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Williams Hematology

Notice

Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

Williams Hematology

Tenth Edition

Kenneth Kaushansky, MD, MACP

Senior Vice President, Health Sciences

Dean, Renaissance School of Medicine

Stony Brook University

Stony Brook, New York

Josef T. Prchal, MD

Professor of Hematology and Malignant Hematology

Adjunct in Genetics and Pathology

University of Utah & Huntsman Cancer Institute

Salt Lake City, Utah

1. interní klinika VFN a Ústav patologické fyziologie

1. LF School of Medicine

Universita Karlova, Prague, Czech Republic

Linda J. Burns, MD

Consultant and Senior Scientific Director

Center for International Blood and Marrow Transplant Research Milwaukee, Wisconsin

Marshall A. Lichtman, MD, MACP

Professor Emeritus of Medicine and of Biochemistry and Biophysics

Dean Emeritus, School of Medicine and Dentistry

James P. Wilmot Cancer Institute

University of Rochester Medical Center Rochester, New York

Marcel Levi, MD, PhD, FRCP

Professor of Medicine

University College London Hospitals

London, United Kingdom Professor of Medicine

University of Amsterdam Amsterdam, The Netherlands

David C. Linch, FRCP, FRCPath, FMed Sci

Professor of Haematology Cancer Program Director

UCL/UCLH Biomedical Research Centre

University College London London, United Kingdom

Copyright © 2021 by McGraw Hill. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher.

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CONTRIBUTORS

Ranjana H. Advani, MD [96] Division of Oncology Department of Medicine Stanford University Stanford, California

Gheath Alatrash, DO, PhD [25] Associate Professor Department of Stem Cell Transplantation and Cellular Therapy Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center Houston, Texas

Doru T. Alexandrescu, MD [121] Department of Medicine Division of Dermatology

University of California, San Diego VA San Diego Health Care System San Diego, California

Carl E. Allen, MD, PhD [71] Department of Pediatrics

Baylor College of Medicine

Texas Children’s Cancer and Hematology Centers

Texas Children’s Hospital Houston, Texas

Karl E. Anderson, MD [59] Professor of Medicine Division of Gastroenterology

The University of Texas Medical Branch at Galveston Galveston, Texas

Kenneth Anderson, MD [104, 106] Director, Lipper Myeloma Center

Dana-Farber Cancer Institute

Kraft Family Professor of Medicine

Harvard Medical School

Boston, Massachusetts

Daniel A. Arber, MD [66]

Donald West and Mary Elizabeth King Professor and Chair of Pathology University of Chicago Chicago, Illinois

David Avigan, MD [24]

Beth Israel Deaconess Medical Center

Harvard Medical School

Boston, Massachusetts

Farrukh T. Awan, MD, MS [91] Associate Professor of Medicine

The University of Texas, Southwestern Medical Center Dallas, Texas

Jennifer Babik, MD, PhD [31] Division of Infectious Diseases Department of Medicine

University of California, San Francisco San Francisco, California

Lina Badimon, PhD, FESC, FAHA [134] Professor

Cardiovascular Science Program-ICCC CiberCV

Hospital de la Santa Creu I Sant Pau Barcelona, Spain

Robert A. Baiocchi, MD, PhD [89] Professor

Division of Hematology Department of Internal Medicine

Wexner Medical Center and James Cancer Center

The Ohio State University Columbus, Ohio

Kelty R. Baker, MD, FACP [52] President

Kelty R. Baker, M.D. P.A. Houston, Texas

Jacques Banchereau, PhD [21] Director of Immunological Sciences

Jackson Laboratory for Genomic Medicine Farmington, Connecticut

Marije Bartels, MD, PhD [48] Pediatric Hematologist Van Creveldkliniek

University Medical Center Utrecht Utrecht University Utrecht, The Netherlands

Rafael Bejar, MD, PhD [86] Associate Professor of Medicine Moores Cancer Center

University of California, San Diego La Jolla, California

Annelise Bennaceur-Griscelli, MD, PhD [27] Professor of Hematology

Assistance Publique-Hôpitaux de Paris–Paris Saclay Division of Hematology

Université Paris Saclay

INSERM U935-INGESTEM National iPSC Infrastructure Villejuif, France

Bruce Beutler, MD [19] Center for the Genetics of Host Defense

University of Texas, Southwestern Medical Center Dallas, Texas

Giada Bianchi, MD [104, 106]

Instructor in Medicine

Harvard Medical School

Associate Director, Amyloidosis Program

Brigham and Women’s Hospital/Dana Farber Cancer Institute

Associate Physician

Division of Hematology, Department of Medicine

Brigham and Women’s Hospital Boston, Massachusetts

David A. Bond, MD [89]

Division of Hematology

Department of Internal Medicine

Wexner Medical Center and James Cancer Center

The Ohio State University Columbus, Ohio

Niels Borregaard,* MD, PhD [64]

The Granulocyte Research Laboratory Department of Hematology

National University Hospital Copenhagen, Denmark

Mettine H. A. Bos, PhD [112]

Assistant Professor

Division of Thrombosis and Hemostasis

Einthoven Laboratory for Vascular and Regenerative Medicine

Leiden University Medical Center

Leiden, The Netherlands

Jonathan E. Brammer, MD [93]

Assistant Professor

Division of Hematology

James Cancer Center

The Ohio State University Columbus, Ohio

Paul F. Bray, MD [111]

Professor of Internal Medicine

Division of Hematology and Hematologic Malignancies

Program in Molecular Medicine

University of Utah Salt Lake City, Utah

Alessandro Broccoli, MD, PhD [100]

Institute of Hematology “Seràgnoli” University of Bologna Bologna, Italy

Virginia C. Broudy, MD [80]

Scripps Professor of Hematology Department of Medicine (Hematology) University of Washington (Hematology) Seattle, Washington

Francis K. Buadi, MD [107]

Division of Hematology

Mayo Clinic Rochester, Minnesota

*Deceased

Harry R. Buller, MD, PhD [133]

Professor of Vascular Medicine

Department of Vascular Medicine

Amsterdam UMC

Amsterdam Medical Centers

University of Amsterdam Amsterdam, The Netherlands

Linda J. Burns, MD [1, 3]

Consultant and Senior Scientific Director

Center for International Blood and Marrow Transplant Research Milwaukee, Wisconsin

John C. Byrd, MD [91]

Warren Brown Chair of Leukemia Research

Distinguished University Professor

The Ohio State University Columbus, Ohio

Brad R. Cairns, PhD [10]

Howard Hughes Medical Institute

Department of Oncological Sciences

Huntsman Cancer Institute

University of Utah School of Medicine

Salt Lake City, Utah

Michael A. Caligiuri, MD [5, 73, 77, 78]

Department of Hematology and Hematopoietic Cell Transplantation

Deana and Steve Campbell Physician-in-Chief Distinguished Chair President, City of Hope National Medical Center

Los Angeles, California

Elias Campo, MD, PhD [95]

Hematopathopathology Section Department of Anatomic Pathology

Hospital Clinic of Barcelona University of Barcelona Barcelona, Spain

Jaime Caro, MD [57]

Professor of Medicine, Emeritus Division of Hematology

Cardeza Foundation for Hematological Research

Sidney Kimmel Medical College Philadelphia, Pennsylvania

Martin P. Carroll, MD [13]

Associate Professor of Medicine Division of Hematology and Oncology

Department of Medicine

Perelman School of Medicine

University of Pennsylvania Philadelphia, Pennsylvania

Guillaume Cartron, MD, PhD [98]

Professor

Hematology Department

University Hospital of Montpellier Montpellier, France

Alessandro Casini, MD, PD [124]

Staff Physician

Division of Angiology and Hemostasis

Faculty of Medicine

University Hospitals of Geneva Geneva, Switzerland

Jorge J. Castillo, MD [108]

Clinical Director

Bing Center for Waldenstrom Macroglobulinemia

Division of Hematological Malignancies

Dana-Farber Cancer Institute;

Associate Professor

Harvard Medical School Boston, Massachusetts

Carla Casulo, MD [101]

Associate Professor of Medicine, Oncology Program Director, Hematology/Oncology Fellowship

Lymphoma Service

Wilmot Cancer Institute

University of Rochester Rochester, New York

Bruce A. Chabner, MD [28]

Professor Medicine

Massachusetts General Hospital

Harvard Medical School Boston, Massachusetts

Richard W. Childs, MD [20]

Clinical Director

Chief, Laboratory of Transplantation Immunotherapy

National Heart, Lung, and Blood Institute

National Institutes of Health

Bethesda, Maryland

Theresa L. Coetzer, PhD [47]

Department of Molecular Medicine and Haematology

School of Pathology

Faculty of Health Sciences

University of the Witwatersrand Johannesburg, South Africa

Claudia S. Cohn, MD [138]

Associate Professor

Laboratory Medicine and Pathology

University of Minnesota Minneapolis, Minnesota

Barry S. Coller, MD [111]

David Rockefeller Professor of Medicine

Head, Allen and Frances Adler Laboratory of Blood and Vascular Biology

Physician-in Chief, Rockefeller University Hospital

Vice President for Medical Affairs

Rockefeller University New York, New York

Michiel Coppens, MD, PhD [131]

Associate Professor of Medicine

Amsterdam UMC

University of Amsterdam Department of Vascular Medicine

Amsterdam Cardiovascular Sciences Amsterdam, The Netherlands

Gay M. Crooks, MB, BS [74]

Professor

Departments of Pathology and Lab Medicine and Pediatrics Division of Pediatric Hematology/Oncology

David Geffen School of Medicine

University of California, Los Angeles Los Angeles, California

David C. Dale, MD [63] Professor of Medicine University of Washington School of Medicine Seattle, Washington

Chi V. Dang, MD, PhD [13]

Scientific Director

Ludwig Institute for Cancer Research New York, New York Professor, The Wistar Institute Philadelphia, Pennsylvania

Utpal P. Davé, MD [4]

Co-Director, Hematopoiesis and Hematologic Malignancies Program

Indiana University Melvin and Bren Simon Comprehensive Cancer Center;

Associate Professor of Medicine and Microbiology and Immunology Division of Hematology and Oncology

R.L. Roudebush VA Medical Center Indiana University School of Medicine Indianapolis, Indiana

Madhav V. Dhodapkar, MD [21]

Brock Chair and Professor of Hematology Oncology Director, Winship Center for Cancer Immunology Emory University Atlanta, Georgia

Michael Dickinson, MBBS (Hons), DMedSci, FRACP, FRCPA [97]

Peter MacCallum Cancer Centre

Royal Melbourne Hospital

Sir Peter MacCallum Department of Oncology

University of Melbourne Melbourne, Australia

Angela Dispenzieri, MD [107] Division of Hematology

Mayo Clinic Rochester, Minnesota

May Dong, BA [13]

Medical Student

University of Massachusetts Medical School Worcester, Massachusetts

Anne G. Douglas, MD [67, 68]

Resident, Department of Neurology Perelman School of Medicine

University of Pennsylvania Philadelphia, Pennsylvania

Steven D. Douglas, MD [67, 68]

Professor of Pediatrics

Chief Section of Immunology

Senior Vice Chair, Pediatrics

Committee on Appointments and Promotions Chair, Pediatrics

Committee on Prestigious Awards and Honors Perelman School of Medicine

University of Pennsylvania Philadelphia, Pennsylvania

Martin Dreyling, MD, PhD [99] Professor of Medicine

Department of Medicine III LMU Hospital Munich, Germany

Connie J. Eaves, PhD, FRS(C) [27]

Distinguished Scientist

Terry Fox Laboratory

British Columbia Cancer Research Institute

Professor

Department of Medical Genetics & School of Biomedical Engineering

University of British Columbia Vancouver, Canada

Yvonne A. Efebera, MD, MPH [77]

Professor Department of Internal Medicine

Division of Hematology, Blood and Marrow Transplant Director and Founder, Comprehensive Amyloidosis Clinic Director, Careers in Internal Medicine

The Ohio State University Columbus, Ohio

William B. Ershler, MD [8]

Director

Division of Benign Hematology

Inova Schar Cancer Institute

Inova Fairfax Hospital Falls Church, Virginia

Miguel A. Escobar, MD [122] Professor of Medicine and Pediatrics

Director, Gulf States Hemophilia and Thrombophilia Center

University of Texas Health Science Center McGovern Medical School Houston, Texas

Andrew G. Evans, MD, PhD [101]

Director of Hematopathology

Associate Professor of Pathology and Laboratory Medicine

University of Rochester School of Medicine and Dentistry

Rochester, New York

Ross M. Fasano, MD [56]

Center for Transfusion and Cellular Therapies

Department of Pathology and Laboratory Medicine

Emory University School of Medicine

Atlanta, Georgia

Amir T. Fathi, MD [28]

Associate Professor of Medicine

Massachusetts General Hospital

Harvard Medical School Boston, Massachusetts

Brian J. Franz, PhD [137] Vitalant

Phoenix, Arizona

Kathleen Freson, PhD [119]

Director of Center for Molecular and Vascular Biology

Professor

Department of Cardiovascular Sciences

Katholieke Universiteit Leuven Leuven, Belgium

Aharon G. Freud, MD, PhD [93] Associate Professor

Department of Pathology

The Ohio State University Columbus, Ohio

Jonathan W. Friedberg, MD, MMSc [101] Director, Wilmot Cancer Institute

Samuel Durand Professor of Medicine and Oncology University of Rochester Rochester, New York

Monica Fung, MD, MPH [31] Division of Infectious Diseases Department of Medicine

University of California, San Francisco San Francisco, California

Stephen J. Galli, MD [66] Professor of Pathology and of Microbiology and Immunology

Stanford University School of Medicine

Stanford University Medical Center Stanford, California

Tomas Ganz, PhD, MD [38, 43, 44] Departments of Medicine and Pathology

David Geffen School of Medicine

University of California, Los Angeles Los Angeles, California

Terry B. Gernsheimer, MD [139] Department of Medicine

University of Washington

Seattle Cancer Care Alliance Seattle, Washington

Stanton L. Gerson, MD [26]

Case Comprehensive Cancer Center

Case Western Reserve University University Hospital of Cleveland Cleveland, Ohio

Morie A. Gertz, MD, MACP [107] Division of Hematology Mayo Clinic Rochester, Minnesota

Larisa J. Geskin, MD, FAAD [102] Department of Dermatology Columbia University Irving Medical Center New York, New York

David Ginsburg, MD [125]

James V. Neel Distinguished University Professor Departments of Internal Medicine, Human Genetics, and Pediatrics

Howard Hughes Medical Institute

University of Michigan Medical School Ann Arbor, Michigan

Elizabeth K.K. Glennon, PhD [14] Postdoctoral Scientist

Center for Global Infectious Disease Research Seattle Children’s Research Institute Seattle, Washington

Lucy A. Godley, MD, PhD [11] Section of Hematology/Oncology Department of Medicine

The Comprehensive Cancer Center

The University of Chicago Chicago, Illinois

Kandace Gollomp, MD [117] Assistant Professor of Pediatrics

The Children’s Hospital of Philadelphia University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

Blanca Gonzalez, MD, PhD [95] Hematopathopathology Section Department of Anatomic Pathology Hospital Clinic of Barcelona University of Barcelona Barcelona, Spain

Victor R. Gordeuk, MD [50] Professor of Medicine University of Illinois Chicago, Illinois

Jason Gotlib, MD, MS [65] Professor of Medicine Division of Hematology

Stanford Cancer Institute

Stanford University School of Medicine Stanford, California

Steven Grant, MD [15] Professor of Medicine

Shirley Carter and Sture Gordon Olsson

Professor of Oncology

Virginia Commonwealth University Richmond, Virginia

Ralph Green, MD, PhD, FRCPath [42, 45]

Professor of Pathology and Medicine Department of Pathology and Laboratory Medicine University of California, Davis Sacramento, California

Xylina T. Gregg, MD [39]

Utah Cancer Specialists Salt Lake City, Utah

Michael R. Grever, MD [92] Professor Emeritus Division of Hematology Department of Internal Medicine

The Ohio State University Columbus, Ohio

John Gribben, MD, DSc, FRCP, FRCPath, FMedSci [76]

Barts Cancer Institute Centre for Haemato-Oncology

Queen Mary University of London London, United Kingdom

Emma M. Groarke, MD [8] Fellow, Hematology Branch National Heart, Lung, and Blood Institute

National Institutes of Health

Mark Hatfield Clinical Research Center Bethesda, Maryland

Katherine A. Hajjar, MD [114, 135]

Brine Family Professor of Cell and Developmental Biology Professor and Vice Chair for Research Department of Pediatrics; Professor of Pediatrics in Medicine

Senior Associate Dean for Faculty Weill Cornell Medicine New York, New York

Amel Hamdi, PhD [60] Department of Physiology Lady Davis Institute McGill University Montreal, Quebec, Canada

Robert D. Harrington, MD [80] Professor Department of Medicine (Infectious Diseases) University of Washington; Chief of Medicine

Section Chief, Infectious Diseases Harborview Medical Center Seattle, Washington

Xiangrong He, MD [138]

Clinical Fellow

Laboratory Medicine and Pathology

Mayo Clinic Rochester, Minnesota

Jeanne E. Hendrickson, MD [56]

Professor

Departments of Laboratory Medicine and Pediatrics

Yale University School of Medicine

New Haven, Connecticut

Paul C. Herrmann, MD, PhD [53]

Professor and Chair

Department of Pathology and Human Anatomy

Loma Linda University School of Medicine Loma Linda, California

Gabriela S. Hobbs, MD [28]

Instructor in Medicine

Massachusetts General Hospital Harvard Medical School Boston, Massachusetts

Steven Horwitz, MD [103]

Associate Attending Lymphoma Service, Department of Medicine

Memorial Sloan Kettering Cancer Center

New York, New York

Chi-Joan How, MD [28]

Fellow in Medical Oncology

Massachusetts General Hospital Boston, Massachusetts

Russell D. Hull, MBBS, MSc [133]

Emeritus Professor of Medicine

Foothills Medical Centre and University of Calgary, Calgary, Canada

Achille Iolascon, MD, PhD [40] Professor of Medical Genetics

Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II Naples, Italy

Joseph E. Italiano, Jr., PhD [111]

Associate Professor of Medicine

Division of Hematology

Brigham and Women’s Hospital

Vascular Biology Program

Boston Children’s Hospital

Harvard Medical School Boston, Massachusetts

Jill M. Johnsen, MD [125]

Associate Member

Bloodworks

Associate Professor of Medicine

University of Washington

Seattle, Washington

Patrick Connor Johnson, MD [28]

Fellow in Medical Oncology

Massachusetts General Hospital Boston, Massachusetts

Lynn B. Jorde, PhD [9]

Mark and Kathie Miller Presidential Professor and Chair Department of Human Genetics

University of Utah School of Medicine

Salt Lake City, Utah

Alexis Kaushansky, PhD [14]

Associate Professor

Department of Pediatrics

School of Medicine

University of Washington; Center for Global Infectious Disease Research

Seattle Children’s Hospital Seattle, Washington

Kenneth Kaushansky, MD, MACP [3, 16, 17, 84, 110, 115, 116, 118]

Senior Vice President, Health Sciences

Dean, Renaissance School of Medicine

Stony Brook University

Stony Brook, New York

Rami Khoriaty, MD [40]

Assistant Professor, Department of Internal Medicine

Assistant Professor, Department of Cell and Developmental Biology

Section Head, Classical Hematology

Core Member, Rogel Cancer Center University of Michigan

Ann Arbor, Michigan

Thomas J. Kipps, MD, PhD [75] Director, Hematology Malignancy Program Director, Center for Novel Therapeutics

Distinguished Professor of Medicine

Moores Cancer Center

University of California, San Diego San Diego, California

Adam S. Kittai, MD [91]

Assistant Professor of Medicine

The Ohio State University Columbus, Ohio

Mark J. Koury, MD [4] Professor of Medicine, Emeritus Division of Hematology/Oncology

Vanderbilt University School of Medicine Nashville, Tennessee

Taco Kuijpers, MD, PhD [61, 64]

Professor of Immunology

Consultant Pediatric Infectious Diseases and Clinical Immunology

Amsterdam University Medical Center

University of Amsterdam Amsterdam, The Netherlands

Abdullah Kutlar, MD [50] Professor of Medicine

Augusta University

Augusta, Georgia

Robert A. Kyle, MD, MACP [109] Professor of Medicine Laboratory Medicine and Pathology

Mayo Clinic College of Medicine Rochester, Minnesota

Geoffrey A. Land, PhD, HCLD, F(AAM) [137] Vitalant

Phoenix, Arizona

Angela M. Lager [11]

Section of Hematology/Oncology Department of Medicine

The Comprehensive Cancer Center

The University of Chicago Chicago, Illinois

Lewis L. Lanier, PhD [20] Professor Department of Microbiology and Immunology University of California, San Francisco San Francisco, California

Richard A. Larson, MD [90] Professor of Medicine

Section of Hematology/Oncology Department of Medicine

The Comprehensive Cancer Center

The University of Chicago Chicago, Illinois

Michelle M. Le Beau, PhD [11] Section of Hematology/Oncology Department of Medicine

The Comprehensive Cancer Center

The University of Chicago Chicago, Illinois

Houry Leblebjian, Pharm D [28] Department of Pharmacy Dana Farber Cancer Institute Boston, Massachusetts

Frank W.G. Leebeek, MD, PhD [130] Professor of Hematology Department of Hematology

Erasmus University Medical Center Rotterdam, The Netherlands

Matthew M. Lei, Pharm D [28] Department of Pharmacy

Massachusetts General Hospital Boston, Massachusetts

Marcel Levi, MD, PhD, FRCP [3, 18, 32, 113, 115, 120, 121, 127]

Professor of Medicine

University College London Hospitals

London, United Kingdom; Professor of Medicine

University of Amsterdam Amsterdam, The Netherlands

Jerrold H. Levy, MD, FAHA, FCCM [140]

Professor of Anesthesiology

Cardiothoracic Anesthesiology, Critical Care, and Surgery (Cardiothoracic)

Duke University School of Medicine Durham, North Carolina

Zhenyu Li, MD, PhD [111]

Cardiovascular Research Center University of Kentucky Lexington, Kentucky

Marshall A. Lichtman, MD, MACP [1, 3, 36, 54, 62, 69, 70, 82, 85, 87, 88, 105]

Professor Emeritus of Medicine and of Biochemistry and Biophysics

Dean Emeritus, School of Medicine and Dentistry

James P. Wilmot Cancer Institute

University of Rochester Medical Center Rochester, New York

Jane L. Liesveld, MD [87, 88]

Professor of Medicine (Hematology-Oncology)

James P. Wilmot Cancer Institute

University of Rochester Medical Center Rochester, New York

David C. Linch, FRCP, FRCPath, FMed Sci [3, 94]

Professor of Haematology Cancer Program Director UCL and UCL Hospitals Biomedical Research Centre University College London London, United Kingdom

Ton Lisman, PhD [130]

Professor of Experimental Surgery Surgical Research Laboratory Section of Hepatobiliary Surgery and Liver Transplantation Department of Surgery

University Medical Center, Groningen Groningen, The Netherlands

Pete Lollar, MD [126]

Aflac Cancer and Blood Disorders Center Department of Pediatrics

Emory University Atlanta, Georgia

Christine Lomas-Francis, MSc, FIBMS [136]

Immunohematology and Genomics

New York Blood Center Long Island City, New York

Gerard Lozanski, MD [92]

Professor of Pathology Clinical Department of Pathology

The Ohio State University Columbus, Ohio

Naomi L.C. Luban, MD [56] Professor of Pediatrics and Pathology School of Medicine and Health Sciences

George Washington University; Medical Director, Office of Human Subjects Protection Senior Hematologist Children’s National Hospital Washington, DC

Fabienne Lucas, MD, PhD [76] Department of Pathology Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts

Nicola C. Maciocia, MBChB, BSc, FRCPath [23] Department of Haematology Cancer Institute

London, United Kingdom

Paul M. Maciocia, MBChB, PhD, FRCPath [23] Department of Haematology Cancer Institute

London, United Kingdom

Anthony G. Mansour, MD [78] Department of Hematology and Hematopoietic Cell Transplantation

City of Hope National Medical Center Los Angeles, California

Elaine R. Mardis, PhD [10]

The Steve and Cindy Rasmussen Institute for Genomic Medicine Nationwide Children’s Hospital Columbus, Ohio

Kenneth L. McClain, MD, PhD [71] Department of Pediatrics

Baylor College of Medicine

Texas Children’s Cancer and Hematology Centers

Texas Children’s Hospital Houston, Texas

Jeffrey McCullough, MD [138] Global Blood Advisor

Edina, Minnesota; Emeritus Professor

Laboratory Medicine and Pathology

University of Minnesota Minneapolis, Minnesota

Neha Mehta-Shah, MD, MSCI [103]

Assistant Professor Department of Medicine

Division of Oncology

Washington University School of Medicine in St. Louis St. Louis, Missouri

Guiomar Mendieta, MD, MSc [134]

Cardiovascular Institute, Cardiology Department

Hospital Clinic

University of Barcelona

Cardiovascular Science Program, ICCC

Hospital de la Santa Creu I Sant Pau Barcelona, Spain

Marzia Menegatti, BSc, PhD [123]

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center

Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and Fondazione Luigi Villa Milan, Italy

Manoj P. Menon, MD, MPH [80]

Associate Professor

Department of Medicine (Hematology)

University of Washington; Section Chief

Hematology and Medical Oncology

Harborview Medical Center; Assistant Professor

Vaccine and Infectious Disease

Clinical Research Divisions

Fred Hutchinson Cancer Research Center

Seattle, Washington

Dean D. Metcalfe, MD [66]

Chief, Mast Cell Biology Section

Laboratory of Allergic Diseases

National Institute of Allergy and Infectious Diseases

National Institutes of Health Bethesda, Maryland

Saskia Middeldorp, MD, PhD [131]

Professor

Department of Vascular Medicine

Amsterdam Cardiovascular Sciences

Amsterdam UMC

University of Amsterdam Amsterdam, The Netherlands

Martha P. Mims, MD, PhD [7]

Professor of Medicine and Chief Hematology/Oncology

Baylor College of Medicine Houston, Texas

Anjali Mishra, PhD [93]

Assistant Professor

Sidney Kimmel Cancer Center

Thomas Jefferson University Philadelphia, Pennsylvania

Ananya Datta Mitra, MD [42, 45]

Section of Hematopathology

Department of Pathology and Laboratory Medicine

University of California, Davis Health, School of Medicine

Sacramento, California

Joel Moake, MD [52]

Professor of Medicine Emeritus

Baylor College of Medicine

Senior Research Scientist

Department of Bioengineering

Rice University

Houston, Texas

Narla Mohandas, DSc [33]

Laboratory of Red Cell Physiology

New York Blood Center

New York, New York

Jeffrey J. Molldrem, MD [25] Professor and Chair, ad interim Division of Cancer Medicine

Department of Hematopoietic Biology and Malignancy

The University of Texas MD Anderson Cancer Center Houston, Texas

Eva Marie Y. Moresco, PhD [19]

Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas, Texas

Diana Morlote, MD [2, 46]

Assistant Professor

Hematopathology and Molecular Genetic Pathology Division of Genomics and Bioinformatics

Department of Pathology

The University of Alabama at Birmingham Birmingham, Alabama

Alison Moskowitz, MD [103]

Associate Attending Lymphoma Service Department of Medicine

Memorial Sloan Kettering Cancer Center

New York, New York

Eric Mou, MD [96] Division of Oncology Department of Medicine

Stanford University Stanford, California

William A. Muller, MD, PhD [114]

Janardan K. Reddy Professor of Pathology Feinberg School of Medicine

Northwestern University Chicago, Illinois

Natarajan Muthusamy, DVM, PhD [73] Professor, Hematology

The Ohio State University Columbus, Ohio

Christopher S. Nabel, MD, PhD [28] Fellow in Medical Oncology

Massachusetts General Hospital Boston, Massachusetts

Srikanth Nagalla, MBBS, MS [57]

Associate Professor of Medicine

Program Director, Hematology/Oncology Fellowship Division of Hematology/Oncology

University of Texas, Southwestern Medical Center

Dallas, Texas

Marguerite Neerman-Arbez, PhD [124] Professor

Department of Genetic Medicine and Development University of Geneva Faculty of Medicine Geneva, Switzerland

Robert S. Negrin, MD [29] Professor of Medicine

Chief, Division of Blood and Marrow Transplantation

Stanford University School of Medicine Stanford, California

Luigi D. Notarangelo, MD [79]

Laboratory of Clinical Immunology and Microbiology

National Institute of Allergy and Infectious Diseases

National Institutes of Health Bethesda, Maryland

Hans D. Ochs, MD [79]

Professor of Pediatrics

Jeffrey Modell Chair of Pediatric Immunology Research Center for Immunity and Immunotherapies

Seattle Children’s Research Institute University of Washington Seattle, Washington

Elizabeth K. O’Donnell, MD [104, 106] Assistant Professor of Medicine

Massachusetts General Hospital Harvard Medical School Boston, Massachusetts

Willem Ouwehand, MD, PhD, FMedSci [119]

Professor of Experimental Haematology Honorary Consultant of Haematology

National Health Service Blood Transfusion Honorary Faculty Member Wellcome Trust Sanger Institute; Department of Haematology University of Cambridge NHS Blood and Transplant Building

Cambridge Biomedical Campus Cambridge, United Kingdom

Charles H. Packman, MD [55] Professor of Medicine

Department of Hematologic Oncology and Blood Disorders

Levine Cancer Institute

University of North Carolina School of Medicine

Charlotte, North Carolina

Teresa Padró, PhD, FESC [134] Cardiovascular Science Program-ICCC CiberCV

Hospital de la Santa Creu I Sant Pau Barcelona, Spain

James Palis, MD [6] Professor of Pediatrics

Director, Center for Pediatric Biomedical Research University of Rochester Medical Center Rochester, New York

Charles J. Parker, MD [41]

Professor of Medicine

Department of Medicine

Division of Hematology and Hematologic Malignancies

University of Utah School of Medicine

Salt Lake City, Utah

Karl S. Peggs, MB BCh, MA, MRCP, FRCPath [22]

Senior Lecturer in Stem Cell Transplantation and Immunotherapy

Director

Adult Stem Cell Transplantation Services

University College London Cancer Institute London, United Kingdom

Flora Peyvandi, MD, PhD [123]

Director, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center

Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico

Vice Director, Department of Pathophysiology and Transplantation

Università degli Studi di Milano

Milan, Italy

John D. Phillips, PhD [59]

Division of Hematology

Department of Medicine

University of Utah School of Medicine

Salt Lake City, Utah

Mortimer Poncz, MD [117]

University of Pennsylvania School of Medicine

The Children’s Hospital of Philadelphia

Professor of Pediatrics

Chief, Pediatric Hematology

Philadelphia, Pennsylvania

Prem Ponka,* MD, PhD, FCMA [60]

Department of Physiology

McGill University and Lady Davis Institute

Montreal, Quebec, Canada

Pierluigi Porcu, MD [93]

Professor of Medical Oncology, Dermatology, and Cutaneous Biology

Director, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation

Department of Medical Oncology

Sidney Kimmel Cancer Center

Thomas Jefferson University

Philadelphia, Pennsylvania

Jacqueline N. Poston, MD [139]

Department of Medicine

University of Washington

Seattle Cancer Care Alliance

Fred Hutchinson Cancer Research Center

Bloodworks NW Research Institute Seattle, Washington

Jaroslav F. Prchal, MD, FRCPC [83]

Director

Department of Oncology

St. Mary’s Hospital Center

Montreal, Quebec, Canada

Josef T. Prchal, MD [3, 34, 35, 51, 58, 60, 83, 85]

Professor of Hematology and Malignant Hematology

Adjunct in Genetics and Pathology

University of Utah & Huntsman Cancer Institute

Salt Lake City, Utah

1. interní klinika VFN a Ústav patologické fyziologie, 1. LF School of Medicine

Universita Karlova, Prague, Czech Republic

Martin A. Pule, MRCP, FRCPath [23]

Department of Haematology

Senior Lecturer in Haematology

Clinical Haematologist Consultant

UCL Cancer Institute

London, United Kingdom

Sergio A. Quezada, PhD [22]

Department of Haematology

University College London Cancer Institute

London, United Kingdom

Noopur S. Raje, MD, PhD [28]

Professor of Medicine

Massachusetts General Hospital

Harvard Medical School

Boston, Massachusetts

Jacob H. Rand, MD [132]

Professor of Pathology and Laboratory Medicine

New York Presbyterian Weill Cornell New York, New York

A. Koneti Rao, MD, FACP, FAHA [119]

Sol Sherry Professor of Medicine

Director, Benign Hematology, Hemostasis and Thrombosis

Co-Director, Sol Sherry Thrombosis Research Center

Professor of Thrombosis Research and Pharmacology

Professor of Clinical Pathology and Laboratory Medicine

Lewis Katz School of Medicine

Temple University Philadelphia, Pennsylvania

Gary E. Raskob, PhD [133]

Dean, Hudson College of Public Health

Regents Professor, Epidemiology and Medicine

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma

Lubica Rauova, PhD [117]

University of Pennsylvania School of Medicine

Research Associate Professor of Pediatrics

The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

*Deceased

Vishnu V.B. Reddy, MD [2, 46]

Section Head, UAB Hospital Hematology Bone Marrow Lab Director, Hematopathology Fellowship Program

Division of Laboratory Medicine

Professor, Department of Pathology

The University of Alabama at Birmingham Birmingham, Alabama

Mark T. Reding, MD [122]

Associate Professor of Medicine

Director, Center for Bleeding and Clotting Disorders University of Minnesota Medical Center Minneapolis, Minnesota

Pieter H. Reitsma, PhD [112]

Professor of Experimental Medicine

Einthoven Laboratory for Experimental Vascular and Regenerative Medicine

Leiden University Medical Center

Leiden, The Netherlands

Shoshana Revel-Vilk, MD, MCs [72]

Associate Professor of Pediatrics

Gaucher Unit and Pediatric Hematology/Oncology Unit

Shaare Zedek Medical Center

Hebrew University Medical School Jerusalem, Israel

Andrew R. Rezvani, MD [29]

Assistant Professor of Medicine

Associate Clinical Chief, Division of Blood and Marrow Transplantation

Stanford University School of Medicine Stanford, California

Paul G. Richardson, MD [28]

R.J. Corman Professor of Medicine

Dana Farber Cancer Institute

Harvard Medical School

Boston, Massachusetts

Jia Ruan, MD, PhD [135]

Associate Professor of Clinical Medicine

Lymphoma Program

Division of Hematology and Medical Oncology

Weill Cornell Medicine

New York, New York

Roberta Russo, PhD [40]

Assistant Professor of Medical Genetics

Department of Molecular Medicine and Medical Biotechnology

CEINGE

Biotecnologie Avanzate

University of Naples Federico II Naples, Italy

Joel Saltz, MD, PhD [12]

Founding Chair and Professor of Biomedical Informatics

Renaissance School of Medicine

Stony Brook University

Stony Brook, New York

Clémentine Sarkozy, MD, PhD [98]

Department of Therapeutic Innovation

Gustave Roussy

Université Paris-Saclay Villejuif, France

Sam Schulman, MD, PhD, FRCPS [32] Professor, Department of Medicine

Director, Thrombosis Service

Hamilton Health Sciences General Hospital

McMaster University Hamilton, Ontario, Canada

Steven Scoville, MD, PhD [5]

General Surgery

The Ohio State University Columbus, Ohio

Marie Scully, MB BS, MRCP, FRCPath, MD [128]

Professor

Department of Haematology

Cardiometabolic Programme

National Institute of Health Research

University College London/University College London Hospitals

Biomedical research Centre

University College London Hospital London, United Kingdom

Christopher S. Seet, MD, PhD [74]

Assistant Professor

Department of Medicine

Division of Hematology-Oncology

David Geffen School of Medicine

University of California, Los Angeles Los Angeles, California

George B. Segel, MD [6, 36]

Emeritus Professor of Pediatric Professor of Medicine

James P. Wilmot Cancer Institute

University of Rochester Medical Center Rochester, New York

Uri Seligsohn, MD [127]

Professor and Director

Amalia Biron Research Institute of Thrombosis and Hemostasis Department of Hematology

Chaim Sheba Medical Center

Tel-Hashomer and Sackler Faculty of Medicine

Tel Aviv University

Tel Aviv, Israel

John F. Seymour, FAHMS, MB, BS, PhD, FRACP [97]

Peter MacCallum Cancer Centre

Royal Melbourne Hospital; Professor

Sir Peter MacCallum Department of Oncology

University of Melbourne Melbourne, Australia

Beth Shaz, MD [140]

New York Blood Center

New York, New York

Vivien A. Sheehan, MD, PhD [50]

Assistant Professor of Pediatrics

Baylor College of Medicine

Houston, Texas

Taimur Sher, MD [107] Division of Hematology/Oncology

Mayo Clinic Jacksonville, Florida

Sujit Sheth, MD [49] Department of Pediatrics

Weill Cornell Medicine

New York, New York

William Shomali, MD [65] Division of Hematology

Stanford Cancer Institute

Stanford University School of Medicine Stanford, California

Suthesh Sivapalaratnam, MD, PhD, MRCP (London) [119]

Senior Lecturer Department of Haematology

Royal London Hospital London, United Kingdom

Sarah J. Skuli, MD [13] Fellow

Division of Hematology and Oncology Department of Medicine

Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Susan S. Smyth, MD, PhD [111] Professor and Chief Division of Cardiovascular Medicine

Physician Investigator

Lexington Veterans Affairs Medical Center University of Kentucky Lexington, Kentucky

Philippe Solal-Céligny, MD, PhD [98] Professor of Haematology Institut de Cancérologie de l’Ouest Saint-Herblain, France

Michael A. Spinner, MD [96] Division of Oncology Department of Medicine

Stanford University Stanford, California

David P. Steensma, MD [86]

Associate Professor of Medicine

Edward P. Evans Chair of Myelodysplastic Syndromes Research Dana-Farber Cancer Institute

Harvard Medical School

Boston, Massachusetts

Sean R. Stowell, MD, PhD [126]

Center for Transfusion and Cellular Therapies Department of Pathology and Laboratory Medicine

Emory University Atlanta, Georgia

Sankar Swaminathan, MD [81]

Don Merril Rees Presidential Endowed Chair Professor and Division Chief Division of Infectious Diseases

University of Utah School of Medicine

Salt Lake City, Utah

Jeff Szer, MB BS, FRACP [72] Professor of Medicine

Peter MacCallum Cancer Centre

The Royal Melbourne Hospital University of Melbourne and Clinical Haematology Melbourne, Victoria, Australia

Tsewang Tashi, MD [83]

Huntsman Cancer Center University of Utah Salt Lake City, Utah

Swee Lay Thein, MD [49]

National Heart, Lung, and Blood Institute

The National Institutes of Health Bethesda, Maryland

Perumal Thiagarajan, MD [34] Professor of Medicine and Pathology

Baylor College of Medicine

Director of Transfusion Medicine and Hematology Laboratory

Michael E. DeBakey VA Medical Center Houston, Texas

Megan Trager, MD [102] Department of Dermatology

Columbia University Irving Medical Center New York, New York

Steven P. Treon, MD, PHD, FACP, FRCP [108] Professor of Medicine

Harvard Medical School; Director

Bing Center for Waldenstrom’s Macroglobulinemia

Dana Farber Cancer Institute Boston, Massachusetts

Giorgio Trinchieri, MD [20]

National Institutes of Health Distinguished Investigator Chief, Laboratory of Integrative Cancer Immunology

Center for Cancer Research

National Cancer Institute

National Institutes of Health

Bethesda, Maryland

Ali G. Turhan, MD, PhD [27]

Professor of Hematology

Assistance Publique-Hôpitaux de Paris–Paris Saclay

Division of Hematology

Université Paris Saclay

INSERM U935-INGESTEM National iPSC Infrastructure Villejuif, France

Eduard J. van Beers, MD, PhD [48] Hematologist

Van Creveldkliniek

University Medical Center Utrecht Utrecht University Utrecht, The Netherlands

Cornelis van’t Veer, PhD [112] Associate Professor Center for Experimental and Molecular Medicine

Amsterdam University Medical Centres University of Amsterdam Amsterdam, The Netherlands

Richard van Wijk, PhD [48] Associate Professor

Central Diagnostic Laboratory

University Medical Center Utrecht Utrecht University Utrecht, The Netherlands

Ralph R. Vassallo, MD, FACP [137] Vitalant

Scottsdale, Arizona; Clinical Professor

Department of Pathology University of New Mexico Albuquerque, New Mexico

Kamalakannan Vijayan, PhD [14] Fellow PhD

Seattle Children’s Research Institute Seattle, Washington

Gemma Vilahur, PhD, FESC [134] Cardiovascular Science Program-ICCC CiberCV

Hospital de la Santa Creu I Sant Pau Barcelona, Spain

Dietlind L. Wahner-Roedler, MD, MS, FACP [109] Professor of Medicine Department of Medicine Mayo Clinic College of Medicine Rochester, Minnesota

Luojun Wang, MD [95] Pathology Fellow

Hematopathopathology Section Department of Anatomic Pathology Hospital Clinic of Barcelona University of Barcelona Barcelona, Spain

Robert Weinstein, MD [30] Professor of Medicine and Pathology

University of Massachusetts Medical School Chief, Division of Transfusion Medicine

University of Massachusetts Memorial Medical Center Worcester, Massachusetts

Matthew Weinstock, MD [24]

Beth Israel Deaconess Medical Center

Harvard Medical School Boston, Massachusetts

Karl Welte, MD [63] Professor of Hematology University to Tubingen Tubingen, Germany

Sidney W. Whiteheart, PhD, FAHA [111] George Schwert Endowed Professor of Biochemistry University Research Professor University of Kentucky College of Medicine Lexington, Kentucky

Lucia R. Wolgast, MD [132] Director, Clinical Laboratories Montefiore Moses Hospital Associate Professor, Albert Einstein College of Medicine Montefiore Medical Center Albert Einstein College of Medicine Bronx, New York

Neal S. Young, MD [8, 37] Chief, Hematology Branch National Heart, Lung, and Blood Institute Mark Hatfield Clinical Research Center National Institutes of Health Bethesda, Maryland

X. Long Zheng, MD, PhD [129] Professor and Russell J. Eilers, MD Endowed Chair Chair of Department of Pathology and Laboratory Medicine The University of Kansas Medical Center Kansas City, Kansas

Liang Zhou, MD, PhD [15] Instructor, Hematology/Oncology Medical College of Virginia Virginia Commonwealth University Richmond, Virginia

Pier Luigi Zinzani, MD, PhD [100] Chief of Lymphoma and CLL Unit Institute of Hematology “Seràgnoli” University of Bologna Bologna, Italy

Ari Zimran, MD [72]

Associate Professor of Medicine Gaucher Unit, Shaare Zedek Medical Center Hebrew University Medical School Jerusalem, Israel

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PREFACE

The first edition of Williams Hematology (né Hematology) was published in 1972. This, our 10th edition, represents our continued efforts over one-half century to provide the most current concepts of the genetic basis, pathophysiology, diagnosis, and treatment of hematologic diseases.

The rate of growth in our understanding of diseases of blood cells and coagulation pathways has justified, indeed mandated, the effort of the editors to publish periodic major revisions in this comprehensive textbook of hematology. The sequencing of patient genomes and advances in knowledge in epigenetics, proteomics, and metabolomics, as applied to hematologic disorders, have accelerated the understanding of the pathogenesis of the diseases of our interest and provided new pathways to treatment. Advances in our dissection of molecular and cellular biology and immunology have translated into improved diagnostic and therapeutic methods. Customizing immunotherapy to attack tumor cell antigens and identifying specific molecular targets for therapy in several hematologic disorders have, as anticipated, become reality. Gene therapy is being implemented to cure selected, monogenic, inherited hematologic diseases, such as hemophilia A and B. Sickle cell anemia is a disease about which we have known more than almost any other genetic disorder, yet we have been unable to modulate, significantly, its horrific impact on patients. Finally, we may be edging toward a dramatic improvement in therapy by preventing the suppression of F hemoglobin synthesis after birth, minimizing the fraction of hemoglobin S in postnatal blood. Other promising approaches to gene therapy are also being studied in sickle cell anemia and thalassemia. CRISPR-Cas9 methodology has been a singular application in several of these gene-editing approaches. Hematology continues to be the poster child for the rational design of therapeutics applicable to other fields of medicine.

This edition of Williams Hematology endeavors to facilitate access to information, both within the book and its associated links. Each chapter has been revised or rewritten to provide current information. To reflect the increased application of immunotherapy, chapters on this important topic have been added, including Chapter 22, “Immune Checkpoint Inhibitors”; Chapter 23, “Immune Cell Therapy: Chimeric Antigen Receptor T-Cell Therapy”; and Chapter 24, “Immune Cell Therapy: Dendritic Cell and Natural Killer Cell Therapy,” along with the revised and updated Chapter 25, “Vaccine Therapy.” A new Chapter 12, “Application of Big Data and Deep Learning in Hematology” has been introduced.

At the center of diagnostic hematology is blood and marrow cell morphology. Thus, we have continued the incorporation of informative color images representing the relevant diseases in each chapter, allowing easy access to illustrations of cell morphology important to diagnosis.

The 10th edition of Williams Hematology is also available online as part of the excellent www.accessmedicine.com website. With direct links to a comprehensive drug therapy database and to other important medical texts, including Harrison’s Principles of Internal Medicine and Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Williams Hematology Online is part of a comprehensive resource covering all disciplines within medical education and practice. The online edition of Williams Hematology also includes PubMed links to journal articles cited in the references. New in this online edition is the presentation of clinical cases for readers to explore, each linked to the relevant disease-oriented chapter.

The companion handbook, Williams Manual of Hematology, will be revised to reflect the diagnostic and therapeutic advances entered

into the 10th edition of Williams Hematology. The Manual features the most salient clinical content from the parent text and is useful in time-restricted clinical situations. The Manual will be available for the iPhone and other mobile formats. It has been particularly useful for physicians studying for the American Board of Internal Medicine Cer tification in Hematology and comparable other examinations in other jurisdictions.

The production of this book required the timely cooperation of 233 contributors for the writing or revising of 140 chapters. We are grateful for their insight and work in providing this comprehensive and up-to-date text. Despite the growth of both basic and clinical knowledge and the passion that each of our contributors brings to the topic of their chapter, we have been able to maintain the text in a single volume through attention to chapter length.

The editorial board has lost the experience and intellect of Oliver W. Press, who died from a malignant brain tumor in 2017 and who had joined the board as the expert in lymphopoiesis and lymphoma for the 9th edition. His contributions to the field and to his institution, The Fred Hutchinson Cancer Center, were singular.

The readers of the 10th edition of Williams Hematology will note the expanding international participation in the text with the addition of Professor David Linch, University College, London, who is the editor for the biology and diseases of lymphocytes and the lymphoma sections. Thus, the 10th edition has two of its six editors from the United Kingdom and chapter authors from Belgium, Canada, France, Germany, Israel, Italy, Netherlands, South Africa, Spain, Switzerland, and the United Kingdom in addition to the United States. The preparation of this edition of Williams Hematology required our authors throughout Europe, other international sites, and the United States to remain dedicated to their task despite the impact of the new strain of coronavirus (SARS-CoV-2) infection and its dissemination as coronavirus disease, first identified in late 2019 (COVID-19) and thereafter became a pandemic, a contagion of historic consequences. The editors are grateful for their dedication despite the hardships endured by many of our contributors.

The editors have had expert administrative assistance in the management of the manuscripts for which they were primarily responsible. We thank Susan Daley in Rochester, New York; Teresa MacDonald in London, United Kingdom; and Shelly Saxton in Salt Lake City, Utah, for their very helpful participation in the production of the book. Special acknowledgment goes to Marie Brito in Stony Brook, New York, who was responsible for coordinating the management of 140 chapters, including many new figures, tables, and clinical cases, and managing other administrative matters, a challenging task that Ms. Brito performed with skill and good humor. The editors also acknowledge the interest and support of our colleagues at McGraw Hill, including James F. Shanahan, Vice President and Group Publisher; Karen G. Edmonson, S enior C ontent Acquisitions Editor; Kim Davis, Developmental Director; Leah Carton, Editorial Coordinator; and Revathi Viswanathan, Client Services Manager for Williams Hematology.

Kenneth Kaushansky

Marshall A. Lichtman

Josef T. Prchal

Marcel Levi

Linda J. Burns

David C. Linch

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Part I Clinical Evaluation of the Patient

CHAPTER 1

INITIAL APPROACH TO THE PATIENT: HISTORY AND PHYSICAL EXAMINATION

SUMMARY

The care of a patient with a suspected hematologic abnormality begins with a systematic attempt to determine the nature of the illness by eliciting an in-depth medical history and performing a thorough physical examination. The physician should identify the patient’s symptoms systematically and obtain as much relevant information as possible about their origin and evolution and about the general health of the patient by appropriate questions designed to explore the patient’s recent and remote experience. Reviewing previous records may add important data for understanding the onset or progression of illness. Hereditary and environmental factors should be carefully sought and evaluated. The use of drugs and medications, nutritional patterns, and sexual behavior should be considered. The physician should follow the medical history with a physical examination to obtain evidence for tissue and organ abnormalities that can be assessed through bedside observation to permit a careful search for signs of the illnesses suggested by the history. Skin changes and hepatic, splenic, or lymph nodal enlargement are a few findings that may be of considerable help in pointing toward a diagnosis. Additional history should be obtained during the physical examination, as findings suggest an additional or alternative consideration. Thus, the history and physical examination should be considered as a unit, providing the basic information with which further diagnostic information is integrated, with blood and marrow studies, imaging studies and tissue examination .

Primary hematologic diseases are common in the aggregate, but hematologic manifestations secondary to other diseases occur even more frequently. For example, the signs and symptoms of anemia and the presence of enlarged lymph nodes are common clinical findings that may be related to a hematologic disease, but which also occur frequently as secondary manifestations of disorders not considered primarily hematologic. A wide variety of diseases may produce signs or symptoms of hematologic illness. Thus, in patients with a connective tissue disease, all the signs and symptoms of anemia may be elicited and lymphadenopathy may be notable, but additional findings are usually present that indicate primary involvement of some system besides the hematopoietic (marrow) or lymphopoietic (lymph nodes or other lymphatic sites). In this discussion, emphasis is placed on the clinical findings resulting from either primary hematologic disease or the complications of hematologic disorders so as to avoid presenting an extensive catalog of signs and symptoms encountered in general clinical medicine.

In each discussion of specific diseases in subsequent chapters, the signs and symptoms that accompany the particular disorder are presented, and the clinical findings are covered in detail. This chapter takes a more general systematic approach.

THE HEMATOLOGY CONSULTATION

Table 1–1 lists the major abnormalities that result in the evaluation of the patient by the hematologist. The signs indicated in Table 1–1 may reflect a primary or secondary hematologic problem. For example, immature granulocytes in the blood may be signs of myeloid diseases such as myelogenous leukemia, or, depending on the frequency of these cells and the level of immaturity, the dislodgment of cells resulting from marrow metastases of a carcinoma. Nucleated red cells in the blood may reflect the breakdown in the marrow–blood interface seen in primary myelofibrosis or the hypoxia of congestive heart failure. Certain disorders have a propensity for secondary hematologic abnormalities; kidney, liver, and chronic inflammatory diseases are prominent among such abnormalities. Chronic alcoholism, nutritional fetishes, and the use of certain medications may be causal factors in blood cell or coagulation protein disorders. Pregnant women and persons of older age are prone to certain hematologic disorders: anemia, thrombocytopenia, or intravascular coagulation in the former case, and hematologic malignancies, pernicious anemia, and clonal hematopoiesis with mild cytopenias in the latter. The history and physical examination can provide vital clues to the possible diagnosis and also to the rationale choice of laboratory tests.

THE HISTORY

In today’s technology- and procedure-driven medical environment, the importance of carefully gathering information from patient inquiry and examination is at risk of losing its primacy. The history (and physical examination) remains the vital starting point for the evaluation of any clinical problem.1–3

GENERAL SYMPTOMS AND SIGNS

Performance status (PS) is used to establish semiquantitatively the extent of a patient’s disability. This status is important in evaluating patient comparability in clinical trials, in determining the likely tolerance to cytotoxic therapy, and in evaluating the effects of therapy. Table 1–2 presents well-founded criteria for measuring PS for adults (Karnofsky Score) and children (Lansky Score).4,5 An abbreviated version, as proposed by the Eastern Cooperative Oncology Group (Table 1–3), sometimes is used.6

Weight loss is a frequent accompaniment of many serious diseases, including primary hematologic malignancies, but it is not a prominent accompaniment of most hematologic diseases. Many “wasting” diseases, such as disseminated carcinoma and tuberculosis, cause anemia, and pronounced emaciation should suggest one of these diseases rather than anemia as the primary disorder.

Fever is a common early manifestation of the aggressive lymphomas or acute leukemias as a result of pyrogenic cytokines (eg, interleukin [IL]-1, IL-6, and IL-8) released as a reflection of the disease itself. After chemotherapy-induced cytopenias or in the face of accompanying immunodeficiency, infection is usually the cause of fever. In patients with “fever of unknown origin,” lymphoma, particularly Hodgkin lymphoma, should be considered. Occasionally, primary myelofibrosis, acute leukemia, advanced myelodysplastic syndrome, and other lymphomas may also cause fever. In rare patients with severe pernicious anemia or hemolytic anemia, fever may be present. Pel-Ebstein fever is a prolonged cyclic fever, first associated with Hodgkin lymphoma (it occurs rarely), but may occur, also, in some infections (cytomegalovirus or Mycobacterium tuberculosis infection in an immunocompromised host). Chills may accompany severe hemolytic processes and the bacteremia that may complicate the immunocompromised or neutropenic

TABLE 1–1. Findings That May Lead to a Hematology Consultation

Decreased hemoglobin concentration (anemia)

Leukopenia or neutropenia

Thrombocytopenia

Pancytopenia

Increased hemoglobin concentration (polycythemia)

Leukocytosis or neutrophilia

Eosinophilia

Basophilia or mastocytosis

Monocytosis

Lymphocytosis

Thrombocytosis

Immature granulocytes or nucleated red cells in the blood

Lymphadenopathy

Splenomegaly

Hypergammaglobulinemia: monoclonal or polyclonal

Purpura

Exaggerated bleeding: spontaneous or trauma related

Prolonged partial thromboplastin or prothrombin coagulation times

Venous thromboembolism

Thrombophilia

Elevated serum ferritin level

Obstetrical adverse events (eg, recurrent fetal loss, stillbirth, and HELLP syndrome)

HELLP, hemolytic anemia, elevated liver enzymes, and low platelet count.

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

Karnofsky Scale (age ≥16 years)a

Percentage (%)

patient. Night sweats suggest the presence of low-grade fever and may occur in patients with lymphoma or leukemia.

Fatigue, malaise, and lassitude are such common accompaniments of both physical and emotional disorders that their evaluation is complex and often difficult. In patients with serious disease, these symptoms may be readily explained by fever, muscle wasting, or other associated findings. Patients with moderate or severe anemia frequently complain of fatigue, malaise, or lassitude and these symptoms may accompany the hematologic malignancies. Fatigue or lassitude may occur also with iron deficiency even in the absence of sufficient anemia to account for the symptom. In slowly developing chronic anemias, the patient may not recognize reduced exercise tolerance, or other loss of physical capabilities except in retrospect, after a remission or a cure has been induced by appropriate therapy. Anemia may be responsible for more symptoms than has been traditionally recognized, as suggested by the remarkable improvement in quality of life of most uremic patients treated with erythropoietin.

Weakness may accompany anemia or the wasting of malignant processes, in which cases it is manifest as a general loss of strength or reduced capacity for exercise. The weakness may be localized as a result of neurologic complications of hematologic disease. In vitamin B12 deficiency (eg, pernicious anemia), there may be weakness of the lower extremities, accompanied by numbness, tingling, and unsteadiness of gait. Peripheral neuropathy also occurs with monoclonal immunoglobulinemias. Weakness of one or more extremities in patients with leukemia, myeloma, or lymphoma may signify central or peripheral nervous system invasion or compression as a result of vertebral collapse, a paraneoplastic syndrome (eg, encephalitis), or brain or meningeal involvement. Myopathy secondary to malignancy occurs with the hematologic malignancies and is usually manifest as weakness of proximal muscle groups. Footdrop or wristdrop may occur in lead poisoning, amyloidosis, systemic autoimmune diseases, or as a complication of vincristine therapy. Paralysis may occur in acute intermittent porphyria.

Able to carry on normal activity; no special care is needed

100 Normal; no complaints, no evidence of disease

90 Able to carry on normal activity

80 Normal activity with effort

Unable to work; able to live at home, cares for most personal needs; a varying amount of assistance is needed

70 Cares for self; unable to carry on normal activity or to do active work

60 Requires occasional assistance but is able to care for most needs

50 Requires considerable assistance and frequent medical care

Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly

40 Disabled; requires special care and assistance

30 Severely disabled; hospitalization indicated, although death not imminent

20 Very sick, hospitalization necessary

10 Moribund, fatal process progressing rapidly

Lansky Scale (age ≥1 year and <16 years)b

Able to carry on normal activity; no special care is needed

Fully active

Minor restriction in physically strenuous play

Restricted in strenuous play, tires more easily, otherwise active

Mild to moderate restriction

Both greater restrictions of, and less time spent in active play

Ambulatory up to 50% of time, limited active play with assistance/supervision

Considerable assistance required for any active play; fully able to engage in quiet play

Moderate to severe restriction

Able to initiate quiet activities

Needs considerable assistance for quiet activity

Limited to very passive activity initiated by others

Completely disabled, not even passive play

0 Dead Dead

aThe Karnofsky Scale data is adapted with permission from V Mor, L Laliberte, JN Morris, and M Wiemann.4

bThe Lansky Scale data is adapted with permission from SB Lansky, MA List, LL Lansky, et al.5

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juhlavammissani! Silloin sitä sanotaan: se on uusi ritarillinen Mauno Gaabriel herra!

Molemmat tyttäret sipsuttivat vähän väliä ohitse huoneen läpi ja valaisivat häntä lampuillansa, ja joka kerran nousi hän seisoalleen ja kumarsi. Kun erakko kuitenkin jatkoi lukemistaan ja vähitellen näytti kokonaan unohtavan hänen läsnäolonsa, otti hän viimein reppunsa ja meni takaisin eteiskamariin.

— Alkaa pimetä, — sanoi hän palvelijattarelle, — ja olen niin väsynyt, etten enään jaksa pitää seuraa.

— Herralle olemme laittaneet vuoteen tänne vasemmalle suureen saliin. Se on ainoa lämmitetty huone.

Sali oli valkeaksi sivuttu ja pitkä ja siellä oli kolkkoja tuoliriviä ja pari karkeaa vetopöytää. Aivan oven vieressä oli vuode ja sen uutimet Hollannin palttinaa. Eukko sytytti neljä kynttilää jalustassa ja jätti hänet yksikseen.

Hän katseli palellen ympärilleen ja pani miekkansa pöydälle. Sitten aukaisi hän reppunsa. Kolme kynttilää hän sammutti ja niiden päälle ripusti hän pienen peruukin ja väliperuukin ja kähäräperuukin, mutta neljännellä katsoi hän sängyn alle ja ikkunakomeroihin ja pani sen sitten takaisin jalkaan.

— Julkeata joukkoa! — hymisi hän. — Kernaammin olisin jäänyt ulos hankeen, mutta kun kerran täällä ollaan, niin täytyy pysytellä valveilla ja tämän tästäkin käydä ikkunassa kuuntelemassa ja tähyämässä.

Hän koetti lukita ovea sisäpuolelta, mutta siinä ei ollut salpaa eikä avainta. Koetettuaan kauvan turhaan saada jaloistaan märkiä saappaita, joiden umpea ilma häntä vaivasi, otti hän ylleen yötakin ja heittäytyi saappaisillaan vuoteelle.

Väliin kuului villin hevosen kumeaa poljentaa ja korskumista ajoportista salin lattian alta, mutta hetken kuluttua tuli hiljaisempi olo ja hänestä alkoi tuntua, ettei kynttilä kylläksi valaissut, sillä kaikki nurkat ja loukot olivat pimeitä. Hän nosti nenälasiaan ja pinnisti näköään ja käänsi silmänsä joka puolelle, mutta makasi muuten aivan liikkumatta.

Silloin näki hän ovipielessä heti päänalus-uutimen takana pitkän, suoran lakeijan ruskeassa mustanauhaisessa takissa.

Kouristava kauhistus tarttui hänen kurkkuunsa, ja hänen silmiänsä pyörrytti, mutta hän ajatteli: hyvä jumala tahtoo vain minua koetella, koska uneksin arvomerkkejä ja aateliskirjoja.

Hiljaa ja melkein huomaamatta tarttui hän kiini kumpaankin sängynlaitaan masentaakseen omaa kauhistuvaa ruumistaan ja pisti sitten oikean säärensä uutimista ulos.

— Joonatani, — sanoi hän, — vedäppä saapas jalastani!

Lakeija irvisti niin että musta suu venyi korviin saakka, mutta ei liikkunut paikaltaan.

Ranskan Maunon hampaat kalisivat, mutta hän ei vetänyt säärtänsä takaisin.

— Joonatani, niinkö sinä palvelet aatelisväkeä?

Lakeija irvisti vielä rumemmin ja huiskutti halveksivasti ja kieltävästi kättään.

Nyt ymmärsi Ranskan Mauno, että lakeija näki läpi hänen valeensa ja katseli häntä niinkuin nousukasta ja aatelitonta, ja hänen kauhistuksensa kasvoi niin että hän ähkyi ja valitteli hiljaa, mutta säärtänsä piti hän yhä ulkona.

— Vedä saappaani, Joonatani!

Hänen äänensä oli nyt vain kuisketta.

Lakeija hieroi kupeitaan ja irvisti mutta seisoi alallaan ovipielessä.

Samassa hirnahti hevonen ajoportista pitkään ja kimakasti, ja etäältä lumituiskusta vastasi useita hevosia.

Ranskan Mauno hyppäsi ylös sängystään.

— Minä laiminlyön palvelukseni! — huusi hän. — Se on vihollinen!

Hän juoksi pöytään päin ottaakseen miekkansa, mutta hänen rinnallaan seurasi lakeija pitkillä askelilla ja tuijotti häntä silmiin.

Silloin lamautui hän jälleen ja pysähtyi. Sillä välin tarttui lakeija miekkaan toisella kädellään ja kurotti toisen kynttilänjalustan yli ja nosti kahdella sormellaan suuren kähäräperuukin ilmaan ja pudotti sen sitten niinkuin sammuttajan palavan kynttilän yli.

— Taivaan herra Jumala! — sopersi Ranskan Mauno. Harvoin olen ollut huoneessasi ja sen sijaan lellinyt ja leikitellyt kaikenlaisessa turhuudessa, mutta auta minua tänä ainoana hetkenä, etten

laiminlyö virkaani ja joudu häpeään. Sitten rankaise minua ijankaikkisesti.

Hirnumista kuului yhä lähempää ja lähempää ja polkien ja korskuen karkasi villiintynyt hevonen piilostaan.

Silloin koukisti Ranskan Mauno nyrkkinsä päänsä yli ja ryntäsi pimeässä lakeijan päälle.

— Sinä Belsebubin kyöpeli! — huusi hän.

Hän tempasi miekan itselleen ja huitoi joka puolelle pimeässä, ja tuolit kaatuivat maahan. Missään ei hän Joonataniin osannut, mutta lopuksi töytäsi hän käsillään seinään, ja ovi aukeni. Molemmat sisarukset tulivat sieltä lamppuineen ja suurisilmäisine kalpeine kasvoineen ja aivan aivinaisillaan ymmärtämättä siitä hävetä. He vain hivelivät toisiaan ja tuijottivat muukalaista, joka metelillään oli heidät herättänyt. Hän ei tällä kertaa joutunut heitä tervehtimään, mutta aukaisi ikkunan ja hyppäsi maahan. Yönutussaan ja miekka kädessä juoksi hän seinäviertä, ja takanaan kuuli hän käreän äänen ikkunasta, mutta ei tiennyt, oliko se ärmätin vaiko Joonatanin vai olivatko ne molemmat sama.

— Minä näin, että sinä olit narri, — huusi ääni, — suuri narri, verraton narri, ja minä tahdoin sinusta päästä. Mutta jos nyt ratsumiehet näkevät sinut ja tässä syntyy kahakka… taloni, kotini, pesäni muuttuu tuhkakasaksi ennen kukon laulua…

Taakseen katsomatta juoksi Ranskan Mauno metsään, ja koko ajan ajatteli hän: Nyt on upseerin valtakirja kysymyksessä! Ja sitten aateliskirja, aateliskirja!

Kuutamo paistoi lumituiskussa, ja hän näki puolalaisia keinuvine höyhentöyhtöineen vilahtavan ohitseen niinkuin varjoja. Kun he tulivat liian lähelle, heittäytyi hän pitkäkseen risukkoon tai asettui puunrungon taakse.

Viimein äkkäsi hän vanhan, lumen peittämän murroksen, ja hirsien takaa nousi sotamies ja kysyi kuiskaten:

— Wer da?

— Jumala kanssamme! Hyvä toveri! — vastasi Ranskan Mauno ja kapusi murroskolmioon. — Vihollinen on kimpussamme!

— Minä olen kauvan ollut kuulevinani kavion kopsetta, — sanoi Oxehufvud hiljaa. — Viisainta ehkä olisi juosta alas talolle ja miehittää se.

— Kapteeni, älkää käskekö minua tietä näyttämään! Minut otettiin siellä vastaan vieraaksi ja minä olen ritarismies ja annan ennen ampua kuoliaaksi itseni.

— Ja mitenkä teitä siellä kohdeltiin?

— Niinkuin ylhäisyyttä.

— Saammehan nähdä… Nyt se taitaa olla liian myöhäistä. Tähdätkää! Ampukaa!

Joukko puolalaisia laukkasi hevosineen esiin ja hyökkäsivät keihäineen hirsiä vastaan, mutta ensimmäinen rivilaukaus teki heille pystyt.

— Ohahoo! Ohahoo! — kaikui metsässä, ja ratsastavia varjoja ja pitkiä riviä jalkaväkeä keräytyi niin pitkältä kuin silmä näki. Hämärässä näyttivät ne mustilta viidakoilta, jotka liikkuivat tuulessa.

— Taidammepa saada hyvän saunan vihollisen kanssa, — sanoi Oxehufvud. — Meitä on kaksikymmentäviisi miestä ja ympärillämme on varmaan kolme täyttä pataljoonaa.

— Nyt on meitä ainoastaan neljäkolmatta, — vastasi Ranskan Mauno ja tempasi käteensä musketin kaatuneelta sotamieheltä.

— Nyt on meitä vain yhdeksäntoista, — sanoi Oxehufvud hetken kuluttua.

Luotia satoi murroskolmioon ja tappoi miehiä myötäänsä. Heti kun ratsumiehet peräytyivät, lakkasivat ruotsalaiset ampumasta, mutta kun hiljaisuus jälleen vietteli puolalaiset esille ja saattoi heidät luulemaan ettei ainoatakaan elävää sielua enää ollut murroksessa, saivat he heti vastaansa luotia ja miekkoja ja kiviä ja puukappaleita. Niin kesti vimmattua taistelua tunti tunnilta. Oxehufvud hiipi pitkin rytöä ja luki itsekseen:

— Kahdeksan, kymmenen, kolmetoista… nyt ei meitä ole enempää. Paha luku.

Hänkin oli ottanut musketin, ja polvillaan kaivoi hän ampumavaroja erään kaatuneen patruunalaukusta.

— Toveri! — sanoi hän nousematta pystyyn ja veti Ranskan Maunoa yönutusta. — Minä tein pahoin toverille päivällä kun oltiin suolla.

— Nyt on meitä vain seitsemän, — vastasi Ranskan Mauno ja latasi ja ampui. — Mutta pian olemmekin kestäneet kolme tuntia.

— Toveri ei ole ensimmäinen, joka on minulle näyttänyt, ettei ruotsalaisten aina pitäisi nauraa keikailukukoilleen. Nähkääs toverini, joskus sattuu tässä maailmassa, että se, joka alkaa korealla peruukilla, voi lopettaa korealla työllä.

— Nyt on meitä vain kaksi.

— Tuskin kahta, sillä minä olen jo saanut osani, — vastasi Oxehufvud ja vaipui takaisin hirsiä vastaan. — Tuskin kahta!

Ranskan Mauno seisoi nyt yksin kaatuneitten joukossa. Hän repi yltään yönuttunsa ja kääri muutamia riepuja vasemman käsivartensa ympäri, joka vuoti kovin verta. Myöskin liivinsä heitti hän pois, ja nenälasin pisti hän saapasvarteen. Sitten asettui hän muitten joukkoon ja niin syvälle oksien ja risujen alle kuin hän saattoi kömpiä.

Kun puolalaiset tulevalla kertaa laukkasivat hevosineen esille, oli siellä hiljaista.

He ajoivat hirsien yli hurjasti kiljuen, ja ryöstäminen alkoi, mutta kun he näkivät hänen verissään ja puoleksi riisuttuna jättivät he hänet makaamaan, ja aamun koitteessa läksivät he pois.

Nyt, ajatteli Ranskan Mauno, nyt on minulla upseerin valtakirja! Aateliskirja tulee sitten.

Hän konttasi esiin ryteiköstä, ja ylhäältä talon vierestä löysi hän hangesta peruukkinsa, jotka oli heitetty hänen jälkeensä ikkunasta.

Sen heittiö! — kuiskasi hän. — Se on kiitos siitä että pelastin hänen pesänsä.

Koko päivän kulki hän metsiä peruukit kainalossaan, ja vasta illalla myöhään huusivat ruotsalaisten leirin esivartijat häntä.

Telttoja ja risuvajoja oli tehty metsään ilman mitään suojaavia esivarustuksia. Vankkureilla tai raajojensa edessä istuivat vaimot eri kujassa ja tuutivat lapsiaan sylissään tai kuiskuttelivat sotamiestensä kanssa alakuloisesti ja hiljaa. Nuotioiden ympärillä tuprusivat liitupiiput arpisissa käsissä, Siellä kertoivat kornetti Bråkenhjelm ja peloton luutnantti Pistol seikkailujaan. Luutnantti Örbom antoi miesten sormillaan koettaa Klissovassa saatua luotia, joka vielä löytyi oikean korvan takana ja oli mennyt sisään vasemman silmän alta ja läpi koko pään. Pietari Adlerfelt, tanssimestari, valitti että viholliset yhä vielä niinkuin Väinäjoellakin ampuivat niin matalalta, että he lopuksi pilasivat hänen kauniit koipensa. Siellä ilveili sukkela Dumky ja piti vielä käsivarressaan sitä sukkanauhaa, jonka hän hovipoikana oli ottanut silesialaiselta herttuattarelta. Svante Horn, jota hänen uskollinen palvelijansa Lidbom siteli, mutisi, ettei hän koskaan voinut käydä päälle saamatta heti kasakanpiikkiä tai miekkaa ruumiiseensa, ja hänen edessään seisoi rehtevä harmaapää-ukko välskäri Teuffenweiser, joka yhtenään asetti nenälleen ja otti pois silmälasiaan ja aina pyysi piiskaryyppyä ennenkuin ryhtyi rikkaampia sairaita hoitamaan. Kaikki keskustelivat he sotamiehen kohtalosta, joka soi toisen harmaantua vaivoissa ja kunniassa luodin koskettamattakaan, mutta salli toisen elämänsä keväässä kaatua ensimmäisestä luodista. Ei mitään juomalauluja kaikunut, mutta kuningas antoi puutorven ja oboen iloisesti soida koko yön. Se oli sotaleiri, jonka hiljainen hälinä oli niinkuin kirkkaan metsäpuron solina kesäkasteisten lehtien alla.

Henkivartijat olivat vastoin kuninkaan tahtoa peittäneet hänen

telttansa olilla ja panneet olkien päälle turpeita, niin että se näytti sysihaudalta. Se ei seisonut leirin keskellä vaan kaikkein äärimmäisenä ja melkein pimeässä. Sisälle telttapatsaan viereen olivat he rakentaneet kivistä tulisijan ja kantoivat sinne vähän väliä hehkuvan kuuman kanuunanluodin. Pesuvati oli puhdasta hopeaa, ja pöydällä seisoi Aleksanteri Suuren elämänkertomuksen ja kultalyötteisen raamatun vieressä pieni hopeoitu kuva Pompekoirasta, joka oli kuollut, mutta tuolin ja telttasängyn vaaleansininen silkkipäällys oli jo kulunut ja tahrautunut. Keskellä sänkyä makasivat koirat Turkki ja Nuuskuri, mutta kuningas nukkui havusijalla maassa. Kalja oli loppunut, ja Hultman-lakeijalla ei ollut muuta tarita hänelle illalliseksi kuin pikarillinen sulanutta lunta ja kaksi teräskovaa korppua. Sitten oli hän levittänyt viitan hänen ylitseen ja pannut kudotun yölakin hänen päähänsä. Siinä nukkui nyt voittojensa kukkuloilla Ruotsin kuningas, ja hänen kapea päänsä oli kääntynyt viimeisen hehkuvan kuulan himmenevään hohteeseen päin. Kaukaan aikaan ei hän ollut lukenut sitä iltarukousta, jota hän muinoin tavaili kamarissaan, kun tuuli hohisi Karlbergin puiston lehmuksissa. Hänen jumalansa oli vähitellen muuttunut vanhan testamentin ukkosjumalaksi, kostavaksi Herraksi Seebaotiksi, jonka käskyt hän kuuli sielussaan tarvitsematta rukoilla, ja Taara ja Aasat ajoivat yömyrskyn jyryssä ympäri leiriä ja tervehtivät torvillaan nuorinta poikaansa maan päällä.

Silloin alkoivat koirat vainuta ja murista, ja puolikasvuinen Max Würtembergiläinen, Pikku Prinssi, tuli haltioissaan ja onnesta säteillen teltan suulle.

— Majesteetti, — huusi hän kirkkaalla lapsen äänellä, — herätkää, herätkää! Viisikolmatta smoolantilaista on ollut ulkona ottelemassa

vihollisen kanssa!

Hänen takanaan seisoi Ranskan Mauno nojaten urheaan kapteeni Schmiedebergiin, joka itse vielä kulki kainalosauvoilla kuormastolla tapahtuneen taistelun jälkeen, jolloin hän kahdentoista miehen kanssa oli taistellut kolmeasataa puolalaista vastaan.

Ranskan Mauno ei koskaan kantanut päätänsä ylpeämmin ja tyytyväisemmin, vaikka hän herposi väsymyksestä, mutta kun hän kuuli olevansa kuninkaan teltalla, pysähtyi hän arasti. Hän kumartui ja pesi kiiruusti veritahrat käsistään. Hatun ja väliperuukin ja pikkuperuukin heitti hän maahan, ja sääntöjä ajattelematta pani hän suuren kähäräperuukin päähänsä. Kun hän oli reilassa ojensi hän kätensä pitkin sivujaan ja astui teltan suulle ja kertoi ja sopersi ja hampaat tärisivät.

Kuningas, joka istui yhä havuvuoteella, kertoi sitten itse hitaasti ja tutkien joka sanan ettei menettäisi pienintäkään osaa seikkailusta.

Hän iloitsi niinkuin lapsi ihmeellistä satua kuullessaan. Viimein ojensi hän hänelle kätensä.

— Oxehufvud puhui oikein, — sanoi hän. — Herroilla on ollut kelpo löyly vihollisen kanssa. Koska se puolalainen ärmätti pilkalla pyysi saada lainaksi viittä louisdoria, tahdon minä, antaa kymmenen, ja herran pitää mennä takaisin heittämään rahat ikkunasta sisään.

Ranskan Mauno poistui takaperin teltan aukosta, ja Schmiedeberg otti häntä vyöltä kiini ja vei hänet uteliaina odottavain toverien piiriin. Siinä oli vänrikkejä ja luutnantteja ja kapteeneja, jotka olivat hänen ikäisiään, mutta jo nousseet arvossa ylemmäksi häntä.

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