of such testing strategies.10,11 Measurement of Hemoglobin
Hemoglobin is intensely colored, and this property has been used in
methods for estimating its concentration in blood. Erythrocytes con-
AUTOMATED ANALYSIS OF RED CELLS tain a mixture of hemoglobin, oxyhemoglobin, carboxyhemoglobin,
Some red cell parameters (eg, mean cell volume [MCV], red cell num- methemoglobin, and minor amounts of other forms of hemoglobin.
ber, hemoglobin concentration, and red cell distribution width [RDW]) To determine hemoglobin concentration in the blood, red cells are
are directly measured, whereas others (eg, hematocrit, mean cell hemo- lysed and hemoglobin variants are converted to the stable compound
globin [MCH], mean cell hemoglobin concentration [MCHC]) are cyanmethemoglobin for quantification by absorption at 540 nm. All
derived from these primary measurements. forms of hemoglobin are readily converted to cyanmethemoglobin
except sulfhemoglobin, which is rarely present in significant amounts.
Measurement of the Red Cell Count and Hematocrit In automated blood cell counters, hemoglobin is usually measured
In electronic instruments, the hematocrit (Hct; fractional volume of by a modified cyanmethemoglobin or an alternate lauryl sulphate
blood occupied by erythrocytes) is calculated from the product of direct method. In practice, the major interference with this measurement is
measurements of the erythrocyte count and the MCV: (Hct [L/100 L] = chylomicronemia, but newer instruments identify and minimize this
RBC [× 10−12/L] × MCV [fL]/10). Falsely elevated MCV and decreased interference. Noninvasive transcutaneous monitoring of total hemo-
red cell counts can be observed when red cell autoantibodies are present globin concentration, as well as methemoglobin and carboxyhemo-
and retain binding capability at room temperature (cold agglutinins and globin, using multiwavelength pulse oximetry has become available.14

Chapter 2: Examination of Blood and Marrow Cells 13
Although these instruments offer the opportunity to track hemoglobin Reticulocyte Count and RNA Content
concentration trends in patients subject to blood loss and fluid shifts,15 The reticulocyte is a newly released anucleate red cell that enters the
it is not yet clear that they have sufficient precision to guide transfusion blood with residual detectable amounts of RNA (Chaps. 33 and 34).
decisions.16,17 Such hemoglobin measurements may be unreliable under The number of reticulocytes in a volume of blood permits an estimate
conditions of peripheral circulatory hypoperfusion. of marrow erythrocyte production, which is useful in evaluating the
The hemoglobin level varies with age (Table 2–1 lists reference pathogenesis of anemia by distinguishing inadequate production from
ranges for children). Chapter 6 discusses changes in hemoglobin in accelerated destruction (Chap. 34). The manual method for enumerat-
the neonatal period. After the first week or two of extrauterine life, ing reticulocytes by placing a sample of blood in a tube containing new
the hemoglobin falls from levels of approximately 17 g/dL to levels of methylene blue and preparing a blood film to enumerate the propor-
approximately 12 g/dL by 2 months of age; with most of the decline tion of cells that show blue beaded precipitates (residual ribosomes) has
occurring within first week of life,18 likely by neocytolysis mechanism largely been replaced by automated methods, which are incorporated
(Chap. 34). Thereafter, the levels remain relatively constant throughout into high-volume hematology analyzers.30 Reticulocytes are identified
the first year of life. Any child with a hemoglobin level below 11 g/dL by direct fluorescence measurement after staining with RNA-binding
should be considered anemic.19 Chapter 7 discusses changes in hemo- dyes or light scatter measurements to detect staining if nonfluorescent
globin concentration with pregnancy and Chap. 8 discusses changes in RNA-binding dyes are used.
hemoglobin levels in older persons. Automated reticulocyte counts are typically reported in absolute
When it comes to gender variation in hemoglobin, it has been numbers (reticulocytes per μL or per L of blood), obviating the need to
found that adult women have significantly lower red blood cell counts, correct for a reduced red cell count (anemia), if present.
hemoglobin levels, and hematocrits than men (Table 2–2 outlines the Many hematology analyzers now report some quantitative mea-
published reference ranges for adults).20 These differences, which are sure of reticulocyte RNA content. Increase in the immature (highest
also seen in other adult animals, including nonmenstruating and non- RNA content) reticulocyte fraction is an early sign of marrow recovery
placental mammals, have been linked to effects of sex hormones in from cytotoxic therapy31 or treatment for nutritional anemias.
erythropoiesis.21 Estimates of reticulocyte-specific hemoglobin content (CHr and
RET-He, which are comparable) by light-scatter measurements of retic-
Standard Red Cell Indices ulocytes are closely related to adequacy of iron availability to erythroid
The size and hemoglobin content of erythrocytes (red cell indices), precursors during the preceding 24 to 48 hours, and have been described
based on population averages, have traditionally been used to assist in as diagnostically useful in detecting functional iron deficiency in com-
the differential diagnosis of anemia.22 plex clinical settings, such as chronic inflammation32 and chronic renal
Mean Cell Volume Automated blood counters measure the MCV disease.33 The increase in serum ferritin as an acute-phase reactant com-
directly by either electrical impedance or light scatter measurements bined with the physiologic variation of serum iron and iron-binding
of individual red cells. The MCV has been used to guide the diagnos- capacity limits the value of conventional parameters in these settings.
tic workup in patients with anemia; for example, testing patients with CHr may be a better predictor of depleted marrow iron stores than tra-
microcytic anemia for iron deficiency or thalassemia, and those with ditional serum iron parameters in nonmacrocytic patients,34 and is a
macrocytic anemia for folate or vitamin B12 deficiency. more sensitive predictor of iron deficiency than hemoglobin for screen-
Mean Cell Hemoglobin The MCH, the amount of hemoglobin ing infants35 and adolescents for iron deficiency.
per red cell, increases or decreases in parallel with the red cell vol-
ume (ie, MCV) and generally provides similar diagnostic information, Other Red Cell Findings
although because this parameter is affected by both hypochromia Nucleated Red Cells Nucleated red cells are present in newborns, par-
and microcytosis, it is at least as sensitive as the MCV in detecting ticularly if physiologically stressed, and in a variety of disorders, includ-
iron-deficiency states.23 Another advantage of the MCH is the con- ing hypoxic states (congestive heart failure), severe hemolytic anemia,
sistency across different analyzer types, as it is derived from two of primary myelofibrosis (Chap. 85), and infiltrative disease of the marrow
the most accurately measured parameters: hemoglobin and red cell (Chap. 46). Most modern automated hematology analyzers are capable
count.24 The MCHC (which measures the concentration rather than of detecting and quantitating nucleated red blood cells, which were a
amount of hemoglobin per red blood cell) is not used much diagnos- source of spuriously elevated leukocyte counts in earlier instruments, at
tically, and is primarily useful for quality control purposes, such as a level of 1–2 nucleated red cells per 100 leukocytes.
detecting sample turbidity. Malarial Parasites Malarial parasites also can be detected by
Because these red cell indices are average quantities, they may not some current analyzers, based on detecting parasite-infected red cells
detect abnormalities in blood with mixed-cell populations. or neutrophils containing ingested hemozoin in regions of the multi-
Red Cell Distribution Width The RDW is an estimate of the vari- parameter display that are not characteristically populated in normal
ance in volume within the population of red cells, which is expressed as blood (sometimes causing spurious eosinophilia36).
1 SD of red cell volume measurements divided by the MCV. Instrument
manufacturers calculate RDW using different algorithms, so that refer-
ence ranges vary according to analyzer model. A large literature has now
AUTOMATED ANALYSIS OF LEUKOCYTES
developed around the evidence that the RDW is a biomarker predicting Leukocyte Count and Differential
morbidity and mortality in a broad variety of clinical settings,25 such as Leukocyte counts are performed by automated cell counters on blood
angina/myocardial infarction26; heart failure; trauma; pneumonia; sepsis; samples appropriately diluted with a solution that lyses the erythro-
intensive care treatment; renal and liver disease; and in the general pop- cytes (eg, an acid or detergent), but preserves leukocyte integrity. Man-
ulation.27 RDW may be a surrogate for systemic inflammation28 and/or ual counting of leukocytes is used only when the instrument reports a
oxidative stress, but the predictive value of RDW is independent of other potential interference or the count is beyond instrument linearity limits.
inflammatory markers,29 suggesting that this biomarker is also tracking Instruments that perform an automated five-part differential can mea-
other mechanistic processes. Identification of physiologic mechanisms sure absolute neutrophil counts accurately down to 108/L (100/μL).37
linking RDW to adverse clinical outcomes is important in using this pre- Automated leukocyte counts may be falsely elevated as a result of
dictive biomarker to inform therapeutic decisions.25 cryoglobulins or cryofibrinogen; clumped platelets or fibrin from an

Kaushansky-Ch02_p0011-0030.indd 14
14
Part I: Clinical Evaluation of the Patient
TABLE 2–1. Reference Ranges for Leukocyte Count, Differential Count, and Hemoglobin Concentration in Children*
Neutrophils
Leukocytes
Age Total (× 109/L) Total Band Segmented Eosinophils Basophils Lymphocytes Monocytes Hemoglobin g/dL Blood
12 months 11.4 (6.0–17.5) 3.5 (1.5–8.5) 0.35 (0–1.0) 3.2 (1.0–8.5) 0.30 (0.05–0.70) 0.05 (0–0.2) 7.0 (4.0–10.5) 0.55 (0.05–1.1) 12.6 (11.1–14.1)
31 3.1 28 2.6 0.4 61 4.8
4 years 9.1 (5.5–15.5) 3.8 (1.5–8.5) 0.27 (0–1.0) 3.5 (1.5–7.5) 0.25 (0.02–0.65) 0.05 (0–0.2) 4.5 (2.0–8.0) 0.45 (0–0.8) 12.7 (11.2–14.3)
42 3.0 39 2.8 0.6 50 5.0
6 years 8.5 (5.0–14.5) 4.3 (1.5–8.0) 0.25 (0–1.0) 4.0 (1.5–7.0) 0.23 (0–0.65) 0.05 (0–0.2) 3.5 (1.5–7.0) 0.40 (0–0.8) 13.0 (11.4–14.5)
51 3.0 48 2.7 0.6 42 4.7
10 years 8.1 (4.5–13.5) 4.4 (1.8–8.0) 0.24 (0–1.0) 4.2 (1.8–7.0) 0.20 (0–0.60) 0.04 (0–0.2) 3.1 (1.5–6.5) 0.35 (0–0.8) 13.4 (11.8–15.0)
54 3.0 51 2.4 0.5 38 4.3
21 years 7.4 (4.5–11.0) 4.4 (1.8–7.7) 0.22 (0–0.7) 4.2 (1.8–7.0) 0.20 (0–0.45) 0.04 (0–0.2) 2.5 (1.0–4.8) 0.30 (0–0.8) M: 15.5 (13.5–17.5)
59 3.0 56 2.7 0.5 34 4.0 F: 13.8 (12.0–15.6)
*The means and ranges are in thousands of cells per mL. This table is provided as a guide. Reference ranges should be validated by the clinical laboratory for the specific methods in use.
The number in italic is mean percentage of total leukocytes.
For leukocyte and differential count, see Altman PL, Dittmer DS (eds): Blood and Other Body Fluids. Federation of American Societies for Experimental Biology, Washington, DC, 1961.
For hemoglobin concentration, see Rudolph AM, Hoffman JI (eds): Pediatrics, 18th ed, pp 1011, 1012. Appleton and Lange, Norwalk, CT, 1987.
16/10/20 7:56 AM
TABLE 2–2. Published Reference Ranges for Key Blood Variables

NORIP107 Wakeman92 Cheng93 Bain106
Date 2003 2004 1994 1994 1994 1996 1996
Ethnicity Nordic U.K. U.S. European U.S. African U.S. Mexican U.K. European U.K. African
descent descent descent descent descent
No. 1800 250 3125 1712 1735 200 115
Hgb (g/dL) (M) 13.4–17.0 13.7–17.2 13.2–16.9 12.0–16.2 13.1–16.7 NA NA
(F) 11.7–15.3 12.0–15.2 10.7–15.1 10.2–14.4 11.4–15.0
Hct (%) (M) 40–50 40–50 39–50 36–48 39–50 NA NA
(F) 35–46 37–46 34–45 32–43 33–45
MCV (fL) 82–98 83–98 (M) 79–97 (M) 75–97 (M) 83–96 (M) NA NA
85–98 (F) 77–97 (F) 75–97 (F) 81–98 (F)
WBC (× 109/L) 3.5–8.8 3.6–9.2 4.1–11.7 (M) 3.5–9.5 (M) 4.6–10.6 (M) 3.6–9.2 (M) 2.8–7.2 (M)
4.3–12.0 (F) 3.4–10.5 (F) 4.3–11.3 (F) 3.5–10.8 (F) 3.2–7.8 (F)
Neutrophils NA 1.7–6.2 2.7–8.1 (M) 1.5–7.4 (M) 2.2–6.6 (M) 1.7–6.1 (M) 0.9–4.2 (M)
(× 109/L)
2.5–6.9 (F) 1.5–8.4 (F) 2.5–7.9 (F) 1.7–7.5 (F) 1.3–4.2 (F)
Lymphocytes NA 1.0–3.4 1.1–3.7 (M) 1.1–3.6 (M) 1.3–3.4 (M) 1.0–2.9 (M) 1.0–3.2 (M)
(× 109/L)
1.2–3.7 (F) 1.3–3.9 (F) 1.3–3.9 (F) 1.0–3.5 (F) 1.1–3.6 (F)
Monocytes NA 0.2–0.8 0.13–0.86 (M) 0.11–0.72 (M) 0.14–0.70 (M) 0.18–0.62 (M) 0.15–0.58 (M)
(× 109/L)
0.11–0.78 (F) 0.12–0.83 (F) 0.12–0.79 (F) 0.14–0.61 (F) 0.15–0.39 (F)
Platelets 145–348 140–320 161–385 161–381 166–388 143–332 115–290
(× 109/L) (M)
(F) 165–387 180–380 178–434 178–452 171–411 169–358 125–342
F, female; Hct, hematocrit; Hgb, hemoglobin; M, male; MCV, mean cell; NA, measurement not available; NORIP, Nordic Reference Interval Project;
U.K., United Kingdom; U.S., United States; WBC, white blood cell count.
*
Ranges calculated from adult (>18 years) data, assuming equal contribution of subjects from each of multiple adult age groups, derived from
the National Health and Nutrition Examination Survey (NHANES) III.
This table is provided as a guide. Reference ranges should be validated by the clinical laboratory for the specific methods in use.
inadequately anticoagulated or mixed sample, ethylenediaminetetraace- most difficult for both automated instruments and the human observer
tic acid (EDTA)-induced platelet aggregation, nucleated red blood cells, to identify. If one needs to search for infrequent abnormal cells or eval-
or nonlysed red cells, and falsely decreased because of EDTA-induced uate leukocyte morphology, there is still no substitute for microscopic
neutrophil aggregation. examination of a properly stained blood film by a trained observer.
Modern automated instruments use multiple parameters to iden- The normal differential leukocyte count varies with age and eth-
tify and enumerate the five major morphologic leukocyte types in nicity. As described in Chap. 6, polymorphonuclear neutrophils are
blood: neutrophils, basophils, eosinophils, lymphocytes, and mono- predominant in the first few days after birth, but thereafter lympho-
cytes, as well as indicate the possible presence of immature or abnormal cytes account for the majority of leukocytes. This pattern persists up to
cells. Customarily, both absolute (cells per L or μL) and relative (per- approximately 4–5 years of age, when the polymorphonuclear leuko-
cent of leukocytes) counts are reported in the leukocyte differential. It cyte again becomes the predominant cell and remains so throughout
is the absolute values that relate to pathologic states, and percentages the rest of childhood and adult life. Chapters 7 and 8 discuss the leuko-
are sometimes misleading (eg, absolute neutropenia appearing as a rel- cyte count in pregnancy and in older persons. The leukocyte count may
ative lymphocytosis) if the absolute values are not carefully examined. decrease slightly in older subjects because of a fall in the lymphocyte
Some have proposed to eliminate the reporting of differential count count with age. Neutrophil counts are lower in individuals of African
percentages entirely for this reason.38 “Band” neutrophils cannot be descent, and in some Middle Eastern populations than in persons of
identified as such by automated analyzers, although they will usually European descent, and is of no pathologic significance.40
trigger a manual review flag if present in increased numbers. Eosin-
ophils are accurately counted by current state-of-the-art instruments,
but automated basophil counts remain imprecise.9 Many instruments AUTOMATED ANALYSIS OF PLATELETS
have “blast” flags designed to pick up leukemic blasts, but the sensitivity Platelet Count
of such flags alone varied from 65% to 94% in a study,9 and is lower in Platelets are usually counted electronically by enumerating particles in
leukopenic patients.39 Lymphoma cells and reactive lymphocytes are the the unlysed sample within a specified volume window (eg, 2–20 fL),

where volume may be measured by electrical impedance or light certain blood cell counts is notably higher than usually found in blood
scatter.41 Current instruments typically construct a platelet volume his- chemistry analytes. This is a reflection of the adaptive responsiveness
togram based on platelet size within a reliably measured platelet vol- of the marrow and other tissues to cytokine and hormonal signaling.
ume window and mathematically extrapolate this histogram to account For instance, the leukocyte and differential counts are affected by stress,
for platelets whose size overlaps with debris (smaller) or small red cells diurnal variation, tobacco smoking, and ethnic origin. Platelet count
(larger). This works because platelet volumes in health or disease fol- and MPV show substantial ethnic variation.56 The platelet and absolute
low a log-normal distribution. Automated platelet counting by current neutrophil counts are lower in individuals of African ethnic origin.40
instrumentation is accurate and far more precise than manual meth- American men and women of African descent have lower hemoglobin
ods. At very low platelet counts (less than 20 × 109/L), results are less concentrations than do men and women of European descent, a differ-
precise42 and there is a method-dependent tendency to overestimate ence that is reduced by half, but still significant, when subjects with iron
platelet counts.43 Conversely, platelet activation in disorders such as deficiency (Chap. 44), thalassemia (Chap. 49), sickle trait, and renal
disseminated intravascular coagulation (DIC) and acute leukemia may disease (Chap. 35) are excluded.57 Tables 2–1 and 2–2 list the reference
result in systematic slight undercounting of platelets. Although the rea- ranges for children, and African American, Hispanic, and white adults.
son behind this phenomenon is poorly understood, it has been postu- As with all laboratory parameters, clinical interpretation of patient
lated that automated analyzers with different counting principles have results should be based on laboratory specific reference ranges. Conse-
different intrinsic detection limits for identifying degranulated small quently, these tables are not presented to guide interpretation of specific
platelets.44 laboratory results, but to indicate the challenges facing laboratories and
Falsely Decreased or Elevated Platelet Counts Causes of falsely physicians in constructing and interpreting reference ranges of even
decreased platelet counts include incomplete anticoagulation of the standard and traditional assays.
sample (sometimes accompanied by small clots in the specimen or
fibrin strands on the stained film) and platelet clumping (pseudoth-
rombocytopenia) or “satellitism” (adherence of platelets to neutrophils), M
ORPHOLOGIC EXAMINATION
caused by aggregation induced by nonpathogenic antibodies recogniz-
ing platelet adhesion molecule epitopes exposed as a result of chelation
OF THE BLOOD
of divalent cations in the anticoagulated sample.41 Platelet clumping Microscopic examination of the blood spread on a glass slide or cover-
occurs in approximately 0.1% of hospitalized patients.45 The same phe- slip yields useful information regarding all the cells of the blood. The
nomenon may occur to a lesser degree in citrate, which is often used to process of preparing a thin blood film causes mechanical trauma to the
obtain platelet count in such cases. Magnesium EDTA anticoagulant, cells, introducing artifacts that can be minimized by good technique.
as compared to sodium EDTA anticoagulant, is reported to more effec- The optimal part of the stained blood film to use for morphologic
tively inhibit platelet aggregation in these patients and provide an accu- examination of the blood cells should be sufficiently thin that a small
rate platelet count.46 proportion of erythrocytes in a ×1000 magnification field touch each
Classical causes of falsely elevated platelet count include severe other, but not so thin that no red cells are touching. Figure 2–2 is a
microcytosis, cryoglobulins, and leukocyte cytoplasmic fragmenta- composite image taken from the optimal portion of the film showing
tion.41 Infrequently, it may be necessary to confirm automated results the five major leukocyte types, normal red cells, and platelets. Selection
by a microscopic (phase contrast) platelet count or platelet estimate of a portion of the blood film for analysis that is too thick or too thin
from the blood film, bearing in mind that these methods are impre- for proper morphologic evaluation is the most common error in blood
cise. When reviewing the blood film, platelet count may be roughly film interpretation. For example, leukemic blasts may appear dense
estimated as 2000 times the number of platelets in 10 consecutive oil and rounded and lose their characteristic features when viewed in the
immersion (1000×) fields.47 thick part of the film. For specific purposes, the thick portion or side
Mean Platelet Volume Increased mean platelet volume (MPV) and “feathered” edges of the film are of interest (for instance, to detect
may be related in a complex way to thrombopoietic stimuli that affect microfilariae and malarial parasites or to search for large abnormal cells
megakaryocyte ploidy, and not platelet age per se. A platelet volume and platelet clumps).
distribution width (PDW) can be calculated by the same method as the The blood film is first scanned at low magnification (×200) to con-
RDW, and is correlated with platelet count and MPV.48 firm reasonably even distribution of leukocytes and to check for abnor-
Newly Released (Reticulated) Platelets The number of plate- mally large or immature cells in the side and feathered edges of the film.
lets with high RNA content (sometimes termed reticulated platelets or The feathered edge is examined for platelet clumps. Abnormal cells, red
immature platelet fraction, measured by flow cytometry with RNA-binding cell aggregation or rouleaux, background bluish staining consistent with
fluorescent dyes, or by certain automated analyzers49) is a marker of paraproteinemia, and parasites are all findings that can be suggested by
marrow megakaryocytopoiesis and is proposed as a way of differenti- medium magnification examination (×400). The optimal portion of the
ating decreased production of platelets from circulatory destruction or film is then examined at high magnification (×1000, oil immersion) to
removal as a cause of thrombocytopenia, in an analogous fashion to systematically assess the size, shape, and morphology of the major cell
the use of the reticulocyte count. The percentage of reticulated platelets lineages.
is increased in destructive thrombocytopenias, but remains within the
reference range in hypoproductive states.50 Reticulated platelet number
or RNA content correlates with imminent platelet recovery after che- RED CELL MORPHOLOGY
motherapy.51 Reticulated platelet number is correlated with risk of death Normal erythrocytes on dried films are nearly uniform in size, with
in patients with acute coronary syndrome52 and DIC,53 and with hypore- a mean diameter of approximately 7.5 μm (normal and abnormal red
sponsiveness to platelet function inhibitors54 or aspirin.55 cells are described in more detail in Chap. 33). The normal-sized ery-
throcyte is about the diameter of the nucleus of a small lymphocyte.
The MCV is a more sensitive measure of red cell volume than of the
REFERENCE RANGES red cell diameter; however, an experienced observer should be able to
The use of reference ranges for quantitative hematology measure- recognize abnormalities in average red cell size when the MCV is sig-
ments deserves some additional comment. The physiologic variation of nificantly elevated or decreased. Anisocytosis is the term that describes

A B C
D E F
Figure 2–2. Images from a normal blood film showing major leukocyte types. The red cells are normocytic (normal size) and normochromic (nor-
mal hemoglobin content) with normal shape. The scattered platelets are normal in frequency and morphology. A. A platelet caught sitting in the
biconcavity of the red cell in the preparation of the blood film. This normal finding should not be mistaken for a red cell inclusion. Images are taken
from the optimal portion of the blood film for morphologic analysis. Image shows a (A) segmented (polymorphonuclear) neutrophil and in the inset
a band neutrophil; (B) monocyte; (C) small lymphocyte; (D) large granular lymphocyte, note larger size than lymphocyte in (C) and increased amount
of cytoplasm containing scattered eosinophilic granules; and (E) eosinophil. Virtually all normal blood eosinophils are bilobed and filled with relatively
large (compared to the neutrophil) eosinophilic granules. F. Basophil and in inset a basophil that was less degranulated during film preparation,
showing relatively large basophilic granules. The eosinophilic and basophilic granules are readily resolvable by light microscopy (×1000), whereas the
neutrophilic granule is not resolvable but in the aggregate imparts a faint tan coloration to the neutrophil cytoplasm, quite distinctly different from
the blue-gray cytoplasmic coloring of the monocyte and lymphocyte.
variation in erythrocyte size, and is the morphologic correlate of the Increased central pallor (hypochromia) is associated with disorders
RDW. Macrocytes and microcytes are red cells larger or smaller than characterized by diminished hemoglobin synthesis, such as iron defi-
normal, and their presence consistent with the measured MCV suggests ciency (Chap. 44). Evaluation of red cell hemoglobin content, as well
certain diagnostic possibilities. Early (“shift” or “stress”) reticulocytes as red cell size, is dependent on examining the proper part of the blood
(ie, those with the most residual RNA) appear in stained films as large, film. Cells at the far “feathered edge” will always be large and lack cen-
slightly bluish cells, referred to as polychromatophilic cells (Chap. 34). tral pallor, whereas cells in the thick part of the film will look small
These cells are roughly the morphologic counterpart of the immature and rounded and will also lack central pallor. A sharp refractile border
reticulocyte fraction identified by automated instruments. demarcating the central area of pallor is an artifact secondary to inade-
The normal erythrocyte on a blood film is circular with central quate drying of the film before staining (associated with high humidity,
pallor. Poikilocytosis is a term used to describe variations in the shape and more common in anemic samples). Chapter 33 describes the inclu-
of erythrocytes. The predominant appearance of a specific abnormality sions that may be observed in erythrocytes on blood films.
in red cell shape can be an important diagnostic clue in patients with Erythrocytes are usually distributed evenly throughout the blood
anemia. Figure 2–3 lists morphologic changes in the erythrocytes and film. In some cases, the cells become aligned in overlapping stacks,
associated disorders. Erythrocytes with evenly spaced spikes (echino- referred to as rouleaux (Chap. 108), resembling overlapping rows of
cytes or crenated cells) can be an artifact caused by prolonged storage, coins. Rouleaux are normal in the thick part of the film, but when found
or may reflect metabolic erythrocyte abnormalities. in the optimal viewing portion of the film, suggest a pathologic increase

Figure 2–3. Disorders associated with certain red cell

Name Characteristic of Also seen in morphologic changes. Poikilocytosis is a general term
Spherocyte Hereditary spherocytosis, Clostridial perfringens used to indicate the presence of abnormally shaped red
(Chaps. 33, 47, immune hemolytic septicemia, Wilson cells, such as dacryocytes (teardrop-shaped red cells),
55) anemia disease schistocytes (fragmented red cells), and elliptocytes, as is
Iron deficiency, megaloblastic found in the most extreme form in hereditary pyropoiki-
Elliptocyte Hereditary elliptocytosis anemia, thalassemia, locytosis. MDS, myelodysplastic syndromes.
(Chaps. 33, 47) myelofibrosis, MDS
Dacryocyte Severe iron deficiency,
(teardrop) Myelofibrosis megaloblastic anemia,
(Chaps. 33, 85) thalassemia, MDS
Schistocyte Microangiopathic, Occasional schistocytes are
(Chaps. 33, 52, mechanical hemolytic seen in many disorders
127, 128) anemia affecting red cells.
Echinocyte Renal failure, Common in vitro artifact
(Chaps. 33, 38) malnutrition after storage
Acanthocyte Spur cell anemia,

Postsplenectomy
(Chaps. 33, 57) abetalipoproteinemia
Target cell Cholestasis, hemoglobin Iron deficiency,

(Chaps. 33, 49) C disease thalassemia
Stomatocyte Hereditary
Alcoholism
(Chaps. 33, 47) stomatocytosis
in immunoglobulin (Ig), particularly IgM macroglobulinemia. Occa- by a strand of chromatin. It represents the inactive X chromosome of
sionally, high concentrations of IgA or IgG in patients with myeloma the pair (Chap. 9). The cytoplasm is diffusely pale pink and contains
may also produce rouleaux. many small, tan to pink granules distributed evenly throughout the cell.
Bands are identical in appearance to mature neutrophils except that the
nucleus is not segmented but is sausage-shaped or U-shaped (see Fig.
PLATELET MORPHOLOGY 2–2). Nuclear chromatin is slightly less condensed than the mature neu-
Platelets appear in normal stained blood film as small blue or color- trophil (Chap. 61).
less bodies with red or purple granules (see Fig. 2–2). Normal platelets Eosinophils are on the average slightly larger than neutrophils
average approximately 1–2 μm in diameter, but show wide variation (Chap. 65). The nucleus usually has 2 lobes (see Fig. 2–2). The chroma-
in shape, from round to elongated, cigar-shaped forms. In improperly tin pattern is the same as that of the neutrophil, but the nucleus tends to
prepared films, platelets may form large aggregates in some areas and be more lightly stained. The differentiating characteristic of these cells is
appear to be diminished or absent in others. The frequent occurrence the presence of many refractile, orange-red granules that are distributed
of giant platelets or platelet masses may indicate a myeloproliferative evenly throughout the cell and may be visible overlying the nucleus.
neoplasm or improper collection of the blood specimen. The latter cir- These granules are larger than those in the neutrophil and are more
cumstance can occur when venipuncture technique is faulty and plate- uniform in size. Occasionally, some of the granules in eosinophils stain
lets become activated before the blood sample is thoroughly mixed with light blue rather than orange-red.
anticoagulant. These platelet masses are apparent typically in the thin Basophils are similar to the other polymorphonuclear cells and
“feathered edge” of the film, with corresponding fewer platelets else- are slightly smaller than neutrophils (Chap. 66). The nucleus may stain
where. Platelet clumping throughout the blood film, or platelet “satelli- more faintly and usually is less segmented and has less distinct chro-
tism” (adherence of platelets to neutrophils), may be a result of platelet matin condensation than is the case in neutrophils. The large deeply
agglutinins (Fig. 2–4). A platelet will occasionally overlie an erythro- basophilic granules of basophils are fewer in number and less regular in
cyte, where it may be mistaken for an inclusion body or a parasite. The size and shape than in the eosinophil. The granules are visible overlying
differentiation depends on the observation of a halo around the platelet, the nucleus and, in some cells, almost completely obscure the lightly
determination that it lies above the plane of the erythrocyte, and obser- stained nuclear chromatin. Because the granular constituents are water
vation of the characteristics of a normal platelet in the “inclusion.” soluble, some granules may stain only faintly or not at all or may be lost
from the cell during preparation (see Fig. 2–2).
Lymphocytes on blood films are usually smaller than other leu-
LEUKOCYTE MORPHOLOGY kocytes, approximately 10 μm in diameter, but larger lymphocytes (up
The cells normally found in blood are mature neutrophils, lymphocytes, to 20 μm in diameter) occasionally are seen (see Fig. 2–2). The small
and monocytes, with smaller numbers of eosinophils and basophils lymphocyte, the predominant type in normal blood, is round and con-
(see Fig. 2–2). Neutrophils are round cells ranging from 10 to 14 μm tains a relatively large, round, densely stained nucleus (Chap. 73). The
in diameter on a blood film. The nucleus is lobulated, with two to four cytoplasm is scanty and stains pale to dark blue. In the large lympho-
lobes connected by a thin chromatin thread. The defining feature of cytes, the nuclear-to-cytoplasmic ratio is lower and the chromatin is
the mature neutrophil is the round lobes with condensed chromatin, slightly less condensed than in the small lymphocytes. The nucleus is
because the chromatin thread may overlie the nucleus and not be visi- usually round but may be oval or indented. The cytoplasm is abundant
ble. The chromatin stains purple and is coarse and arranged in clumps. and may contain a few azurophilic granules. Large granular lymphocytes
The nucleus of 1% to 16% of the neutrophils from females may have an contain azurophilic granules and relatively abundant cytoplasm, and
appendage that is shaped like a drumstick and is attached to one lobe generally represent cytotoxic T or natural killer (NK) cells (Chap. 93).

A B C
D E F
G H
Figure 2–4. Findings in peripheral blood films. A. Toxic granules in neutrophils. In inflammatory states the neutrophil may develop overt purplish
granules as shown in this example of reactive neutrophilia. B. Chédiak-Higashi disease. Note the giant eosinophilic granule in the monocyte and the
numerous enlarged granules in the lymphocyte (Chap. 66). C. Hurler syndrome. Note characteristic prominent dense cytoplasmic inclusions in the
mononuclear cell. These inclusions are accumulations of glycosaminoglycans resulting from a deficiency of α-L-iduronidase in leukocytes and other
tissues. D. Examples of apoptosis of 2 neutrophils in normal anticoagulated blood during standing at room temperature. Nuclear condensation and
fragmentation are evident. A normal neutrophil is also present. E. Döhle bodies. These RNA remnants of rough endoplasmic reticulum appear as blue
rod-shaped structures (arrow points to one) in neutrophils involved in inflammatory reactions. F. May-Hegglin disease. The large blue-gray inclusions
(arrow) represent precipitates of nonmuscle myosin heavy chain type IIA. Note also the 2 macrothrombocytes (the size of red cells) characteristic of
this disorder (Chap. 120). The neutrophil inclusions stain with fluorescent antibodies to nonmuscle myosin heavy chain type IIA. G. Marrow film. A
strand of endothelial cells derived from vascular tissue caught on the biopsy needle. Individual endothelial cells may be found, rarely in a blood film.
H. Platelet satellitism. Three neutrophils surrounded by adherent platelets. This blood film was prepared from an ethylenediaminetetraacetic acid–
anticoagulated sample. (Reproduced with permission from Lichtman’s Atlas of Hematology, www.accessmedicine.com.)
Reactive lymphocytes, as seen in viral infections caused by Epstein-Barr result of fine granules (staining pink) seen on the background of RNA-
virus, cytomegalovirus, adenovirus, or other organisms, are large with containing cytoplasm (staining blue), and helps to distinguish between
indented nuclei and abundant blue cytoplasm (Chap. 81). Nuclear chro- monocytes and reactive lymphocytes. The monocyte nuclear chromatin
matin condensation is variable, and nucleoli may be evident. A low contains a fine, string-like structure as opposed to the smudgy-appearing
nuclear-to-cytoplasmic ratio and greater degree of chromatin conden- clumps of the lymphoid chromatin. Nuclear shape and cytoplasmic vac-
sation distinguishes reactive lymphocytes from neoplastic cells. uolization are less reliable for distinguishing features between mono-
Monocytes are the largest normal cells in the blood, usually mea- cytic and lymphoid cells.
suring from 15 to 22 μm in diameter (see Fig. 2–2). The nucleus is
of various shapes—round, kidney, oval, or lobular—and frequently
appears to be folded (Chap. 67). The lacy chromatin is arranged in fine LEUKOCYTE INCLUSIONS
strands with sharply defined margins. The cytoplasm is light gray, con- Abnormal Granules
tains variable numbers of fine lilac or purple granules, and is often vac- In a systemic inflammatory reaction, neutrophil granules may appear
uolated. The gray (as opposed to blue) color of monocyte cytoplasm is a larger than normal and stain more darkly, often assuming a dark

blue-black color. This has been called toxic granulation (Fig. 2–4). offered by examination of the aspirate smear. However, a marrow biopsy
These granules if unusually prominent can be confused with the larger is essential for quantifying marrow cellularity, diagnosing myeloprolif-
granules of basophils. In mucopolysaccharidoses, coarse, dark granules erative neoplasms and other disorders associated with reticulin fibro-
may be found in the neutrophils, and large azurophilic granules in some sis, evaluating lymphoid neoplasms that may not be well-represented
lymphocytes and monocytes (Fig. 2–4). Huge misshapen granules are in the aspirate, and diagnosing infiltrative diseases of the marrow.62–64
found in the neutrophils, and giant azurophilic granules are present in In myelodysplastic syndromes, marrow biopsy is useful for evaluat-
the lymphocytes of patients exhibiting the Chédiak-Higashi anomaly ing abnormal localization of immature precursor cells and abnormal
(Fig. 2–4; Chap. 64). Auer rods are sharply outlined, red-staining rods megakaryocytes. Marrow necrosis, amyloid, and gelatinous transforma-
found in the cytoplasm in blast cells, and occasionally in more mature tion are more readily detected in marrow sections than in aspirate films.
leukemic cells, in the blood of some patients with acute myeloid leuke- Morphology of marrow cells is still the gold standard for diagnosis
mia or myelodysplastic syndromes (Chaps. 86 and 87). of hematologic malignancy and allows construction of a good differ-
ential diagnosis for nonmalignant disorders. Immunohistochemistry
Neutrophil Inclusions performed in the marrow core biopsy or paraffin-embedded marrow
Light blue round or oval Döhle bodies, approximately 1–2 μm in diame- aspirate clot provides excellent phenotype–morphology correlation on
ter, may be seen in the cytoplasm of neutrophils of patients with infec- an individual cell basis, but is limited to epitopes that resist destruction
tions, burns, and other inflammatory states (see Fig. 2–4). The blue by fixation, decalcification (core biopsy only), and paraffin embedding.
staining is caused by RNA of the rough-surfaced endoplasmic reticulum The International Council for Standardization in Hematology has pub-
contained in Döhle bodies. These bodies are thought to be a reflection lished guidelines for standardization of marrow immunohistochemistry.65
of accelerated maturation of neutrophils with residual endoplasmic Flow cytometry allows study of almost any surface or intracellular pro-
reticulum from the promyelocyte stage. They usually occur in circum- tein, with the added ability to detect important quantitative changes in
stances in which toxic granulation may be present. May-Hegglin anom- cellular proteins and simultaneous determination of multiple proteins
aly is one of several myosin heavy chain 9 (MYH9) disorders, autosomal within the same cell. However, flow cytometry requires that cells be via-
dominant macrothrombocytopenias secondary to defective megakary- ble and dissociated from tissue. Molecular assays include classic meta-
ocyte maturation and fragmentation, with leukocyte inclusion bodies phase cytogenetics, fluorescence in situ hybridization (FISH), reverse
(also Alport-like, Epstein, Fechtner, and Sebastian syndromes; Chap. 111). transcriptase polymerase chain reaction (PCR), and massively parallel
The leukocytic inclusions, pale blue-stained, irregularly shaped inclu- sequencing (also known as next-generation sequencing) of a targeted
sions are precipitates of nonmuscle myosin heavy chains (see Fig. 2–4). gene panel or the whole exome/genome. Gene expression arrays allow
Neutrophil function is normal. analysis of complex patterns of RNA expression by sophisticated math-
ematical algorithms to discover diagnostic patterns based on gene
expression. For most molecular assays, fresh tissue (blood or marrow
LEUKOCYTE ARTIFACTS AND
aspirate) is preferred. Nevertheless, many molecular assays may be per-
ENDOTHELIAL CELLS formed on formalin-fixed, paraffin-embedded tissue as long the tissue
Damaged (“Smudge,” “Basket”) and Apoptotic Cells has not been decalcified with hydrochloric acid.66,67
During blood film preparation, leukocytes may be damaged, resulting
in an enlarged nucleus with homogeneous, slightly reddish chromatin
strands with a large blue nucleolus. There is no specific association with MARROW ASPIRATION AND
disease other than chronic lymphocytic leukemia (Chap. 91), where BIOPSY TECHNIQUE
increased cell fragility commonly results in variable numbers of smudge
cells. Eosinophils and basophils often are partially or largely degranu- At birth, all bones contain hematopoietic marrow. Fat cells begin to
lated in preparation of the blood film with the granules scattered beside replace hemopoietic marrow in the extremities in the fifth to seventh
the cell. Occasional neutrophils may be seen in stages of apoptosis after year. By adulthood, the hemopoietic marrow is limited to the axial
standing in anticoagulated blood at room temperature (see Fig. 2–4). skeleton and the proximal portions of the extremities (Chaps. 4 and 8).
Fatty marrow appears yellow, whereas hematopoietic marrow is red.
Endothelial Cells Red marrow contains fat, however, and fat droplets are visible grossly
If the blood film is prepared from the first drop of blood issuing from in aspirated marrow specimens. Histologically, yellow marrow consists
fingerstick, endothelial cells may be present singly, in clumps, or as almost entirely of fat cells and supporting connective tissue. Red mar-
strings of attached cells (see Fig. 2–4). These cells en face may simulate row contains an abundance of hematopoietic cells, fat cells, and con-
the appearance of abnormal cells and may be misinterpreted as blasts or nective tissue. The marrow fills the spaces between the trabeculae of
metastatic tumor cells. bone in the marrow cavity. Marrow is soft and friable and can be readily
aspirated or biopsied with a needle.
The posterior iliac crest (Fig. 2–5) is the preferred site for marrow
EXAMINATION OF THE MARROW aspiration and biopsy. In adults, the anterior iliac crest and rarely the
sternum have been used (Fig. 2–6). The sternum should be used for
INDICATIONS FOR MARROW EXAMINATION aspiration only. The anterior iliac crest is less preferred than the pos-
The International Council for Standardization in Hematology has pub- terior crest in adults because of its thick cortical bone. The anterome-
lished guidelines for marrow aspirate and biopsy to promote consis- dial surface of the tibia is an option for infants younger than 1 year old
tency in performance and reporting.58 Although marrow aspiration and (particularly newborns), but the posterior iliac crest is still the preferred
biopsy techniques are safe, they should be performed with a clear idea as site. Serious adverse outcomes after marrow aspiration or biopsy are
to how the results will help distinguish the differential diagnoses under rare, occurring in less than 0.05%. One direct fatality and 3 episodes of
consideration or provide followup of treatment.59–61 prolonged but not permanent disability were reported in nearly 55,000
When examination of the marrow is indicated, the decision as to marrow biopsies.68 Morbidity most frequently involved hemorrhage,
whether an aspirate or an aspirate plus biopsy is desired should be made. which was associated more with platelet function impairment than
Aspiration is always attempted because of the superior morphology with thrombocytopenia or coagulation factor defects.68 Infection and

ascending aorta varies greatly and may be as little as 4–5 mm,69 giving
rise to the rare but dramatic consequence of aortal wall tear. To prevent
3 mm 2 mm this, a guard should be in place on the needle if a sternal aspirate is
1 12 cm taper
required.
For either a marrow biopsy or aspiration, sedation minimizes anx-
1 iety and pain,70 particularly in children,71 for whom propofol, with or
cm 10 cm without fentanyl, administered under carefully controlled conditions72
with monitoring of oxygen saturation, blood pressure, and vital signs, is
Biopsy needle frequently used. Midazolam (Versed) is a popular choice for conscious
1 12 cm sedation of adult patients, although a variety of other premedications
taper have been used. There is a relative lack of empirical research and con-
Stylet sensus guidelines on the subject of pain reduction during adult marrow
2 mm procedures.73,74 The experience of marrow procedures from the patient’s
Probe point of view is worth reading.75 The only significant correlates with
A severe/unbearable pain (experienced by 4% of patients) during marrow
examination were quality of the information about the procedure pro-
vided before the examination and previous painful experiences.76
Posterior superior iliac spine

MARROW ASPIRATION
Several different types of needles are available for marrow aspiration.59
For adults, a 16-gauge needle is sufficiently large to permit aspiration
of adequate specimens; larger needles are unnecessary. The patient is
prone or in the left or right lateral decubitus position. Sterile precau-
tions must be observed. The skin over the puncture site is shaved if
necessary and cleansed with a disinfectant solution. The skin, subcu-
taneous tissues, and periosteum are infiltrated with a local anesthetic
solution, such as 1% lidocaine. Adequate infiltration of the anesthetic
at the periosteal surface is important to minimize severe pain during
the procedure, but no more than 20 mL of 1% lidocaine should be used
in an adult.77 Adequate anesthesia can be achieved with much less lido-
caine in virtually all cases. The skin surface may be anesthetized prior to
B application of anesthetic to the periosteal surface by injection. After the
anesthesia has taken effect, usually in 3–5 minutes, a small cut (3–5 mm)
Figure 2–5. A. Jamshidi biopsy instrument. B. Site of marrow biopsy. may be made on the skin to prevent tearing by the aspiration needle
(A, reproduced with permission from Jamshidi K, Swaim WR. Bone marrow depending on gauge. The needle is inserted through the small cut in the
biopsy with unaltered architecture: a new biopsy device. J Lab Clin Med. skin, subcutaneous tissue, and cortex of the bone using a slight twisting
1971 Feb;77(2):335-342.) motion. In obese patients, the length of the needle must be sufficient
to reach the iliac crest. The stylet should be locked into place on the
reactions to anesthetic agents are other infrequent complications. Pene- hub of the needle to prevent plugging of the needle with tissue prior to
tration of the bone with damage to the underlying structures is possible needle entry into the marrow cavity. Penetration of the cortex can be
with all marrow aspirations, but the hazard is greatest in sternal aspira- sensed by a slight, rapid forward movement accompanied by a sudden
tions because the sternum at the second interspace is approximately 1 cm increase in the ease of advancing the needle. The stylet of the needle is
thick in adults, and the distance from posterior sternal cortex to the removed promptly, the hub is attached to a 10- or 20-mL syringe, and
approximately 0.5–1.5 mL of fluid is aspirated. Aspirating beyond this
volume may result in peripheral blood diluting the marrow, often mak-
ing the sample inadequate for pathologic examination and flow cytom-
etry. If additional specimen volume is required, another syringe is fitted
on the marrow needle, the syringe and needle is rotated and an adjacent
area is entered and marrow is aspirated. The stylet may be reinserted and
1 the marrow needle slightly repositioned between aspirations. The actual
X 2 aspiration of the marrow causes a transient painful sensation for most
3 patients. When aspiration is complete, the needle is immediately removed
from the bone. Pressure is applied to the skin over the aspiration site for
approximately 5 minutes to minimize bruising at the site. If platelet num-
ber or function is decreased, firm pressure should be applied for at least
10–15 minutes. The bloody fluid that is aspirated contains light-colored
X
particles (fragments) of marrow approximately 0.5–1 mm in diameter,
which are referred to as marrow spicules. They often are readily visible
in the syringe, but may not be detected until the syringe contents are dis-
Figure 2–6. Sites used for marrow aspiration. (Modified with permission charged on glass slides for blood film preparation.
from Schwartz SO, Hartz WH Jr, Robbins JH. Hematology in Practice. If nothing enters the syringe when aspiration is performed, the
New York, NY: McGraw Hill; 1961.) needle may not be properly placed in the marrow cavity. The needle

can be cautiously advanced 1–2 mm after reinsertion of the stylet and the best for evaluating cellular morphology and differential counts of the
aspiration attempted again, or the needle can be removed from the bone marrow. The marrow aspirate particle film is best for estimating marrow cel-
and reinserted in a nearby site in the anesthetized area. The thickness of lularity and megakaryocyte abundance, but morphology is obscured in the
the bone must be considered when the needle is being adjusted in the thicker parts of the film. A marrow aspirate concentrate film, which is pre-
bone. Occasionally the needle must be rotated on its longitudinal axis, pared from a concentrate of nucleated cells (marrow buffy coat) achieved
or in a larger orbit, in order to loosen the marrow mechanically before by centrifugation of a small volume of anticoagulated marrow, is sometimes
the marrow can be aspirated. If a small amount of blood has been aspi- used for detecting low-abundance cells when the marrow is hypocellular.
rated, a new needle should be used because of the probability of clotting The relative proportions of cell lineages are not maintained in the concen-
the aspirate when it finally is obtained. Aspiration with a 50-mL syringe trate film preparation (often erythroid precursors are relatively enriched).
may succeed if use of a smaller syringe fails. Fibrotic or densely packed In addition, this preparation is subject to anticoagulant-induced changes
leukemic marrow may resist all attempts at aspiration, in which case a in nuclear morphology or cytoplasmic vacuolization. The touch imprint
biopsy may be used to create cell suspensions for ancillary studies such from the biopsy is quite valuable and sometimes diagnostically necessary
as cytogenetics and flow cytometry.78 The most common cause of failure for evaluating cellular morphology when the aspirate is hypocellular.81 The
to obtain marrow is faulty positioning of the needle; a second attempt touch imprint is prepared by gently rolling the biopsy across a glass slide
at aspiration usually succeeds. A specimen preparation checklist used (using an applicator stick to move the specimen) before it is placed in fix-
at the time of the procedure to verify presence of spicules, length of ative, taking care to avoid crushing. The touch preparations are allowed to
biopsy, and other protocol items increases biopsy specimen length and dry and are stained in the same manner as marrow aspirate films.
decreases frequency of nondiagnostic samples.79
SPECIAL STUDIES
MARROW BIOPSY It is essential to formulate the diagnostic question before performing a
Needle biopsy usually is performed with the Jamshidi needle, using the marrow aspiration to ensure an adequate sample is obtained for all the
same preparation as described above. The Jamshidi instrument (see Fig. 2–5) special studies that may be needed to make the correct diagnosis.82 A ster-
consists of a cylindrical needle with constant bore, except for a concen- ile anticoagulated sample containing viable unfixed cells in single-cell sus-
trically tapered distal portion ending in a sharp, beveled cutting tip. The pension is the best substrate for nearly all special studies. Specifically, flow
stylet fits precisely inside the opening at the tapered tip, interlocks at the cytometry is best performed on EDTA- or heparin-anticoagulated aspi-
hub of the needle, and extends 1–2 mm beyond the end of the needle. rate specimens, which are stable for at least 24 hours at room temperature.
An 11-gauge needle is most commonly used in the United States. After For cytogenetic or cell culture analysis, preservative-free heparin-
the skin and the periosteum of the biopsy site are anesthetized, a 3-mm anticoagulated marrow should be added to tissue culture medium and
incision may be made in the skin if not already done prior to the aspirate. analyzed as soon as possible to maintain optimal cell viability. Cytogenetic
The needle, with obturator in place, is inserted into the skin incision and samples are generally not adversely affected by overnight incubation.83
through the subcutaneous tissue to the cortex of the bone. The needle In cases where the marrow aspirate is dry, a duplicate biopsy specimen
is directed toward the posterior iliac spine and advanced with a twist- can be disaggregated to produce a cell suspension for morphology, flow
ing motion. Penetration of the cortex is sensed by a decreased resistance cytometry, and cytogenetic studies.78 FISH for detection of chromosomal
to forward movement of the needle. The obturator is removed, and the deletions, duplications, and translocations can be performed in marrow
needle is slowly advanced with reciprocal clockwise–counterclockwise biopsies when EDTA-based decalcification protocols are used.66
twisting motions around the long axis. After sufficient penetration of the For molecular analysis of fresh specimens, sample storage should
bone (up to approximately 3 cm), the needle is rotated several times on be minimized, and storage at 4 °C is preferable. EDTA is the preferred
its axis and withdrawn approximately 2–3 mm. Some needles now come anticoagulant because heparin can interfere with some molecular
with a “trap” that snares the biopsy so that the needle can be directly assays. DNA is relatively stable, but RNA has a variable half-life in an
removed. The needle is reinserted to the original depth at a slightly dif- intact cell and is degraded rapidly in a cell lysate by ubiquitous ribonu-
ferent angle, taking care not to bend the needle, and rotated several times cleases. Sample storage prior to RNA isolation should be minimized.84
to free the specimen from attachments in the marrow cavity. The needle Collection tubes have been designed for stabilization of RNA, but for
is slowly withdrawn, with the same twisting motion used during inser- maximal RNA recovery, samples should be transported to the labora-
tion. The core of marrow inside the needle is removed by inserting the tory immediately, where cell suspensions (typically buffy coat or mono-
probe through the cutting tip and extruding the specimen through the nuclear cell preparations) can be prepared and nucleic acids extracted
hub of the needle. The technique reliably produces good quality biopsy under conditions that inhibit ribonucleases. DNA and mRNA can be
specimens. Marrow biopsy may be performed before marrow aspira- extracted and analyzed from paraffin-embedded tissue sections85 and
tion is attempted (or in a slightly different site on the iliac crest) to avoid dried stained marrow aspirate films,86 with variable degree of degrada-
hemorrhage and distorted marrow architecture in the biopsy core. An tion dependent on the length of sequence required.
FDA-approved battery-powered drill that inserts a biopsy needle into the
posterior iliac bone of adult patients provides more consistent and longer HISTOLOGIC SECTIONS
biopsy cores and shortens procedure time.80 Typically, the core marrow biopsy specimen is processed for histo-
logic examination by fixation in neutral buffered formalin, followed
PREPARATION OF MARROW by decalcification and embedding in paraffin. Decalcification can be
accomplished with acid reagents or EDTA. EDTA is preferred because
SPECIMENS FOR STUDY it provides better preservation of nucleic acid and protein antigens. Sec-
tions of high-quality that are cut at 3 μm and stained with hematoxylin
ASPIRATE FILMS AND TOUCH PREPARATIONS and eosin are satisfactory for routine work.
Several types of preparations can be made from the marrow aspirate to Clotted marrow aspirate may also be placed in neutral buffered
maximize use of the diagnostic material. Most important is the direct formalin, processed, cut, and stained in the same fashion as the marrow
marrow aspirate film, which is made immediately from a drop of mar- biopsy. An advantage of the clot sections is the absence of decalcifica-
row suspension from the unmanipulated aspirate. This preparation is tion artifact.

of marrow space occupied by hematopoietic cells as opposed to fatty

MORPHOLOGIC INTERPRETATION OF and nonhematopoietic tissue of iliac crest marrow decreases from a
MARROW PREPARATIONS mean of 80% in early childhood to 50% by age 30 years, with further
decreases after age 70 years.71 Consequently, marrow cellularity should
Final interpretation of the marrow biopsy and aspirate should be inte-
be evaluated with reference to normal individuals of the same age as the
grated with results from the clinical history, blood film, cell counts,
patient.92 When evaluating cellularity, consider that the marrow spaces
laboratory data, cell marker studies, and molecular or cytogenetic data.
directly adjacent to cortical bone frequently are fatty and are not repre-
Few other histologic specimens exist in which a state-of-the-art inter-
sentative of the cellularity of the deeper marrow spaces. A grid can be
pretation is dependent on such an array of supportive data.
used to estimate marrow cellularity of a biopsy.93
Cellularity and distribution of individual lineages are best assessed
ADEQUACY OF THE MARROW SAMPLE by examination of the biopsy specimen. Erythroid cells typically are
arranged in clusters, whereas megakaryocytes are scattered throughout
The first question in interpreting the marrow is whether the sample is
the biopsy. Erythroid and megakaryocytic cellularity are best appreciated
adequate for diagnosis (Fig. 2–7). At the time of the procedure, the pres-
at low power. In the aspirate, a myeloid-to-erythroid (M:E) cell ratio fre-
ence of marrow particles in the aspirate is the best indicator that the
quently is calculated to give some impression of the relative cellularity of
needle entered the medullary cavity and marrow was successfully with-
these two major lineages. As a rule of thumb, the M:E cell ratio should
drawn. Marrow particles are bony with a glistening appearance caused
be between 2:1 and 4:1 (Table 2–3 lists the reference ranges in men and
by fat in the particles. Specimens containing cortical bone, muscle, or
women). The relative proportions of cell types should be assessed only
other tissue with little or no medullary bone are inadequate for mar-
on the direct marrow film, biopsy imprint, or particle preparation, not
row interpretation. Samples with extensive crush artifact or hemorrhage
a concentrate film, which has been manipulated by centrifugation. A
are suboptimal, underscoring the importance of proper technique in
decreased M:E cell ratio can be interpreted as either myeloid hypocellu-
obtaining a useful sample. An unspoken assumption is that the piece of
larity or erythroid hyperplasia, depending on the overall marrow cellu-
marrow provided for diagnostic evaluation is representative of the mar-
larity. Megakaryocyte numbers can be assessed from the direct marrow
row as a whole. Based on reproducibility of bilateral biopsies, this more
aspirate film, where at least 5 megakaryocytes should be present in the
likely is true in leukemia than in lymphoma and metastatic tumor.87 A
optimal portion of the film. In the particle preparation, most large par-
biopsy specimen should contain at least a 0.5-cm length of marrow cavity.
ticles should contain 1 or more megakaryocytes. Megakaryocyte num-
However, for detection of lymphoma or metastatic tumor, current rec-
ber varies markedly in direct marrow aspirate films of normal subjects
ommendations suggest a biopsy length of 1.6–2.0 cm.88 A significant
and depends on the degree of admixture of the specimen with blood.
proportion of biopsies obtained in routine practice may fall short of this
Megakaryocytes are enriched at the feathered edge of concentrate films.
recommended length.89
In terms of aspirate examination, it is important to remember that
some cell types, notably fibroblasts and metastatic tumor cells, are not INFILTRATIVE DISEASES OF THE MARROW
as readily removed from the marrow space by aspiration as are normal Infiltrative diseases of the marrow include neoplasms, which can be
precursors. Marrow aspirations resulting in a dry tap usually are a con- hematopoietic or nonhematopoietic in nature (Chap. 46), fibrosis
sequence of significant pathology (only 7% show normal histology on caused by either primary hematopoietic disorders (eg, myelofibrosis)
biopsy90) and indicate the need to examine a biopsy specimen, which or infiltrative diseases (eg, metastatic tumors, storage disorders such as
should include a touch imprint.81 Gaucher and Niemann-Pick diseases [Chap. 72], and amyloidosis).
MARROW CELLULARITY INFECTIONS

The “gold standard” for overall marrow cellularity is examination of an Infectious organisms with an intracellular location, such as Leishmania,
adequate marrow biopsy specimen.91 The normal cellularity percentage Histoplasma, and Toxoplasma,94 can be visualized in monocytic cells by
A B
Figure 2–7. Marrow aspirate smear and core biopsy. A. Aspirate smear showing heterogeneous hematopoietic cells adjacent to a marrow particle
(arrow) B. Marrow core biopsy after decalcification and hematoxylin and eosin staining.

TABLE 2–3. Normal Values for Marrow Differential Cell Count at Different Ages (Percent of Cells)
Rosse et al101: Infants Tibial Marrow Glaser et al124: Subjects Bain104: Subjects Ages
Ages 1–20 Years, 21–56 Years, Iliac Marrow,
Subjects Ages <1 Subjects Age 1 Subjects Age 18 Sternal Marrow, 1 mL 0.1–0.2 mL Aspirated, Men
Type of Cell month (n> = 57) month (n = 7) months (n = 19) Aspirated (n = 30), Women (n = 20)
Myeloblast − − − 1.2 (0–3) 1.4 (0–3.0)
Promyelocyte 0.79 ± 0.91 0.76 ± 0.65 0.64 ± 0.59 1.8 (0–4) 7.8 (3.2–12.4)
Myelocyte 3.95 ± 2.93 2.50 ± 1.48 2.49 ± 1.39 16.5 (8–25)
Neutrophilic 7.6 (3.7–10.0)
Eosinophilic 1.3 (0–2.8)
Basophilic
Metamyelocyte 19.37 ± 4.84 11.34 ± 3.59 12.42 ± 4.15 23 (14–34) 4.1 (2.3–5.9)
Band form 28.89 ± 7.56 14.10 ± 4.63 14.20 ± 5.63 − **
Segmented
Neutrophil 7.37 ± 4.64 3.64 ± 2.97 6.31 ± 3.91 12.9 (4.5–29) Men: 32.1 (21.9–42.3);
women: 37.4 (28.8–4.9)
Eosinophil 2.70 ± 1.27 2.61 ± 1.40 2.70 ± 2.16 − 2.2 (0.3–4.2)
Basophil 0.12 ± 0.20 0.07 ± 0.16 0.10 ± 0.12 − 0.1 (0–0.4)
Lymphocyte 14.42 ± 5.54 47.05 ± 9.24 43.55 ± 8.56 16 (5–36) 13.1 (6.0–20.0)
Monocyte 0.88 ± 0.85 1.01 ± 0.89 2.12 ± 1.59 − 1.3 (0–2.6)
Plasma cell 0.00 ± 0.02 0.02 ± 0.06 0.06 ± 0.08 − 0.6 (0–1.2)
Proerythroblast 0.02 ± 0.06 0.10 ± 0.14 0.08 ± 0.13 0.5 (0–1.5)
Erythroblast Men: 28.1 (16.2–40.1)§;
women: 22.5 (13.0–32.0)§
Basophilic 0.24 ± 0.25 0.34 ± 0.33 0.50 ± 0.34 1.7 (0–5)
Polychromatophilic 13.06 ± 6.78 6.90 ± 4.45 6.97 ± 3.56 18 (5–34)
Orthochromatic 0.09 ± 0.73 0.54 ± 1.88 0.44 ± 0.49 2.7 (0–8)
Megakaryocyte 0.06 ± 0.15 0.05 ± 0.09 0.07 ± 0.12 − 31 (6–77)†
Macrophage 0.4 (0–1.3)
Others ¶
Transitional cells* 1.18 ± 1.13 1.95 ± 0.94 1.99 ± 1.00 −

Broken cell 5.79 ± 2.78 5.50 ± 2.46 5.05 ± 2.15 −
M:E ratio 4.4 4.4 4.8 2.9 (1–5) Men: 2.1 (1.1–4.1); women:
2.8 (1.6–5.2)
*
Immature lymphoid cells.
**
Bands included in segmented neutrophil count.
§
All erythroblast forms (basophilic, polychromatophilic, orthochromatic) grouped together.
†
Number of megakaryocytes near the advancing edge of the film (mean, range).
¶
Osteoclasts noted in 8 of 50 subjects, osteoblasts in 5 of 50 subjects, no mast cells observed.
morphologic examination of the marrow (Fig. 2–8). Identification of NECROSIS AND GELATINOUS
mycobacterial organisms in the marrow by acid-fast staining lacks sen-
sitivity but allows early diagnosis in one-third of cases with HIV-related
TRANSFORMATION
Mycobacterium avium complex infection.95 Microscopic examination Marrow necrosis may occur in a variety of disorders, particularly sickle
and culture of the marrow are the most sensitive diagnostic tests for cell disease (Chap. 50), and neoplastic processes involving the marrow
disseminated leishmaniasis.96 Mycobacteria also can be cultured from (Chap. 46). Marrow sections stained with hematoxylin and eosin show
marrow. Marrow morphology also is a sensitive diagnostic tool for loss of normal marrow architecture, indistinct cellular margins, and a
detecting disseminated histoplasmosis.97 The presence of marrow gran- background of amorphous eosinophilic material. Patients with severe
ulomas, recognizable only on biopsy specimens, necessitates examina- weight loss may develop gelatinous transformation of the marrow, char-
tion by special stains for fungal and mycobacterial organisms, but the acterized by amorphous extracellular material (proteoglycans), fat atro-
differential diagnosis is extensive.98,99 phy, and marrow hypoplasia.100

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A BUBBLE REPUTATION
One crowded hour of glorious life
Is worth an age without a name.
I had never suspected Sweeting of a desire to be “somebody.”

Indeed, the jeunesse dorée, in whose ranks Nature had seemed
unquestioningly to bestow him, is not subject to diffidence, or prone
to the wisdom which justifies itself in a knowledge of its own
limitations. I was familiar with his placid, cherubic face at a minor
club or two, in the Park, in Strand restaurants and Gaiety stalls; and
it had never once occurred to me to classify him as apart from his
fellows of the exquisite guild. If, like Keats, he could appreciate the
hell of conscious failure, its most poignant anguish, I could have
sworn, would borrow from some too-late realization of the correctest
“form” in a hat-brim or shirt-collar. I could have sworn it, I say, and I
should have been, of course, mistaken. Keats may have claimed it
as his poetical prerogative to go ill-dressed, and to object, though
John, to be dubbed “Johnny.” It remained to Sweeting to prove that a
man might be a very typical “Johnny” and a poet to boot. But I will
explain.
One day I entered the reading-room of the Junior Winston and
nodded to Sweeting, who was seated solitary at the newspaper-
table. While I was hunting for the “Saturday Review”—which was
conducting, I had been told, the vivisection of a friend of mine—my
attention was attracted by something actually ostentatious in
Sweeting’s perusal of his sheet, and I glanced across. Judge my
astonishment when I saw in his hands, not “Baily’s” or the “Pink ’Un,”
but the very periodical I sought. I gasped; then grinned.
“Hullo!” I said. “Since when have you taken to that?”
He attempted to reply with a face of wondering hauteur, but gave
up at the first twitch.
“O,” he said rather defiantly, “you lit’ary professionals think no
one’s in it but yourselves.”
“In what?”
“Why, this sort of thing,” he said, tapping the “Saturday”; “the real
stuff, you know.”
“Indeed,” I said, “we don’t. You’re always welcome to the reversion
of my place in it for one.”
“O, me!” he said airily. “It don’t positively apply there, you see,
being a sort of a kind of a professional myself.”
“My Sweet!” I exclaimed. “A professional—you?”
“O, yes,” he said. “Didn’t you know? Write for the ‘Argonaut.’ Little
thing of mine in it last number.”
I felt faint.
“May I see it?” I murmured. “If I don’t mistake, it’s under your
elbow at this moment.”
“Is it?” he answered, blushing flagrantly, “Lor’ bless me, so it is!”
I took it from his hand, opened it, and read, over his undoubted
signature—Marmaduke Sweeting—the title, “The Fool of the Family.”
“Ah!” I thought, “of course. Like title like author.”
But I was wrong. The tale, a veritable conte drolatique, was as
keen and strong as a Maupassant. I had no choice but to take it at a
draught, smacking my lips after. Then I put the paper softly down
and looked across at him. His harmless features were set in a sort of
hypnotic smile, his hat was tilted over his eyes, and he was making
constant mouthfuls of the large silver knob of his stick. My eyes
travelled to and fro between this figure and the figures of print that
were he. What possible connexion could there be between the two? I
thought of Buffon writing in lace ruffles, and all at once recognized a
virtue in immaculate shirt-cuffs, and decided to consult some
fashionable hosier about raising my price per thousand words. In the
meantime my respect for Sweeting was born.
“So,” I said, “you are somebody after all?”
“Am I?” he answered, grinning bucolic. “Glad you’ve found it out.”
“Why,” I said, “honestly there’s genius in this story; but nothing to
what you’ve shown in concealing that you had any. There must be
much more to come out of the same bin.”
He flushed and laughed and wriggled, as I walked over and sat
beside him.
“O, I dare say!” he said. “Hope so, anyhow.”
“Not a doubt. What made you think of it, now?”
“O! I thought of it,” he said; and, after all, there was no better reply
to an idiotic question. I was beginning humbly to appraise intellectual
self-sufficiency at its value, and to appreciate the hundred disguises
of reason.
I saw a good deal of Sweeting, on his own initiative, after this. He
would visit me in my rooms, and discuss—none too sapiently, I may
have thought in other circumstances, and with the most ingenuous
admiration for his own abilities—the values of certain characters as
portrayed by him in a brilliant series, “The Love-Letters of a
Nonconformist,” which had immediately followed in the “Argonaut”
“The Fool of the Family,” and was taking the town by storm. Thus,
“What d’ee think of that old Lupin, last number,” he would chuckle,
“with his calling virtue an ‘emu,’ don’tcherknow?”
“Ha, yes!” I would correct him, with a nervous laugh. “ ‘Anæmia’
was the word. You meant it, of course.”
“Why, didn’t I say it?” he would answer. “It’s got a big swallow
anyhow”; and then he would check himself suddenly, and, without
further explanation, eye me, and begin to whistle.
Now I might recall the passage to which he referred (to wit, that
every red blood corpuscle, being a seed peccancy, so to speak,
made virtue an anæmia) and try to puzzle out a quite new
significance in it. Suspecting that its author’s apparent naïveté was
only assumed, I was respectfully guarded in my answers, and, when
he was gone, would curiously ponder the perspicacious uses to
which he would put them. He did not consult me, I felt, as an oracle;
but rather drew upon me for the vulgar currency of thought, to which
his exclusiveness was a stranger. He was very secret about his own
affairs; though I understood that he was becoming quite an important
“name” in the literary world. Ostensibly he was not, after that first
essay, to be identified with the “Argonaut,” though any one, having
an ounce of the proper appreciation, could scarcely fail to mark in
the “Love-Letters” the right succession of qualities which had made
the earlier story notable. Indeed, he suffered more than any man I
knew from the penalties attaching to the popular author. The number
of communications, both signed and anonymous, which he received
from admirers was astonishing. Scarce a day passed but he brought
me specimens of them to discuss and laugh over. I did not, I must
admit, think his comments always in good taste; but then I was not
personally subject to the flattering pursuit, and so may have been no
more constituted to judge than a monk is of a worldling.
These testimonies to his fame were from every sort of individual—
the soldier, the divine, the poet, the painter, the actor (and more
especially the actress), the young person with views, the social
butterfly, the gushling late of the schoolroom, the woman of
sensibility late of the latest lifelong passion for art or religion, and
finding, as usual, the taste of life sour on her lips after a recent
debauch of sentiment. They all found something in the “Love-Letters”
to meet their particular cases—some note of subtle sympathy, some
first intimation to their misunderstood spirits of a kindred emotion
which had felt, and could lay its finger with divine solace on the spot.
No longer would they suffer a barren grievance—that hair-shirt which
not a soul suspected but to giggle over. To take, for example, from
the series a typical sentence which served so many for a text—
“To whom does the materialist cry his defiance—to whom but to
God? He cannot rest from baiting a Deity whose existence he
denies. He forgets that irony can wring no response from a vacuum.”
A propos of which wrote the following:—
A Half-pay General.—Don’t tell me, Sir, but you’ve

served, like me, a confounded ungrateful country, and learned
your lesson! Memorialize the devil rather than the War Office.
You’ve hit it off in your last sentence to a T.
A Chorus Girl.—Dear Sir,—You mean me to understand,

I know, and you’re quite right. The British public has no more
ears than a ass, or they’d reconise who ought to be playing
Lotta in “The Belle of Battersea.” It’s such a comfort you can’t
tell. Please forgive this presumptious letter from a stranger.—
Yours very affectionately,
Dolly.
An Apostolic Fisherman.—I like your metaphor. I would

suggest only “ground-baiting a Deity” as more subtly
applicable to the tactics of a worldling. Note: “And Simon
Peter said, ‘I go a-fishing.’ ”
Take, again, this excerpt: “Doctors’ advice to certain patients to

occupy their minds recalls the Irishman’s receipt for making a
cannon, ‘Take a hole and pour brass round it.’ ” Of which a “True
Hibernian” wrote—
Sir,—I’ve always maintained that the genuine “bull,”

fathered on my suffering country, came from the loins of the
English lion. Murder, now! How could a patient occupy his
doctor’s mind as well as his own, unless he was beside
himself? And then he’d have no mind at all.
Or take, once more and to end, the sentence: “The Past is that
paradoxical possession, a Shadow which we would not drop for the
Substance”; which evoked the following from “One who has felt the
Weariness, the Fever, and the Fret”—
How strangely and exquisitely phrased! It brings, I know not

how, the memory of the Channel before me. I have only
crossed it once; but, O! the recollection! the solemn moving
waters to which my soul went out!
These are specimens, but a few, of the responses wrung by

Sweeting from the human chords he touched. There were, in
addition, prayers innumerable for autographs, requests for the
reading of manuscripts, petitions for gratis copies of his works, to be
sold for any and every charity but the betterment of impecunious
authors. He fairly basked in the sunshine of a great reputation. There
was only one flaw in his enormous self-satisfaction. By a singular
perversity and most inexplicable coincidence, every one of these
signed documents was without an address. But, after all,
coincidence, which is only another name for the favouritism of Fate,
must occasionally glut itself on an approved subject. Sweeting was
in favour with the gods, and enjoyed “a high old time of it,”
principally, perhaps, because he did not appear to be ambitious of
impressing any “set” but that with which he was wont to forgather,
and above which he made no affectation now of rising superior.
I had an example one evening of this intellectual modesty, when
casually visiting the Earl’s Court grounds. There I encountered my
friend, the centre and protagonist of a select company in the
enclosure. All exquisitely wore exquisite evening dress (for myself I
always scornfully eschewed the livery), and all gravitated about
Sweeting with the unconscious homage which imbecility pays to
brains—“the desire of the moth for the star.” I could see at once that
he was become their Sirius, their bright particular glory, reflecting
credit upon their order. And he, who might have commanded the
suffrages of the erudite, seemed content with his little conquest—to
have reached, indeed, the apogee of his ambition—a one-eyed king
among the blind. These suffered my introduction with some
condescension, as a mere larva of Grub Street. They knew
themselves now as the stock from which was generated this real
genius. As for me, I was Gil Blas’s playwright at the supper of
comedians. And then, at somebody’s initiative, we were all
swaggering off together along the walks.
Now, I had always had a sort of envy of the esprit de ton which
unites the guild of amiable gadflies; and, finding myself here, for all
my self-conscious intellectual superiority, of the smallest account, I
grew quickly sardonic. If I knew who wrote the “Heptameron,” I didn’t
know, even by sight, the Toddy Tomes who was setting all the town
roaring and droning with his song, “Papa’s Perpendicular Pants.” It is
a peevish experience to be “out of it,” even if the it is no more
intelligible than a Toddy Tomes’s topical; and gradually I waxed quite
savage. Reputation is only relative after all. There is no popular road
to fame. As an abstract acquisition, it may be said to pertain at its
highest to the man who combines quick perceptions with adaptive
sympathies. I was not that man. In all, save exclusively my own
company, I felt “out of it,” awkward because resentful, and resentful
because awkward. I despised these asses, however franked by
Sweeting, yet coveted, vainly, the temporary grace of seeming at
home with them. I got very cross. And then we alighted on Slater.
I knew it for his name by Sweeting’s greeting him in response to
his hail. He was seated at a little table all by himself, drinking
champagne, and alternately turning up and biting the ends of a red
tag of beard, and luridly pulling at a ponderous cigar. He was a
small, dingy person, so obviously inebriated, that the little human
clearing in which he sat solitary was nothing more than the formal
recognition of his state. He also, it was evident, to my disgust,
despised the conventions of dress, but without any of those qualms
of self-consciousness with which I was troubled. He lolled back, his
hat crushed over his eyes, a hump of dicky and knotted tie escaping
from his waistcoat-front, his disengaged thumb hooked into an arm-
hole—as filthy a little vagabond, confident and maudlin and truculent
in one, as you could wish. And he hailed Sweeting as a familiar.
My friend stopped, with a rather sheepish grin.
“Hullo, Slater!” said he. “A wet night, ain’t it?”
Our little group came chuckling all about the baboon. Even then, I
noticed, I was the one looked upon with most obvious disfavour by
the surrounding company.
“Look here,” said Sweeting, suddenly gripping me to the front.
“Here’s one of your cloth, Slate’. Let me introjuce you,” and he
whispered in my ear, “Awfully clever chap. You’ll like him when you
know.”
I suppose my instant and instinctive repulsion was patent even to
the sot. He lurched to his feet, and swept off his crumpled hat with
an extravagant bow. Sweeting’s pack went into a howl of laughter. It
was evident they were not unacquainted with the creature, and
looked to him for some fun.
“My cloth, sir?” vociferated the beast. “Honoured, sir, ’m sure, sir.
Will you allow me to cut my coat according to it, sir? Has any
gentleman a pair of scissors? Just the tails, sir, no more—quite large
enough for me; and you’d look very elegant in an Eton jacket.”
I tried to laugh at this idiotic badinage, and couldn’t.
“O, crikey, wouldn’t he!” said a vulgar onlooker. “Like a sugar-
barrel in a weskit.”
Then, as everybody roared, I lost my temper.
“Don’t be a fool,” whispered Sweeting. “It’s the way he’ll get his
change out of you.”
“Change!” I snapped furious. “No change could be for the worse
with him, I should think. Let me pass, please!”
The odious wretch was pursuing me all the time I spoke, while the
others hemmed me in, edging me towards him and roaring with
laughter. Sweeting himself made no effort to assist me, but stood to
one side, irresistibly giggling, though with a certain anxiety in his
note.
“Call off your puppies!” I cried ragingly, and with the word was sent
flying into the very arms of Slater. I felt something rip, and at a blow
my hat sink over my eyes; and then a chill friendly voice entered into
the mêlée.
“O, look here, Slater, that’ll do, you know!”
I wrenched my eyes free. My champion was not Sweeting, but
Voules, Sir Francis Voules, of whom more hereafter. He was cool
and vicious, and as faultlessly dressed as the others, but in a
manner somehow superior to the foppery of their extreme youth. He
carried a light overcoat on his arm.
“O! will it?” said Slater.
“Yes, I said so,” said Voules, pausing a moment from addressing
me to scan him. Slater slouched back to his table. Nobody laughed
again.
In the meantime, Sir Francis was helping me to restore my hat to
shape, and to don his overcoat.
“Yours is split to the neck,” he said. “Now, let’s go.”
He took my arm, and we strolled off together. The crowd, quite
respectful, parted, and we were engulfed in it.
I was grateful to Voules, of course, but inexplicably resentful of his
cool masterfulness. Truth to tell, we were souls quite antipathetic;
and now he had put me right—with everybody but myself. In a
helpless attempt to restore that balance, I snarled fiercely, smacking
fist into palm—
“I’ll have the law of that beast! You know him, it seems? I can’t
congratulate you on your friends.”
“Sweeting was most to blame,” said Voules quietly.
I grunted, and strode on fuming.
“But, after all,” said Voules, “the poor ass had to back up his
confederate.”
I glanced at him as we walked.
“His confederate?”
“Of course. Didn’t you know? Slater really writes the things for
which Sweeting gets the credit.”
“O, come, Voules! Here’s one of your foolhardy calumnies. You
really should be careful. Some day you’ll get into trouble.”
“O, very well!”
“You talk as if it were an open secret.”
“You know Sweeting as well as I. Do you recognize his style in the
Nonconformist lucubrations? Possibly you’ve had letters from him?”
“I’ve some specimens of letters to him now—letters from admirers.
If anything were needed to refute your absurd statement, there they
are in evidence.”
He gave a little dry laugh; then touched my sleeve eagerly.
“You wouldn’t think it abusing a confidence to show me those
letters?”
“I don’t know why. Sweeting’s laid no embargo on me.”
“Very well. If you’ll let me, I’ll come home with you now.”
I stumbled on in a sort of haze.
I did not believe this to be any more than a mad shot in the dark.
Sir Francis was one of those men who made mischief as Pygmalion
made Galatea. He fell in love with his own conceptions—would go
any lengths to gratify his passion for detraction. Do not suppose,
from his prefix, that he was a bold, bad baronet. He was just an actor
of the new creation—belonged to what was known by doyens of the
old Crummles school as the be-knighted profession. The stage was
an important incident in his social life, and he seldom missed a
rehearsal of any piece to which he was engaged.
“You know this Slater?” I said, as I drove in my latchkey. “As
what?”
“As a clever, disreputable, and perfectly unscrupulous journalist.”
“It's preposterous! What could induce him to part with such a
notoriety?”
“The highest bidder, of course.”
“What! Sweeting? If he’s still the simple Johnny you’d have him
be?”
“I’m yet to learn that the simple Johnny lacks vanity.”
“But, for him, such an unheard-of way to gratify it!”
“Opportunism, sir. There are more things in the Johnny’s
philosophy than we dream of.”
“Well, I simply don’t believe it.”
Voules read, with an immobile face, the letters which Sweeting
had left with me. At the end he looked up.
“Are you open to a bet?”
“Can’t afford it.”
“Never mind, then.” He rose. “Truth for its own sake will do.
Anyhow, I presume you don’t object to countering on Slater?”
“O, do what you like!”
“Thanks. Would you wish to be in at the death?”
“Just as you please.”
“You see,” said he, with a pleasant affectation of righteousness, “if
my surmise is correct—and you’re the first one I’ve ventured to
confide in—it’s my plain duty to prick a very preposterous bubble.
Thank you for lending yourself to the cause of decency. Don’t say
anything until you hear from me. Good-bye!”—and he was gone,
followed by my inclination, only my inclination, to hurl a book after
him.
I sat tight—always the more as I swelled over the delay—till, on
the third day following, Sweeting called on me. He came in very
shamefaced, but with a sort of suppressed triumph to support his
abjectness.
“I couldn’t help it, you know,” he said; “and I gave him a bit of my
mind after you’d gone.”
“Indeed,” I answered good-humouredly; “that was what you
couldn’t well afford, and it was generous of you.”
He was blankly impervious to the sarcasm. Had it been otherwise,
my new-fledged doubts had perhaps fluttered to the ground. After a
moment I saw him pull a paper from his pocket.
“Look here,” he said, vainly trying to suppress some emotion,
which was compound, in suggestion, of elation and terror. “You’ve
made your little joke, haven’t you, over all those other people
forgettin’ to put their addresses? Well, what do you think of that for
the Prime Minister?”
I took from his hand a sheet of large official-looking paper, and
read—
Dear Sir,—You may have heard of my book, “The
Foundations of Assent.” If so, you will perhaps be interested
to learn that I am contemplating a complete revision of its text
in the light of your “Love-Letters.” They are plainly
illuminating. From being a man of no assured opinions, I have
become converted, through their medium, to a firm belief in
the importance of the Nonconformist suffrage. Permit me the
honour, waiving the Premier, to shake by the hand as fellow-
scribe the author of that incomparable series. I shall do myself
the pleasure to call upon you at your rooms at nine o’clock
this evening, when I have a little communication to make
which I hope will not be unpleasing to you. Permit me to
subscribe myself, with the profoundest admiration, your
obedient servant,
J. A. Burleigh.
“Well,” I murmured, feeling suffocated, “there’s no address here

either.”
“No,” he answered; “but, I say, it’s rather crushing. Won’t you come
and help me out with it?”
“What do you want me for?” I protested. “I’ve no wish to be
annihilated in the impact between two great minds. You aren’t
afraid?”
“O, no!” he said, perspiring. “It’ll be just a shake, and ‘So glad,’ and
‘Thanks, awfully,’ I suppose, and nothing more to speak of. But you
might just as well come, on the chance of helping me out of a tight
place. It’s viva voce, don’tcherknow—not like writin’, with all your wits
about you. And I shall get some other fellows there, too, so’s we
aren’t allowed to grow too intimate; and you might as well.”
“I wonder what the ‘communication’ is?” I mused.
“O, nothin’ much, I don’t suppose,” said Sweeting, with a blushing
nonchalance. But it was evident that he had pondered the delirious
enigma and emerged from it Sir Marmaduke.
“Well,” I concluded rather sourly, “I’ll come.”
He went away much relieved, and I fell into a fit of stupor. In the
afternoon a telegram from Voules reached me, “Be at Sweeting’s
8.45 to-night.”
At a quarter to nine I kept my appointment. Sweeting was
insufferably well-to-do, and his rooms were luxurious. They were
inhabited at the moment by an irreproachable and almost silent
company. Among them I encountered many of the young gentlemen
who had been witnesses of, and abettors in, my discomfiture the
other night. But they were all too nervous now to presume upon the
recognition—too oppressed with the stupendous nature of the
honour about to be conferred upon their host—too self-weighted with
their responsibility as his kindred and associates. They could only
ogle him with large eyes over immensely stiff collars, as he moved
about from one to another, panic-struck but radiant. It was the
crowning moment of his life; yet its sweeter aftermath, I could feel,
reposed for him in the sleek necks of champagne-bottles just visible
on a supper-table in the next room. He longed to pass from the test
to the toast, and the intoxicating memory of a triumph happily
accomplished. And then suddenly Slater came in.
He was not expected, I saw in a moment. Indeed, how could such
a death’s-head claim place at such a feast? He was no whit
improved upon my single memory of him, unless, to give the little
beast his due, a shade less inebriated. But he was as grinning,
cocksure, and truculent a little Bohemian as ever. Sweeting stared at
him aghast.
“Good Lord, Slate’,” said he, “what brings you here, now?”
“Why, your wire, old chap,” said the animal.
“I never sent one, I swear.”
“Oho!” cries Slater, glaring. “D’ you want to go back on your word?
Ain’t I fine enough for this fine company?” and he pulled a dirty scrap
of paper out of his pocket, and screeched, “Read what you said
yourself, then!”
The telegram went round from hand to hand. I read, when it came
to my turn: “Come supper my rooms 8.45 to-night. M. Sweeting.”
“I never sent it,” protested our host. “It must be a hoax. Look here,
Slate’. The truth is, the Prime Minister wrote he wanted to make my
acquaintance, because—because of the ‘Letters,’ you know; and—
and he’s due here in a few minutes.”
The creature grinned like a jackal.
“My eyes, what fun!” he said. “I shall love to see you two meet.”
“There’s—there’s fizz in the next room, Slate’,” said the miserable
Sweeting.
“You needn’t tell me,” said Slater. “I’d spotted it already.”
And then, before another word could be said, the door was
opened, and the guest of the evening announced.
He came in smiling, ingratiatory, the familiar willowy figure in
pince-nez. We all rose, and the stricken Sweeting advanced to meet
him. The great man, looking, it is true, a little surprised over his
reception, held out his hand cordially.
“And is this——” he purred—and paused.
Sweeting did not answer: he was beyond it; but he nodded, and
opened his mouth, as if to beg that the “communication” might be
posted into it, and the matter settled off-hand.
“I did not, I confess,” said the Premier, glancing smilingly round,
“expect my little visit of duty—yes, of duty, sir—to provoke this signal
welcome on the part of a company in which I recognize, if I mistake
not, a very constellation of the intellectual aristocracy.”
Here a youth, with a solitaire in his eye, and a vague sense of
parliamentary fitness, ejaculated “Hear, hear!” and immediately
becoming aware of the enormity, quenched himself for ever.
“It makes,” went on the right hon. gentleman, “the strict limit to my
call, which less momentous but more exacting engagements have
obliged me to prescribe, appear the more ungracious. In view of this
enforced restriction, I have equipped myself with a single question
and a message. Your answer to the first will, I hope—nay, I am
convinced—justify the tenor of the second.”
He released, with a smile, the hand which all this time he had
retained, much to Sweeting’s embarrassment, in his own. Finding it
restored to him, Sweeting promptly put it in his pocket, like a tip.
“I ask,” said the Premier, “the author of ‘The Love-Letters of a
Nonconformist’ to listen to the following excerpt” (he produced a
marked number of the “Argonaut” from his pocket) “from his own
immortal series, as preliminary to some inquiry naturally evoked
thereby”—and he read out, with the intonation of a confident orator:
“ ‘We have (shall I not declare it, my sweet?) the most beautiful
women and the most beautiful poets in the world—two very good
things, but the latter unaccountable. Passion, in perpetuating,
idyllically refines upon the features of its desire; hence the
succession of assured physical loveliness in a race which, however
insensible to the appeals of emotional and intellectual beauty, can
understand and worship the beauty that is plain to see.’ ”
Here the reader paused, and looking over his glasses with a smile,
very slightly shook his head, and murmuring, “The beauty that is
plain to see! H’m! a fence that I will recommend to Rosebery,”
continued, “ ‘Passion endows passion, far-reaching, to bribe the gods
with a compound interest of beauty. It touches heaven in imagination
through its unborn generations. It tops the bunker of the world, and,
soaring, drops, heedless of Time the putter, straight into the
eighteenth hole of the empyrean.”
The Premier stopped again, and, looking gravely at Sweeting,
asked, “What is the eighteenth hole of the empyrean?”
Now I expected my friend to reveal himself, to sally brilliantly,
referring his questioner, perhaps, to some satire in the making, some
latter-day Apocalypse of which here was a sample extracted for bait
to the curious. Well, he did reveal himself, but not in the way I hoped.
He just strained and strained, and then dropped his jaw with the
most idiotic little hee-haw of a laugh I ever heard, and—that was all.
The other, looking immensely surprised, repeated his question:
“What, sir, I ask you, is the eighteenth hole of the empyrean?”
“Why, the one the Irishman poured brass round.”
I started. It was not Sweeting who spoke, but Slater. The little
demon stood grinning in the background, his tongue in his cheek,
and his hands in his trousers pockets.
“H’mph!” said the Prime Minister. “Very apt, sir. I recall the
witticism. It is singularly applicable at the moment to the
reorganization of the Liberal party. ‘Take a hole and pour brass round
it.’ Exactly.”
His manner, there was no denying it, was extremely severe as he
again addressed the perspiring Sweeting—
“Once more, sir,” he said, “I resume our discussion of a passage,
the intellectual rights in which you would seem to have made over to
your friends.” And, with a positive scowl, he continued his reading.
“ ‘So well’ (writes the impassioned Nonconformist) ‘for the national
appreciation of beauty that is physical. On the other hand (tell me,
dear. It would come so reassuringly from your lips), what can
account for the spasmodic recurrence in our midst of the inspired
singer? What makes his reproduction possible among a people
endowed with tunelessness, innocent of a metrical ear?’ ”
Quite abruptly the Prime Minister ended, and, deliberately folding
his paper, hypnotized with a searching stare his unhappy examinee.
“The question, Mr. Sweeting,” said he, “is before the House. You
will recognize it as ending—with some psychologic subtlety, to be
continued in our next—number 10—the last published of the
“Argonaut.” To me, I confess, the answer can be, like the Catholic
Church, only one and indivisible. Upon the question of your
conformity with my view depends the nature of the communication
which I am to have the pleasure, conditionally, of making to you.
Plainly, then, sir, what makes possible the spasmodic recurrence of
the inspired singer in the midst of a people endowed with
tunelessness and innocent of a metrical ear? I feel convinced you
can return no answer but one.”
A dead silence fell upon the room. Sweeting scratched his right
calf with his left foot, and giggled. Then in a moment, yielding the last
of his wits to the unendurable strain, he gave all up, and, wheeling
upon Slater—
“O, look here, Slate’!” he said. “What does?” and without waiting
for the answer, drove himself a passage through his satellites, and
collapsed half dead upon a sofa.
The Premier, with an amazing calm, returned the “Argonaut” to his
pocket.
“Surely, sir,” said he, “this is inexplicable; but” (he made a
denunciatory gesture with his hands) “it remains to me only to inform
you that, conditional on your right reply to your own postulate, it was
to have been my privilege to acquaint you of His Majesty’s intention
to bestow upon you a Civil List pension of £250 a year; which now, of
course——”
He was interrupted by Slater—
“O, that’s all one, sir! Fit the cap on the right head. The answer’s
‘Protection,’ isn’t it? I ought to know, as I wrote, and am writing, the
stuff.”
“You, sir!”
All eyes were turned upon the beastly little genius, as he stood
ruffling with greed and arrogance, and thence to the sofa.
“O, shut up!” said Sweeting feebly. “It was only a joke. I paid him,
handsome I did, to let me have the kudos and letters and things.
He’d the best of the bargain by a long chalk.”
“He-he!” screeched Slater. “Why, you fool, did you think merit
earned such recognition in this suffering world? Hope you enjoyed
reading ’em, Sweet, as I did writing ’em.” He turned, half-cringing,
half-defiant, upon the guest. “I’m the author of the ‘Love-Letters,’ sir
—honour bright, I am; and I wrote every one of the testimonials, too,
that that ass sets such store by. You’ll take those into consideration, I
hope.”
“I shall, sir,” thundered the other—“in my estimate of a fool and his
decoy.”
He blazed round and snatched up his hat.
“Make way, gentlemen!” he roared, and strode for the door.
A slip of pasteboard fluttered from his hand to the carpet; he flung
wide the portal, banged it to behind him, and was gone.
Some one, in a sort of spasmodic torpor, picked up the card, and
immediately uttered a gasping exclamation. We all crowded round
him, and, reading the superscription at which he was pointing, “Mr.
Hannibal Withers, Momus Theatre,” exchanged dumbfounded
glances.
“Why, of course,” stuttered a pallid youth; “it was Withers, Voules’s
pal; I reco’nize him now. He’s the Prime Minister’s double, you know,
and—and he’s been and goosed us.”
“What!” screamed Slater.
But I was off in a fit of hysterical laughter.
It was actually a fact. It is a mistake to suppose that your
professional scandal-monger is prepared to build except on a
substratum of truth. Voules had pricked the bubble as he had
promised. The bargain, it was admitted, had been struck—on
Slater’s side for such a consideration as would submerge him in
champagne had he desired it. He had written and sent the
manuscripts to Sweeting, who had had them typed, and passed
them on to the “Argonaut” as his own. But the real author knew that
his tenure was insecure so long as the other’s colossal vanity was
not ministered to. Hence the correspondence, in which the little
monster burlesqued his own lucubrations. It might all have ended in
a case of perpetual blackmail (Sweeting never could see beyond the
end of his own nose) had not the bait answered so instantly to
Voules’s calculations.
There was a bitter attack on the immorality of the stage in the next
number of the “Argonaut,” which subsequently had to compound with
Voules under threat of an action for libel. But Sweeting had his wish.
He was “somebody,” as never yet. Until he took his notoriety for a
long sea-voyage, he was more crushingly than any gentleman in the
“Dunciad” “damn’d to fame.”
A POINT OF LAW
BY A CAPTIOUS LITIGANT
Given a wet night on circuit, a bar parlour with a chattering fire, a

box of tobacco, a china bowl of punch, and a mixed forensic
company to discuss the lot, and what odds would you lay for or
against the chances of a good story or so?
Grope in your memory (before you answer) among legal
collectanea and the newspaper reports of famous, or infamous,
trials. What then? “Lord!” you admit, “these bones unearthed seem
wretched remains indeed! I find your grooms of the horsehair, young
and old, cracking their ineffable chestnuts for the benefit of an
obsequious tipstavery; I find a bench so conservative that, though it
be pitched in the very markets of chicanery, it is never to be won
from its affected ignorance of those topical affairs which are matters,
else apart, of common knowledge; I find the profession for ever
given to whet its wits on a thousand examples of resourcefulness
and impudence, and most often failing in the retort piquant.” Give me
a cheeky witness to cap the best drollery ever uttered by counsel.
Legal facetiæ, forsooth! The wit that tells is the wit that can cheat the
gallows, not send to it. Any dullard can hang a dog.
Look at the autobiographies of your retired legal luminaries: what
scurvy bald reading they make as a rule. Look at—but no: he rests in
Abraham’s bosom; he is studying the Mosaic law; we may be in
need of him again some day.
There is an odd family likeness between the personalia of lawyers
and of actors. The fellows, out of court, stripped of their
melodramatic trappings, can’t raise a laugh which would tickle any
one less than a bishop. They are obsessed with the idea of their own
importance. Much self-inflation has killed in them all sense of
proportion. They prove themselves, the truth is, dull dogs on
revision.
The law is not so exhausting a study as it appears on first sight to
a layman. Given an understanding of its main principle, which is
syllogism, and there you are already in its Holy of Holies. As, for
instance, I call a man a beast: a cheetah is a beast: I have called the
man a cheater—ergo, he can proceed against me for defamation.
There is its rubric in a nutshell—perfectly simple.
However, exceptis excipiendis, there were Curran, and Erskine,
and some others. There was also Brindley, the great Crown
Prosecutor, whose eloquence was of such persuasiveness that it
was said the very Bench hung upon his word. I had the chance to
meet him once, in such a place and on such a night as I began by
describing. It was in the “Maid’s Head” at Norwich, and my
experience is at your service.
It had, I knew, been a full list and a varied; yet the great man, it
seemed, had found nothing in it all to stimulate his humorous
faculties. The liveliness was all supplied by a pert Deputy Clerk of
the Peace, whose bump of reverence was as insignificant as his
effrontery was tremendous. The Bar began by tolerating him; went
on to humour his sallies; chilled presently over his presumption; grew
patronizing, impatient, and at last rude. He didn’t care; nor I,
certainly. His readiness was the only relief from a congested
boredom.
The talk drifted, in the course of the evening, upon legal posers—
circumstantial evidence, ex-statutory cases, and so forth. There were
some dull examples proffered, and I observed, incidentally, that the
Law, when it couldn’t hark back to precedent, was wont to grow a
little hazy and befogged. Many solemn conundrums were
propounded; but the Deputy Clerk, as usual, pushed himself to the
front with an impertinence—
“If I slink out of the company of a bore, am I guilty of stealing from
his person?”
“Pooh, pooh!” said Brindley, with contempt. “Don’t be flippant, sir.”
The Deputy Clerk was not a whit abashed.
“Sir, to you,” he said. “If that isn’t liked, I’ll propose another. If a
woman is divorced from her husband, and a child is born to her
before the decree is made absolute, is that child, lawfully begot,
legitimate or illegitimate?”
They were glad to take this seriously. I forget what the decision
was—that, given the necessary interval between the decree and its
confirmation, I think, the situation was virtually impossible.
“Very well,” said the Deputy Clerk. “But perhaps one can conceive
such a question rising. Let it pass, however; and answer me this,
gentlemen: If one is imprisoned unjustly—that is to say, for a crime
one has not committed—and, breaking out of prison, gives proof of
one’s innocence, can one be indicted for prison-breaking?”
This, at least, was a fair poser, and discussion on it grew actually
warm.
“Bosh!” said a fierce gentleman. “You ain’t going to justify your
defiance of the law by arguing that the law is liable to make an
occasional mistake—don’t tell me!”
Here a very young barrister dared the revolutionary sentiment that
the law, being responsible in the first instance to itself, might be
treated, if caught-stumbling in flagranti delicto, as drastically as any
burglar with a pistol in his hand. He was called, almost shouted,
down. The suggestion cut at the very root of jurisprudence. The law,
like the king who typified it, could do no wrong; witness its time-
honoured right to pardon the innocent victims of its own errors.
“It may detain and incarcerate one for being only a suspected
person,” said Brindley. “That its suspicions may prove unfounded, is
nothing. It must be cum privilegio, or the constitution goes. A nice
thing if the Crown could be put on its defence for an error in
judgment.”
“A very nice thing,” said the Deputy Clerk.
Brindley snorted at him. “Perhaps,” said he sarcastically, “the
gentleman will state a case.”
The gentleman desired nothing better. I would have backed him to
hold his own, anyhow; but, in this instance, I was gratified to gather
from his manner that he had a real story to tell. And he had.
“Gentlemen,” he said, “it occurred within my father's memory; but
my own is good enough to reproduce it literally. It made a rare stir in
the Norwich of his day, and quite fluttered, I assure you, the
dovecots of the profession.
“The parties chiefly concerned in it were three: old Nicholas
Browbody, his ward Ellen, and Mr. George Hussey, who was put on

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Xiangrong He, MD [138] Patrick Connor Johnson, MD [28]

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Angela M. Lager [11] Zhenyu Li, MD, PhD [111]

Richard A. Larson, MD [90] Jane L. Liesveld, MD [87, 88]

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Gerard Lozanski, MD [92] Guiomar Mendieta, MD, MSc [134]

Joel Moake, MD [52]

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Narla Mohandas, DSc [33] Marguerite Neerman-Arbez, PhD [124]

Eva Marie Y. Moresco, PhD [19] Luigi D. Notarangelo, MD [79]

Eric Mou, MD [96] Willem Ouwehand, MD, PhD, FMedSci [119]

Natarajan Muthusamy, DVM, PhD [73] Charles H. Packman, MD [55]

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Charles J. Parker, MD [41] Jaroslav F. Prchal, MD, FRCPC [83]

John D. Phillips, PhD [59] Sergio A. Quezada, PhD [22]

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Andrew R. Rezvani, MD [29] Christopher S. Seet, MD, PhD [74]

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Ali G. Turhan, MD, PhD [27] Robert Weinstein, MD [30]

Kamalakannan Vijayan, PhD [14] X. Long Zheng, MD, PhD [129]

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CHAPTER 1 THE HEMATOLOGY CONSULTATION

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TABLE 1–2. Performance Status Criteria in Adults and Children

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TABLE 1–3. Eastern Cooperative Oncology Group (ECOG) Ears

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Spleen Nervous System

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EXAMINATION OF BLOOD direct microscopic examination of a stained blood film by a trained

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nation in an automated hematology analyzer. The Sysmex

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