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rd Edition
 3rd Edition

’
HARRISON S
TM

HEMATOLOGY AND
ONCOLOGY
 Derived from Harrison’s Principles of Internal Medicine, 19th Edition
Editors
DENNISL. KASPER, md
William Ellery Channing Pro essor o Medicine, Pro essor o
Microbiology and Immunobiology, Department o Microbiology
and Immunobiology, Harvard Medical School; Division o
In ectious Diseases, Brigham and Women’s Hospital
Boston, Massachusetts
STEPHENL. HAUSER, md
Robert A. Fishman Distinguished Pro essor and Chairman,
Department o Neurology, University o Cali ornia, San Francisco
San Francisco, Cali ornia
J. LARRYJAMESON, md, phd
Robert G. Dunlop Pro essor o Medicine;
Dean, Perelman School o Medicine at the University
o Pennsylvania; Executive Vice-President, University o
Pennsylvania or the Health System, Philadelphia, Pennsylvania
ANTHONYS. FAUCI, md
Chie , Laboratory o Immunoregulation; Director, National
Institute o Allergy and In ectious Diseases, National Institutes o
Health Bethesda, Maryland
DANL. LONGO, md
Pro essor o Medicine, Harvard Medical School; Senior Physician,
Brigham and Women’s Hospital; Deputy Editor, New England
Journal o Medicine, Boston, Massachusetts
JOSEPHLOSCALZO, md, phd
Hersey Pro essor o the T eory and Practice o Medicine, Harvard
Medical School; Chairman, Department o Medicine, and
Physician-in-Chie , Brigham and Women’s Hospital, Boston,
Massachusetts
 3rd Edition

’
HARRISON S
TM

HEMATOLOGY AND
ONCOLOGY
EDITOR
Dan L. Longo, MD
Pro essor o Medicine, Harvard Medical School; Senior Physician, Brigham and Women’s
Hospital; Deputy Editor, New England Journal o Medicine,
Boston, Massachusetts

CONTENTS

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 CONTENTS

Contributors viii 12 rans usion Biology and T erapy . . . . . . . . . . . . 146

Je ery S. Dzieczkowski, Kenneth C. Anderson
Pre ace xi

SECTION IV
SECTION I MYELOPROLIFERATIVE DISORDERS
THE CELLULAR BASIS OF HEMATOPOIESIS
13 Polycythemia Vera and Other
1 Hematopoietic Stem Cells . . . . . . . . . . . . . . . . . . . . . 2 Myeloproli erative Neoplasms . . . . . . . . . . . . . . . 158
David . Scadden, Dan L. Longo Jerry L. Spivak

SECTION II SECTION V
CARDINAL MANIFESTATIONS OF HEMATOLOGIC MALIGNANCIES
HEMATOLOGIC DISEASE 14 Acute Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . 168
2 Anemia and Polycythemia. . . . . . . . . . . . . . . . . . . . 10 Guido Marcucci, Clara D. Bloomf eld
John W. Adamson, Dan L. Longo 15 Chronic Myeloid Leukemia . . . . . . . . . . . . . . . . . . 181
3 Bleeding and T rombosis . . . . . . . . . . . . . . . . . . . . 22 Hagop Kantarjian, Jorge Cortes
Barbara A. Konkle 16 Malignancies o Lymphoid Cells . . . . . . . . . . . . . 193
4 Enlargement o Lymph Nodes and Spleen . . . . . . 32 Dan L. Longo
Patrick H. Henry, Dan L. Longo 17 Less Common Hematologic Malignancies . . . . . 216
5 Disorders o Granulocytes and Monocytes . . . . . . 41 Ayalew e eri, Dan L. Longo
Steven M. Holland, John I. Gallin 18 Plasma Cell Disorders . . . . . . . . . . . . . . . . . . . . . . 231
6 Atlas o Hematology and Analysis Nikhil C. Munshi, Dan L. Longo,
o Peripheral Blood Smears . . . . . . . . . . . . . . . . . . . 57 Kenneth C. Anderson
Dan L. Longo 19 Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
David C. Seldin, John L. Berk
SECTION III
ANEMIAS SECTION VI
DISORDERS OF HEMOSTASIS
7 Iron De ciency and Other
Hypoproli erative Anemias . . . . . . . . . . . . . . . . . . . 72 20 Disorders o Platelets and Vessel Wall. . . . . . . . . 254
John W. Adamson Barbara A. Konkle

8 Disorders o Hemoglobin . . . . . . . . . . . . . . . . . . . . 82 21 Coagulation Disorders . . . . . . . . . . . . . . . . . . . . . . 265

Edward J. Benz, Jr. Valder R. Arruda, Katherine A. High

9 Megaloblastic Anemias . . . . . . . . . . . . . . . . . . . . . . 96 22 Arterial and Venous T rombosis . . . . . . . . . . . . . 278

A. Victor Ho rand Jane E. Freedman, Joseph Loscalzo

10 Hemolytic Anemias and Anemia 23 Deep Venous T rombosis and

Due to Acute Blood Loss . . . . . . . . . . . . . . . . . . . . 111 Pulmonary T romboembolism. . . . . . . . . . . . . . . 285
Lucio Luzzatto Samuel Z. Goldhaber

11 Bone Marrow Failure Syndromes Including 24 Antiplatelet, Anticoagulant,

Aplastic Anemia and Myelodysplasia . . . . . . . . . 131 and Fibrinolytic Drugs . . . . . . . . . . . . . . . . . . . . . . 294
Neal S. Young Je rey I. Weitz
v
 vi
vi Contents

SECTION VII 39 Upper Gastrointestinal ract Cancers . . . . . . . . . 542

BIOLOGY OF CANCER Robert J. Mayer
25 Cancer Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 40 Lower Gastrointestinal Cancers . . . . . . . . . . . . . . 551
Pat J. Morin, Je rey M. rent, Robert J. Mayer
Francis S. Collins, Bert Vogelstein
41 umors o the Liver and Biliary ree. . . . . . . . . . 561
26 Cancer Cell Biology . . . . . . . . . . . . . . . . . . . . . . . . 333 Brian I. Carr
Je rey W. Clark, Dan L. Longo
42 Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 576
Elizabeth Smyth, David Cunningham
SECTION VIII
PRINCIPLES OF CANCER PREVENTION 43 Bladder and Renal Cell Carcinomas. . . . . . . . . . . 582
Howard I. Scher, Jonathan E. Rosenberg,
AND TREATMENT
Robert J. Motzer
27 Approach to the Patient with Cancer. . . . . . . . . . 360
44 Benign and Malignant Diseases
Dan L. Longo
o the Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
28 Prevention and Early Detection o Cancer . . . . . 373 Howard I. Scher, James A. Eastham
Jenni er M. Croswell, Otis W. Brawley,
45 esticular Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 601
Barnett S. Kramer
Robert J. Motzer, Darren R. Feldman,
29 Principles o Cancer reatment . . . . . . . . . . . . . . 386 George J. Bosl
Edward A. Sausville, Dan L. Longo
46 Gynecologic Malignancies . . . . . . . . . . . . . . . . . . . 607
30 In ections in Patients with Cancer . . . . . . . . . . . . 422 Michael V. Seiden
Robert W. Finberg
47 So issue and Bone Sarcomas
31 Hematopoietic Cell ransplantation . . . . . . . . . . 436 and Bone Metastases. . . . . . . . . . . . . . . . . . . . . . . . 616
Frederick R. Appelbaum Shreyaskumar R. Patel, Robert S. Benjamin

32 Neoplasia During Pregnancy . . . . . . . . . . . . . . . . 446 48 Primary and Metastatic umors

Michael F. Greene, Dan L. Longo o the Nervous System . . . . . . . . . . . . . . . . . . . . . . 623
Lisa M. DeAngelis, Patrick Y. Wen
33 Palliative and End-o -Li e Care. . . . . . . . . . . . . . . 454
Ezekiel J. Emanuel 49 Carcinoma o Unknown Primary. . . . . . . . . . . . . 638
Gauri R. Varadhachary, James L. Abbruzzese
SECTION IX
NEOPLASTIC DISORDERS SECTION X
ENDOCRINE NEOPLASIA
34 Cancer o the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . 480
Walter J. Urba, Brendan D. Curti 50 T yroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
J. Larry Jameson, Susan J. Mandel, Anthony P.
35 Head and Neck Cancer . . . . . . . . . . . . . . . . . . . . . 494 Weetman
Everett E. Vokes
51 Endocrine umors o the Gastrointestinal ract
36 Neoplasms o the Lung. . . . . . . . . . . . . . . . . . . . . . 500 and Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
Leora Horn , Christine M. Lovly , Robert . Jensen
David H. Johnson
52 Multiple Endocrine Neoplasia . . . . . . . . . . . . . . . 685
37 T ymoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526 Rajesh V. T akker
Dan L. Longo
53 Pheochromocytoma and
38 Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529 Adrenocortical Carcinoma . . . . . . . . . . . . . . . . . . 700
Marc E. Lippman Hartmut P. H. Neumann
 Contents vii

SECTION XI SECTION XII

REMOTE EFFECTS OF CANCER ONCOLOGIC EMERGENCIES AND LATE
EFFECTS AND COMPLICATIONS OF CANCER
54 Paraneoplastic Syndromes:
Endocrinologic/Hematologic . . . . . . . . . . . . . . . . 712
AND ITS TREATMENT
J. Larry Jameson, Dan L. Longo 56 Oncologic Emergencies . . . . . . . . . . . . . . . . . . . . . 732
Rasim Gucalp, Janice P. Dutcher
55 Paraneoplastic Neurologic Syndromes
and Autoimmune Encephalitis . . . . . . . . . . . . . . . 721 57 Late Consequences o Cancer
Josep Dalmau, Myrna R. Rosen eld and Its reatment . . . . . . . . . . . . . . . . . . . . . . . . . . 750
Carl E. Freter, Dan L. Longo
Review and Sel -Assessment . . . . . . . . . . . . . . . . . 757
Charles M. Wiener, Cynthia D. Brown,
Brian Houston
Index 793
 CONTRIBUTORS
Numbers in brackets re er to the chapter(s) written or co-written by the contributor.
James L Abbruzzese, MD
Chie , Division o Medical Oncology, Department o Medicine;
Associate Director, Clinical Research, Duke Cancer Institute,
Durham, North Carolina [49]
John W Adamson, MD
Clinical Pro essor, Division o Hematology/Oncology, Department
o Medicine, University o Cali ornia at San Diego, San Diego,
Cali ornia [2, 7]
Kenneth C Anderson, MD
Kra Family Pro essor o Medicine, Harvard Medical School; Chie ,
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer
Institute, Boston, Massachusetts [12, 18]
Frederick R Appelbaum, MD
Director, Division o Clinical Research, Fred Hutchinson Cancer
Research Center, Seattle, Washington [31]
Valder R Arruda, MD, PhD
Associate Pro essor, Division o Hematology, Department
o Pediatrics, Perelman School o Medicine, University o
Pennsylvania, Philadelphia, Pennsylvania [21]
Robert S Benjamin, MD
P. H. and Faye E. Robinson Distinguished Pro essor o Medicine,
Department o Sarcoma Medical Oncology, T e University o exas
M.D. Anderson Cancer Center, Houston, exas [47]
Edward J Benz, Jr , MD
Richard and Susan Smith Pro essor o Medicine; Pro essor o
Genetics, Harvard Medical School; President and CEO,
Dana-Farber Cancer Institute; Director and Principal Investigator,
Dana-Farber/Harvard Cancer Center; Boston, Massachusetts [8]
John L Berk, MD
Associate Pro essor o Medicine, Boston University School o
Medicine; Clinical Director, Amyloidosis Center, Boston Medical
Center, Boston, Massachusetts [19]
Clara D Bloom eld, MD
Distinguished University Pro essor; William G. Pace, III Pro essor
o Cancer Research; Cancer Scholar and Senior Advisor, T e Ohio
State University Comprehensive Cancer Center; Arthur G. James
Cancer Hospital and Richard J. Solove Research Institute,
Columbus, Ohio [14]
George J Bosl, MD
Pro essor o Medicine, Weill Cornell Medical College; Chair,
Department o Medicine; Patrick M. Byrne Chair in Clinical
Oncology, Memorial Sloan-Kettering Cancer Center, New York,
New York [45]
Otis W Brawley, MD, FACP
Pro essor o Hematology, Medical Oncology, Medicine and
Epidemiology, Emory University; Chie Medical and Scienti c
O cer, American Cancer Society, Atlanta, Georgia [28]
Cynthia D Brown, MD
Associate Pro essor o Clinical Medicine, Division o Pulmonary,
Critical Care, Sleep and Occupational Medicine Indiana University,
Indianapolis, Indiana [Review and Sel -Assessment]
ix
Brian I Carr, MD, PhD, FRCP
IRCCS de Bellis National Center or GI Diseases, Castellana Grotte,
BA, Italy [41]
Je rey W Clark, MD
Associate Pro essor o Medicine, Harvard Medical School; Medical
Director, Clinical rials Core, Dana-Farber Harvard Cancer Center;
Massachusetts General Hospital, Boston, Massachusetts [26]
Francis S Collins, MD, PhD
Director, National Institutes o Health, Bethesda, Maryland [25]
Jorge Cortes, MD
D. B. Lane Cancer Research Distinguished Pro essor or Leukemia
Research; Deputy Chairman; Section Chie o AML and CML,
T e University o exas M.D. Anderson Cancer Center, Houston,
exas [15]
Jenni er M Croswell, MD, MPH
Medical O cer, Center or Oncology Prevention rials Research
Group, Division o Cancer Prevention, National Cancer Institute,
Bethesda, Maryland [28]
David Cunningham, MD, MB, ChB, FRCP
Pro essor, Head o Gastrointestinal/Lymphoma Unit; Director o
Clinical Research, Royal Marsden NHS rust, London, United
Kingdom [42]
Brendan D Curti, MD
Director, Biotherapy Program, Robert W. Franz Cancer
Research Center, Providence Portland Medical Center, Portland,
Oregon [34]
Josep Dalmau, MD, PhD
ICREA Pro essor, Institut d’Investigació Biomèdica August
Pi i Sunyer, University o Barcelona, Barcelona, Spain; Adjunct
Pro essor, University o Pennsylvania, Philadelphia,
Pennsylvania [55]
Lisa M DeAngelis, MD
Pro essor o Neurology, Weill Cornell Medical College; Chair,
Department o Neurology, Memorial Sloan Kettering Cancer
Center, New York, New York [48]
Janice P Dutcher, MD
Associate Director, Cancer Research Foundation o New York,
Chappaqua, New York; Former Pro essor, New York Medical Col-
lege, Valhalla, New York [56]
Je rey S Dzieczkowski, MD
Physician, St. Alphonsus Regional Medical Center; Medical Direc-
tor, Coagulation Clinic, Saint Alphonsus Medical Group, Interna-
tional Medicine and ravel Medicine, Boise, Idaho [12]
James A Eastham, MD
Chie , Urology Service, Florence and T eodore Baumritter/Enid
Ancell Chair o Urologic Oncology, Department o Surgery, Sidney
Kimmel Center or Prostate and Urologic Cancers, Memorial Sloan
Kettering Cancer Center, New York, New York [44]
 x Contributors
Ezekiel J Emanuel, MD, PhD
Chair, Department o Medical Ethics and Health Policy, Levy
University Pro essor, Perelman School o Medicine and Wharton
School, University o Pennsylvania, Philadelphia, Pennsylvania [33]
Darren R Feldman, MD
Associate Pro essor in Medicine, Weill Cornell Medical Center;
Assistant Attending, Genitourinary Oncology Service, Memorial
Sloan-Kettering Cancer Center, New York, New York [45]
Robert W Finberg, MD
Chair, Department o Medicine, University o Massachusetts
Medical School, Worcester, Massachusetts [30]
Jane E Freedman, MD
Pro essor o Medicine, University o Massachusetts Medical School,
Worcester, Massachusetts [22]
Carl E Freter, MD, PhD, FACP
Pro essor o Medicine; Director, Division o Hematology and
Oncology; Associate Director, Cancer Center, Saint Louis
University, St. Louis, Missouri [56]
John I Gallin, MD
Director, Clinical Center, National Institutes o Health, Bethesda,
Maryland [5]
Samuel Z Goldhaber, MD
Pro essor o Medicine, Harvard Medical School; Director,
T rombosis Research Group, Brigham and Women’s Hospital,
Boston, Massachusetts [23]
Michael F Greene, MD
Pro essor o Obstetrics, Gynecology and Reproductive Biology,
Harvard Medical School; Vincent Department o Obstetrics and
Gynecology, Massachusetts General Hospital, Boston,
Massachusetts [32]
Rasim Gucalp, MD
Pro essor o Clinical Medicine, Albert Einstein College o Medicine;
Associate Chairman or Educational Programs, Department o
Oncology; Director, Hematology/Oncology Fellowship, Monte ore
Medical Center, Bronx, New York [56]
Patrick H Henry, MD
Clinical Adjunct Pro essor o Medicine, University o Iowa, Iowa
City, Iowa [4]
Katherine A High, MD
William H. Bennett Pro essor o Pediatrics, Perelman School
o Medicine, University o Pennsylvania; Investigator, Howard
Hughes Medical Institute, T e Children’s Hospital o Philadelphia,
Philadelphia, Pennsylvania [21]
A Victor Hof rand, DM
Emeritus Pro essor o Haematology, University College, London;
Honorary Consultant Haematologist, Royal Free Hospital, London,
United Kingdom [9]
Steven M Holland, MD
Chie , Laboratory o Clinical In ectious Diseases, National Institute
o Allergy and In ectious Diseases, National Institutes o Health,
Bethesda, Maryland [5]
Leora Horn, MD, MSc
Assistant Pro essor, Division o Hematology and Medical
Oncology, Vanderbilt University School o Medicine, Nashville,
ennessee [36]
Brian Houston, MD
Division o Cardiology, Department o Medicine, Johns Hopkins
Hospital, Baltimore, Maryland [Review and Sel -Assessment]
J Larry Jameson, MD, PhD
Robert G. Dunlop Pro essor o Medicine; Dean, Perelman School
o Medicine at the University o Pennsylvania; Executive
Vice President, University o Pennsylvania or the Health System,
Philadelphia, Pennsylvania [50, 54]
Robert Jensen, MD
Chie , Cell Biology Section, National Institutes o Diabetes,
Digestive and Kidney Diseases, National Institutes o Health,
Bethesda, Maryland [51]
David H Johnson, MD
Donald W. Seldin Distinguished Chair in Internal Medicine;
Pro essor and Chairman, Department o Internal Medicine,
University o exas Southwestern School o Medicine, Dallas,
exas [36]
Hagop Kantarjian, MD
Chairman, Leukemia Department; Pro essor o Leukemia,
T e University o exas M.D. Anderson Cancer Center, Houston,
exas [15]
Barbara A Konkle, MD
Pro essor o Medicine, Hematology, University o Washington;
Director, ranslational Research, Puget Sound Blood Center,
Seattle, Washington [3, 20]
Barnett S Kramer, MD, MPH, FACP
Director, Division o Cancer Prevention, National Cancer Institute,
Bethesda, Maryland [28]
Marc E Lippman, MD, MACP, FRCP
Kathleen and Stanley Glaser Pro essor, Department o Medicine,
Deputy Director, Sylvester Comprehensive Cancer Center,
University o Miami Miller School o Medicine, Miami, Florida [38]
Dan L Longo, MD
Pro essor o Medicine, Harvard Medical School; Senior Physician,
Brigham and Women’s Hospital; Deputy Editor, New England
Journal o Medicine, Boston, Massachusetts [1, 2, 4, 6, 16-18, 26, 27,
29, 32, 37, 53, 54, 57]
Joseph Loscalzo, MD, PhD
Hersey Pro essor o the T eory and Practice o Medicine, Harvard
Medical School; Chairman, Department o Medicine; Physician-in-
Chie , Brigham and Women’s Hospital, Boston, Massachusetts [22]
Christine M Lovly, MD, PhD
Academic, Vanderbilt Ingram Cancer Center, Vanderbilt University
School o Medicine, Nashville, ennessee [36]
Lucio Luzzatto, MD, FRCP, FRCPath
Pro essor o Hematology, University o Genova, Genova; Scienti c
Director, Istituto oscano umori, Florence, Italy [10]
Susan J Mandel, MD, MPH
Pro essor o Medicine; Associate Chie , Division o Endocrinology,
Diabetes and Metabolism, Perelman School o Medicine, University
o Pennsylvania, Philadelphia, Pennsylvania [50]
Guido Marcucci, MD
Pro essor o Medicine; John B. and Jane . McCoy Chair in
Cancer Research; Associate Director o ranslational Research,
Comprehensive Cancer Center, T e Ohio State University College
o Medicine, Columbus, Ohio [14]
 Contributors
Robert J Mayer, MD
Faculty Vice President or Academic A airs, Dana-Farber Cancer
Institute; Stephen B. Kay Family Pro essor o Medicine, Harvard
Medical School, Boston, Massachusetts [39, 40]
Pat J Morin, PhD
Senior Director, Scienti c Review and Grants Administration,
American Association or Cancer Research, Philadelphia,
Pennsylvania [25]
Robert J Motzer, MD
Pro essor o Medicine, Joan and San ord Weill College o Medicine
o Cornell University D. Attending Physician, Genitourinary On-
cology Service, Memorial Sloan-Kettering Cancer Center,
New York, New York [43, 45]
Nikhil C Munshi, MD
Pro essor o Medicine, Harvard Medical School; Boston VA
Healthcare System; Director o Basic and Correlative Sciences;
Associate Director, Jerome Lipper Myeloma Center, Dana-Farber
Cancer Institute, Boston, Massachusetts [18]
Hartmut P H Neumann, MD
Universitaet Freiburg, Medizinische Universitaetsklinik,
Freiburg im Breisgau, Germany [53]
Shreyaskumar R Patel, MD
Robert R. Herring Distinguished Pro essor o Medicine; Center
Medical Director, Sarcoma Center, T e University o exas M.D.
Anderson Cancer Center, Houston, exas [47]
Jonathan E Rosenberg, MD
Associate Attending; Section Chie , Non-Prostate Program,
Division o Solid umor Oncology, Department o Medicine,
Memorial Sloan-Kettering Cancer Center, New York,
New York [43]
Myrna R Rosen eld, MD, PhD
Department o Neurology, Hospital Clínic/IDIBAPS, Barcelona,
Spain [55]
Edward A Sausville, MD, PhD
Pro essor o Medicine, University o Maryland School o Medicine;
Associate Director or Clinical Research, Marlene and Stewart
Greenbaum Cancer Center, Baltimore, Maryland [29]
David Scadden, MD
Gerald and Darlene Pro essor o Medicine; Co-Chair, Harvard Stem
Cell Institute; Co-chair, Department o Stem Cell and Regenerative
Biology, Harvard Medical School; Director, Center or Regenerative
Medicine; Chie , Hematologic Malignancies, Cancer Center,
Massachusetts General Hospital, Boston, Massachusetts [1]
Howard I Scher, MD
Pro essor o Medicine, Joan and San ord Weill College o Medicine
o Cornell University; D. Wayne Calloway Chair in Urologic
Oncology; Attending Physician and Chie , Genitourinary Oncology
Service, Department o Medicine, Memorial Sloan-Kettering Cancer
Center, New York, New York [43, 44]
Michael V Seiden, MD, PhD
Chie Medical O cer, McKesson Specialty Health, T e Woodlands,
exas [46]
David C Seldin, MD, PhD
Pro essor, Departments o Medicine and Microbiology; Chie ,
Section o Hematology-Oncology; Director, Amyloidosis Center,
Boston University School o Medicine; Boston Medical Center,
Boston, Massachusetts [19]
xi
Elizabeth Smyth, MB BAO, MSc
Department o Gastrointestinal Oncology, Royal Marsden NHS
Foundation rust, London and Sutton, United Kingdom [42]
Jerry L Spivak, MD
Pro essor o Medicine and Oncology, Hematology Division,
Johns Hopkins University School o Medicine, Baltimore,
Maryland [13]
Ayalew e eri, MD
Pro essor o Medicine and Hematology, Mayo Clinic, Rochester,
Minnesota [17]
Rajesh V T akker, MD, FMedSci, FR
May Pro essor o Medicine, Academic Endocrine Unit, University
o Ox ord; O.C.D.E.M., Churchill Hospital, Headington, Ox ord,
United Kingdom [52]
Je rey M rent, PhD, FACMG
President and Research Director, ranslational Genomics Research
Institute, Phoenix, Arizona; Van Andel Research Institute, Grand
Rapids, Michigan [25]
Walter J Urba, MD, PhD
Director o Research, Earle A. Chiles Research Institute, Providence
Cancer Center, Portland, Oregon [34]
Gauri R Varadhachary, MD
Pro essor, Department o Gastrointestinal Medical Oncology,
T e University o exas M.D. Anderson Cancer Center, Houston,
exas [49]
Bert Vogelstein, MD
Investigator, Howard Hughes Medical Institute; Director, Ludwig
Center at the Sidney Kimmel Comprehensive Cancer Center;
Clayton Pro essor o Oncology and Pathology; Johns Hopkins
Medical Institutions, Baltimore, Maryland [25]
Everett E Vokes, MD
John E. Ultmann Pro essor; Chairman, Department o Medicine;
Physician-in-Chie , University o Chicago Medical Center, Chicago,
Illinois [35]
Anthony P Weetman, MD, DSc
University o She eld, School o Medicine She eld, United
Kingdom [50]
Je rey I Weitz, MD, FRCP(C), FACP
Pro essor o Medicine and Biochemistry, McMaster University;
Executive Director, T rombosis and Atherosclerosis Research
Institute, Hamilton, Ontario, Canada [24]
Patrick Y Wen, MD
Pro essor o Neurology, Harvard Medical School; Director,
Center or Neuro-Oncology, Dana-Farber Cancer Institute;
Director, Division o Neuro-Oncology, Department o Neurology,
Brigham and Women’s Hospital; Dana-Farber Cancer Institute,
Boston, Massachusetts [48]
Charles M Wiener, MD
Vice President o Academic A airs, Johns Hopkins Medicine
International, Pro essor o Medicine and Physiology, Johns Hopkins
School o Medicine, Baltimore, Maryland [Review and Sel -Assessment]
Neal S Young, MD
Chie , Hematology Branch, National Heart, Lung and Blood
Institute; Director, NIH Center or Human Immunology,
Autoimmunity and Inf ammation, National Institutes o Health,
Bethesda, Maryland [11]
 PREFACE
Harrison’s Principles o Internal Medicine has a long
and distinguished tradition in the eld o hematology.
Maxwell Wintrobe, whose work actually established
hematology as a distinct subspecialty o medicine, was
a ounding editor o the book and participated in the
rst seven editions, taking over or insley Harrison
as editor-in-chie on the sixth and seventh editions.
Wintrobe, born in 1901, began his study o blood in
earnest in 1927 as an assistant in medicine at ulane
University in New Orleans. He continued his studies
at Johns Hopkins rom 1930 to 1943 and moved to the
University o Utah in 1943, where he remained until his
death in 1986. He invented a variety o the measures that
are routinely used to characterize red blood cell abnor-
malities, including the hematocrit, the red cell indices,
and erythrocyte sedimentation rate, and de ned the nor-
mal and abnormal values or these parameters, among
many other important contributions in a 50-year career.
Oncology began as a subspecialty much later. It
came to li e as a speci c subdivision within hematol-
ogy. A subset o hematologists with a special interest
in hematologic malignancies began working with che-
motherapeutic agents to treat leukemia and lymphoma
in the mid-1950s and early 1960s. As new agents were
developed and the principles o clinical trial research
were developed, the body o knowledge o oncology
began to become larger and mainly independent rom
hematology. In ormed by the laboratory study o cancer
biology and an expansion in ocus beyond hematologic
neoplasms to tumors o all organ systems, oncology
developed as a separable discipline rom hematology.
T is separation was also ueled by the expansion o the
body o knowledge about clotting and its disorders,
which became a larger part o hematology.
In most academic medical centers, hematology and
oncology remain connected. However, conceptual dis-
tinctions between hematology and oncology have been
made. Di erences are rein orced by separate ellowship
training programs (although many joint training pro-
grams remain), separate board certi cation examina-
tions, separate pro essional organizations, and separate
textbooks describing separate bodies o knowledge. In
some academic medical centers, oncology is not merely
a separate subspecialty division in a Department o
Medicine but is an entirely distinct department in the
medical school with the same standing as the Depart-
ment o Medicine. Economic orces are also at work to
separate hematology and oncology.
Perhaps I am only ref ecting the biases o an old dog,
but I am unenthusiastic about the increasing ractionation
xiii
o medicine subspecialties. T ere are now invasive and
noninvasive cardiologists, gastroenterologists who do
and others who do not use endoscopes, and organ- or
individual disease- ocused subspecialists (diabetolo-
gists, thyroidologists) instead o organ system– ocused
subspecialists (endocrinologists). T is ractionation
has also begun within hematology and oncology. Some
oncologists specialize in a single type o cancer and divi-
sions o hematology have designated experts in clot-
ting. At a time when the body o knowledge that must
be mastered is increasing dramatically, the duration o
training has not been increased to accommodate the
additional learning that is necessary to become highly
skilled. Extraordinary attention has been ocused on
the hours that trainees work. Apparently, the admin-
istrators are more concerned about undocumented
adverse e ects o every third night call on trainees than
they are about the well-documented adverse e ects on
patients o requent hando s o patient responsibility
to multiple caregivers.
Despite the sub-sub-subspecialization that is
pervasive in modern medicine, students, trainees,
general internists, amily medicine physicians, phy-
sicians’ assistants, nurse practitioners, and special-
ists in nonmedicine specialties still require access to
in ormation in hematology and oncology that can
assist them in meeting the needs o their patients.
Given the paucity o single sources o integrated in or-
mation on hematology and oncology, the editors o
Harrison’s Principles o Internal Medicine decided to
pull together the chapters in the “mother book” related
to hematology and oncology and bind them together
in a subspecialty themed book called Harrison’s Hema-
tology and Oncology. T e rst edition o this book
appeared in 2010 and was based on the 17th edition
o Harrison’s Principles o Internal Medicine. A second
edition based on 18th edition o Harrison’s Principles
o Internal Medicine appeared in 2013. T is third edi-
tion is derived rom the 19th edition o Harrison’s
Principles o Internal Medicine. T e book contains 57
chapters organized into 12 sections: (I) T e Cellular
Basis o Hematopoiesis, (II) Cardinal Mani estations
o Hematologic Diseases, (III) Anemias, (IV) Myelo-
proli erative Disorders, (V) Hematologic Malignan-
cies, (VI) Disorders o Hemostasis, (VII) Biology o
Cancer, (VIII) Principles o Cancer Prevention and
reatment, (IX) Neoplastic Disorders, (X) Endocrine
Neoplasia, (XI) Remote E ects o Cancer, and (XII)
Oncologic Emergencies and Late E ects and Compli-
cations o Cancer and Its reatment.
 xiv
T e chapters have been written by physicians who
have made seminal contributions to the body o knowl-
edge in their areas o expertise. T e in ormation is
authoritative and as current as we can make it, given the
time requirements o producing books. Each contains
the relevant in ormation on the genetics, cell biology,
pathophysiology, and treatment o speci c disease enti-
ties. In addition, separate chapters on hematopoiesis,
cancer cell biology, and cancer prevention ref ect the
rapidly growing body o knowledge in these areas that
are the underpinning o our current concepts o diseases
in hematology and oncology. In addition to the actual
in ormation presented in the chapters, a section o test
questions and answers is provided to rein orce impor-
tant principles. A narrative explanation o what is wrong
with the wrong answers should be o urther value in the
preparation o the reader or board examinations.
Preface
T e bringing together o hematology and oncol-
ogy in a single text is unusual and we hope it is use ul.
Like many areas o medicine, the body o knowledge
relevant to the practice o hematology and oncology is
expanding rapidly. New discoveries with clinical impact
are being made at an astounding rate; nearly constant
e ort is required to try to keep pace. It is our hope that
this book is help ul to you in the struggle to master the
daunting volume o new ndings relevant to the care o
your patients.
We are extremely grate ul to Kim Davis and James
Shanahan at McGraw-Hill or their invaluable assistance
in the preparation o this book.
Dan L. Longo, MD
 NOTICE
Medicine is an ever-changing science. As new research and clinical expe-
rience broaden our knowledge, changes in treatment and drug therapy are
required. T e authors and the publisher o this work have checked with
sources believed to be reliable in their e orts to provide in ormation that is
complete and generally in accord with the standards accepted at the time o
publication. However, in view o the possibility o 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 o this work war-
rants that the in ormation contained herein is in every respect accurate or
complete, and they disclaim all responsibility or any errors or omissions or
or the results obtained rom use o the in ormation contained in this work.
Readers are encouraged to con rm the in ormation contained herein with
other sources. For example and in particular, readers are advised to check the
product in ormation sheet included in the package o each drug they plan to
administer to be certain that the in ormation contained in this work is accu-
rate and that changes have not been made in the recommended dose or in the
contraindications or administration. T is recommendation is o particular
importance in connection with new or in requently used drugs.

Review and sel -assessment questions and answers were taken rom Wiener CM,
Brown CD, Houston B (eds). Harrison’s Sel -Assessment and Board Review, 19th ed.
New York, McGraw-Hill, 2017, ISBN 978-1-259-64288-3.

T e global icons call greater attention to key epidemiologic and clinical di erences in the practice o medicine
throughout the world.

T e genetic icons identi y a clinical issue with an explicit genetic relationship.

xv
 SECTION I

THE CELLULAR BASIS

OF HEMATOPOIESIS
 CH AP TER 1
HEMATOPOIETIC STEM CELLS
David T. Sca d d e n
All o the cell types in the peripheral blood and some
cells in every tissue o the body are derived rom hema-
topoietic (hemo: blood; poiesis: creation) stem cells. I
the hematopoietic stem cell is damaged and can no lon-
ger unction (e.g., due to a nuclear accident), a person
would survive 2–4 weeks in the absence o extraordi-
nary support measures. With the clinical use o hema-
topoietic stem cells, tens o thousands o lives are saved
each year (Chap. 31). Stem cells produce hundreds o
billions o blood cells daily rom a stem cell pool that
is estimated to be only in the tens o thousands. How
stem cells do this, how they persist or many decades
despite the production demands, and how they may
be better used in clinical care are important issues in
medicine.
T e study o blood cell production has become a
paradigm or how other tissues may be organized and
regulated. Basic research in hematopoiesis includes de n-
ing stepwise molecular changes accompanying unc-
tional changes in maturing cells, aggregating cells into
unctional subgroups, and demonstrating hematopoi-
etic stem cell regulation by a specialized microenviron-
ment; these concepts are worked out in hematology,
but they o er models or other tissues. Moreover, these
concepts may not be restricted to normal tissue unc-
tion but extend to malignancy. Stem cells are rare cells
among a heterogeneous population o cell types, and
their behavior is assessed mainly in experimental ani-
mal models involving reconstitution o hematopoiesis.
T us, much o what we know about stem cells is impre-
cise and based on in erences rom genetically manipu-
lated animals.
CARDINAL FUNCTIO NS O F
HEMATO P O IETIC STEM CELLS
All stem cell types have two cardinal unctions: sel -
renewal and di erentiation (Fig. 1-1). Stem cells exist
2
■ Da n L. Lo n g o
to generate, maintain, and repair tissues. T ey unction
success ully i they can replace a wide variety o shorter-
lived mature cells over prolonged periods. T e process
o sel -renewal (see below) assures that a stem cell popu-
lation can be sustained over time. Without sel -renewal,
the stem cell pool would become exhausted and tissue
maintenance would not be possible. T e process o di -
erentiation leads to production o the e ectors o tissue
unction: mature cells. Without proper di erentiation,
the integrity o tissue unction would be compromised
and organ ailure or neoplasia would ensue.
In the blood, mature cells have variable average li e
spans, ranging rom 7 h or mature neutrophils to a ew
months or red blood cells to many years or memory
lymphocytes. However, the stem cell pool is the central,
durable source o all blood and immune cells, maintain-
ing a capacity to produce a broad range o cells rom
a single cell source, yet keeping itsel vigorous over
decades o li e. As an individual stem cell divides, it has
the capacity to accomplish one o three division out-
comes: two stem cells, two cells destined or di erentia-
tion, or one stem cell and one di erentiating cell. T e
ormer two outcomes are the result o symmetric cell
division, whereas the latter indicates a di erent outcome
or the two daughter cells—an event termed asymmetric
cell division. T e relative balance or these types o
outcomes may change during development and under
particular kinds o demands on the stem cell pool.
DEVELOPMENTAL BIOLOGY OF
HEMATOPOIETIC STEM CELLS
During development, blood cells are produced at di -
erent sites. Initially, the yolk sac provides oxygen-
carrying red blood cells, and then the placenta and
several sites o intraembryonic blood cell production
become involved. T ese intraembryonic sites engage
in sequential order, moving rom the genital ridge at a
site where the aorta, gonadal tissue, and mesonephros
 S te m ce ll
S e lf-re newa l Diffe re ntia tion
S te m ce ll
Diffe re ntia te d ce lls
FIGURE 1 -1
Sig n a t u re ch a ra ct e rist ics o t h e ste m ce ll. Stem cells have
two essential eatures: the capacity to di erentiate into a variety
o mature cell types and the capacity or sel -renewal. Intrinsic ac-
tors associated with sel -renewal include expression o Bmi-1, Gf -1,
PTEN, STAT5, Tel/Atv6, p21, p18, MCL-1, Mel-18, RAE28, and HoxB4.
Extrinsic signals or sel -renewal include Notch, Wnt, SHH, and
Tie2/Ang-1. Based mainly on murine studies, hematopoietic stem
cells express the ollowing cell sur ace molecules: CD34, Thy-1
(CD90), c-Kit receptor (CD117), CD133, CD164, and c-Mpl (CD110,
also known as the thrombopoietin receptor).
are emerging to the etal liver and then, in the sec-
ond trimester, to the bone marrow and spleen. As the
location o stem cells changes, the cells they produce
also change. T e yolk sac provides red cells expressing
embryonic hemoglobins while intraembryonic sites
o hematopoiesis generate red cells, platelets, and the
cells o innate immunity. T e production o the cells
o adaptive immunity occurs when the bone marrow is
colonized and the thymus orms. Stem cell proli eration
remains high, even in the bone marrow, until shortly
a er birth, when it appears to dramatically decline. T e
cells in the bone marrow are thought to arrive by the
bloodborne transit o cells rom the etal liver a er cal-
ci cation o the long bones has begun. T e presence o
stem cells in the circulation is not unique to a time win-
dow in development; however, hematopoietic stem cells
appear to circulate throughout li e. T e time that cells
spend reely circulating appears to be brie (measured
in minutes in the mouse), but the cells that do circulate
are unctional and can be used or transplantation. T e
number o stem cells that circulate can be increased in a
number o ways to acilitate harvest and trans er to the
same or a di erent host.
MOBILITY OF HEMATOPOIETIC STEM CELLS
Cells entering and exiting the bone marrow do so
through a series o molecular interactions. Circulating
stem cells (through CD162 and CD44) engage the lec-
tins (carbohydrate binding proteins) P- and E-selectin
on the endothelial sur ace to slow the movement o the 3
cells to a rolling phenotype. Stem cell integrins are then
activated and accomplish rm adhesion between the
stem cell and vessel wall, with a particularly important
C
H
role or stem cell VCAM-1 engaging endothelial VLA-4.
A
P
T
T e chemokine CXCL12 (SDF1) interacting with stem
E
R
cell CXCR4 receptors and ionic calcium interacting
1
with the calcium sensing receptor appear to be impor-
tant in the process o stem cells getting rom the circu-
lation to where they engra in the bone marrow. T is is
H
e
m
particularly true in the developmental move rom etal
a
t
liver to bone marrow.
o
p
o
However, the role or CXCR4 in adults appears to be
i
e
t
i
more related to retention o stem cells in the bone mar-
c
S
t
row rather than the process o getting them there. Inter-
e
m
rupting that retention process through either speci c
C
e
l
molecular blockers o the CXCR4/CXCL12 interaction,
l
s
cleavage o CXCL12, or downregulation o the CXCR4
receptor can all result in the release o stem cells into
the circulation. T is process is an increasingly impor-
tant aspect o recovering stem cells or therapeutic use
as it has permitted the harvesting process to be done
by leukapheresis rather than bone marrow punctures
in the operating room. Granulocyte colony-stimulating
actor and plerixa or, a macrocyclic compound that
can block CXCR4, are both used clinically to mobilize
marrow hematopoietic stem cells or transplant. Re n-
ing our knowledge o how stem cells get into and out
o the bone marrow may improve our ability to obtain
stem cells and make them more e cient at nding their
way to the speci c sites or blood cell production, the
so-called stem cell niche.
HEMATOPOIETIC STEM CELL
MICROENVIRONMENT
T e concept o a specialized microenvironment, or
stem cell niche, was rst proposed to explain why cells
derived rom the bone marrow o one animal could
be used in transplantation and again be ound in the
bone marrow o the recipient. T is niche is more than
just a housing site or stem cells, however. It is an ana-
tomic location where regulatory signals are provided
that allow the stem cells to thrive, to expand i needed,
and to provide varying amounts o descendant daughter
cells. In addition, unregulated growth o stem cells may
be problematic based on their undi erentiated state and
sel -renewal capacity. T us, the niche must also regulate
the number o stem cells produced. In this manner, the
niche has the dual unction o serving as a site o nur-
ture but imposing limits or stem cells: in e ect, acting
as both a nutritive and constraining home.
T e niche or blood stem cells changes with each o
the sites o blood production during development, but
or most o human li e it is located in the bone mar-
row. Within the bone marrow, the perivascular space
4 particularly in regions o trabecular bone serves as a kinase inhibitors, transcription actors like Bmi-1, or
niche. T e mesenchymal and endothelial cells o the microRNA-processing enzymes like Dicer, have little or
marrow microvessels produce kit ligand and CXCL12, di erent e ects on progenitor cells. Hematopoietic stem
both known to be important or hematopoietic stem cells have governing mechanisms that are distinct rom
S
E
cells. Other cell types, such as sympathetic neurons, the cells they generate.
C
T
I
nonmyelinating Schwann cells, macrophages, osteo-
O
N
clasts, and osteoblasts, have been shown to regulate stem
I
cells, but it is unclear whether their e ects are direct or HEMATOPOIETIC STEM CELL
indirect. Extracellular matrix proteins like osteopontin DIFFERENTIATION
also a ect stem cell unction. T e endosteal region is
T
h
Hematopoietic stem cells sit at the base o a branching hier-
e
particularly important or transplanted cells, suggesting
C
e
that there may be distinctive eatures o that region that archy o cells culminating in the many mature cell types
l
l
u
that compose the blood and immune system (Fig. 1-2).
l
a
are yet to be de ned that are important mediators o
r
B
stem cell engra ment. T e unctioning o the niche as T e maturation steps leading to terminally di erenti-
a
s
i
ated and unctional blood cells take place both as a
s
a supportive context or stem cells is o obvious impor-
o
f
tance or maintaining hematopoiesis and in transplan- consequence o intrinsic changes in gene expression
H
e
and niche-directed and cytokine-directed changes in
m
tation. An active area o study involves determining
a
the cells. Our knowledge o the details remains incom-
t
whether the niche is altered in disease and whether
o
p
plete. As stem cells mature to progenitors, precursors,
o
drugs can modi y niche unction to improve trans-
i
e
s
and, nally, mature e ector cells, they undergo a series
i
plantation or normal stem cell unction in hematologic
s
disease. o unctional changes. T ese include the obvious acqui-
sition o unctions de ning mature blood cells, such as
phagocytic capacity or hemoglobin synthesis. T ey also
include the progressive loss o plasticity (i.e., the ability
EXCESS CAPACITY OF HEMATOPOIETIC
to become other cell types). For example, the myeloid
STEM CELLS
progenitor can make all cells in the myeloid series but
In the absence o disease, one never runs out o hema- none in the lymphoid series. As common myeloid pro-
topoietic stem cells. Indeed, serial transplantation stud- genitors mature, they become precursors or either
ies in mice suggest that su cient stem cells are present monocytes and granulocytes or erythrocytes and mega-
to reconstitute several animals in succession, with karyocytes, but not both. Some amount o reversibil-
each animal having normal blood cell production. T e ity o this process may exist early in the di erentiation
act that allogeneic stem cell transplant recipients also cascade, but that is lost beyond a distinct stage in nor-
never run out o blood cells in their li e span, which can mal physiologic conditions. With genetic interventions,
extend or decades, argues that even the limiting num- however, blood cells, like other somatic cells, can be
bers o stem cells provided to them are su cient. How reprogrammed to become a variety o cell types.
stem cells respond to di erent conditions to increase or As cells di erentiate, they may also lose proli era-
decrease their mature cell production remains poorly tive capacity (Fig. 1-3). Mature granulocytes are inca-
understood. Clearly, negative eedback mechanisms pable o proli eration and only increase in number
a ect the level o production o most o the cells, lead- by increased production rom precursors. T e excep-
ing to the normal tightly regulated blood cell counts. tions to the rule are some resident macrophages, which
However, many o the regulatory mechanisms that gov- appear capable o proli eration, and lymphoid cells.
ern production o more mature progenitor cells do not Lymphoid cells retain the capacity to proli erate but
apply or apply di erently to stem cells. Similarly, most have linked their proli eration to the recognition o par-
o the molecules shown to be able to change the size ticular proteins or peptides by speci c antigen recep-
o the stem cell pool have little e ect on more mature tors on their sur ace. Like many tissues with short-lived
blood cells. For example, the growth actor erythropoi- mature cells such as the skin and intestine, blood cell
etin, which stimulates red blood cell production rom proli eration is largely accomplished by a more imma-
more mature precursor cells, has no e ect on stem ture progenitor population. In general, cells within the
cells. Similarly, granulocyte colony-stimulating ac- highly proli erative progenitor cell compartment are
tor drives the rapid proli eration o granulocyte pre- also relatively short-lived, making their way through
cursors but has little or no e ect on the cell cycling o the di erentiation process in a de ned molecular pro-
stem cells. Rather, it changes the location o stem cells gram involving the sequential activation o particular
by indirect means, altering molecules such as CXCL12 sets o genes. For any particular cell type, the di er-
that tether stem cells to their niche. Molecules shown to entiation program is di cult to speed up. T e time it
be important or altering the proli eration, sel -renewal, takes or hematopoietic progenitors to become mature
or survival o stem cells, such as cyclin-dependent cells is ~10–14 days in humans, evident clinically by the
 S te m Ce lls Pro g e nito r Ce lls Line ag e Co mmitte d Mature Ce lls 5
Pre c urs o rs
Aiolos,
LEF1, E2A, PAX-5, AML-1
Co mmo n EBF, PAX-5

C
B Ce ll

H
Lympho id IL4 T Ce ll

A
Pro g e nito r B Ce ll
Pro g e nito r

P
IKAROS,
IL7 Pro g e nito r E2A, NOTCH1,

T
NOTCH,CBF1

E
NOTCH1 GATA3 T Ce ll

R
IL2

1
IL7 IL7
NOTCH1
T/NK Ce ll Id2, Ets -1
IL7 NK Ce ll
Pro g e nito r IL15

H
IKAROS NK Ce ll

e
P U1 Pro g e nito r

m
Plas mac yto id

a
t
FLT-3 Liga nd De ndritic Ce ll

o
IL7

p
He ma topoie tic

o
i
s te m ce ll

e
t
cMyb

i
c
S
Re lB, ICS BP, ld2 Mo no c yto id

t
e
De ndritic Ce ll

m
Multipo te nt FLT-3 Liga nd

C
Pro g e nito r

e
Egn1, Myb

l
l
Mo no c yte

s
Hox, P bx1, M-CS F
Granulo c yte Mo no c yte
S CL, GATA2,
NOTCH Mo no c yte Pro g e nito r
Pro g e nito r Granulo c yte
S CF
C/EBP α
TP O
G-CS F
Bas o phil
GM-CS F IL3, S CF
Granulo c yte Mas t Ce ll
GATA1, FOG Pro g e nito r
Co mmo n C/EBP ε
NF-E2, S CL
Mye lo id Rbtn2
IL5 Eo s ino phil
Pro g e nito r Erythro c yte
IL3, S CF Pro g e nito r
TP O GATA1
RBCs
EP O EP O
Me g akaryo c yte Me g akaryo cyte
Erythro id Pro g e nito r Fli-1
Pro g e nito r TP O AML-1 Plate le ts
TP O

FIGURE 1 -2
Hie ra rch y o h e m a t o p o ie t ic d if e re n t ia t io n . Stem cells are
multipotent cells that are the source o all descendant cells and
have the capacity to provide either long-term (measured in years)
or short-term (measured in months) cell production. Progenitor
cells have a more limited spectrum o cells they can produce and
are generally a short-lived, highly proli erative population also
known as transient ampli ying cells. Precursor cells are cells com-
mitted to a single blood cell lineage but with a continued ability
to proli erate; they do not have all the eatures o a ully mature
cell. Mature cells are the terminally di erentiated product o
the di erentiation process and are the e ector cells o specif c
activities o the blood and immune system. Progress through
the pathways is mediated by alterations in gene expression. The
regulation o the di erentiation by soluble actors and cell-cell
communications within the bone marrow niche are still being
def ned. The transcription actors that characterize particular cell
transitions are illustrated on the arrows; the soluble actors that
contribute to the di erentiation process are in blue. This picture
is a simplif cation o the process. Active research is revealing mul-
tiple discrete cell types in the maturation o B cells and T cells
and has identif ed cells that are biased toward one lineage or
another (rather than uncommitted) in their di erentiation. EPO,
erythropoietin; RBC, red blood cell; SCF, stem cell actor; TPO,
thrombopoietin.

interval between cytotoxic chemotherapy and blood
count recovery in patients.
Although hematopoietic stem cells are generally
thought to have the capacity to orm all cells o the
blood, it is becoming clear that individual stem cells
may not be equal in their di erentiation potential. T at
is, some stem cells are “biased” to become mature cells
o a particular type. In addition, the general concept
o cells having a binary choice o lymphoid or myeloid
di erentiation is not entirely accurate. A cell population
with limited myeloid (monocyte and granulocyte) and
lymphoid potential is now added to the commitment
steps stem cells may undergo.
SELF-RENEWAL
T e hematopoietic stem cell must balance its three poten-
tial ates: apoptosis, sel -renewal, and di erentiation.
6 stem cell cycling and capacity to reconstitute hema-
S te m P roge nitor P re curs or Ma ture topoiesis in adoptive hosts, making them similar to
younger animals. Mature cell numbers are una ected.
T ere ore, molecular events governing the speci c
S
E
Diffe re ntia tion s ta te
unctions o stem cells are being gradually made clear
C
T
I
and o er the potential o new approaches to changing
O
More Le s s
N
stem cell unction or therapy. One critical stem cell
I
S e lf-re ne wa l a bility
unction that remains poorly de ned is the molecular
regulation o sel -renewal.
For medicine, sel -renewal is perhaps the most
T
h
P rolife ra tion a ctivity
e
important unction o stem cells because it is critical
C
e
in regulating the number o stem cells. Stem cell num-
l
l
u
Lymphoid
l
a
e xce ption ber is a key limiting parameter or both autologous and
r
B
(me mory B
allogeneic stem cell transplantation. Were we to have
a
s
a nd T ce lls )
i
s
the ability to use ewer stem cells or expand limited
o
f
numbers o stem cells ex vivo, it might be possible to
H
e
m
FIGURE 1 -3 reduce the morbidity and expense o stem cell harvests
a
t
and enable use o other stem cell sources. Speci cally,
o
Re la t ive u n ct io n o ce lls in t h e h e m a t o p o ie t ic h ie ra rch y.
p
o
umbilical cord blood is a rich source o stem cells. How-
i
The boxes represent distinct unctional eatures o cells in the
e
s
i
ever, the volume o cord blood units is extremely small,
s
myeloid (upper box) versus lymphoid (lower box) lineages.
and there ore, the total number o hematopoietic stem
cells that can be obtained in any single cord blood unit
T e proli eration o cells is generally not associated with is generally only su cient to transplant an individual o
the ability to undergo a sel -renewing division except <40 kg. T is limitation restricts what would otherwise
among memory and B cells and among stem cells. be an extremely promising source o stem cells. wo
Sel -renewal capacity gives way to di erentiation as eatures o cord blood stem cells are particularly impor-
the only option a er cell division when cells leave the tant. (1) T ey are derived rom a diversity o individuals
stem cell compartment, until they have the opportunity that ar exceeds the adult donor pool and there ore can
to become memory lymphocytes. In addition to this overcome the majority o immunologic cross-matching
sel -renewing capacity, stem cells have an additional obstacles. (2) Cord blood stem cells have a large num-
eature characterizing their proli eration machinery. ber o cells associated with them, but (paradoxically)
Stem cells in many mature adult tissues may be hetero- they appear to be associated with a lower incidence o
geneous with some being deeply quiescent, serving as a gra -versus-host disease when compared with simi-
deep reserve, whereas others are more proli erative and larly mismatched stem cells rom other sources. I stem
replenish the short-lived progenitor population. In the cell expansion by sel -renewal could be achieved, the
hematopoietic system, stem cells are generally cytokine- number o cells available might be su cient or use in
resistant, remaining dormant even when cytokines larger adults. An alternative approach to this problem is
drive bone marrow progenitors to proli eration rates to improve the e ciency o engra ment o donor stem
measured in hours. Stem cells, in contrast, are thought cells. Gra engineering is exploring methods o adding
to divide at ar longer intervals, measured in months cell components that may enhance engra ment. Fur-
to years, or the most quiescent cells. T is quiescence thermore, at least some data suggest that depletion o
is di cult to overcome in vitro, limiting the ability to host NK (natural killer) cells may lower the number o
e ectively expand human hematopoietic stem cells. T e stem cells necessary to reconstitute hematopoiesis.
process may be controlled by particularly high levels o Some limited understanding o sel -renewal exists
cyclin-dependent kinase inhibitors like p57 or CDKN1c and, intriguingly, implicates gene products that are
that restrict entry o stem cells into the cell cycle, block- associated with the chromatin state, a high-order orga-
ing the G1-S transition. Exogenous signals rom the nization o chromosomal DNA that inf uences tran-
niche also appear to en orce quiescence, including the scription. T ese include members o the polycomb
activation o the tyrosine kinase receptor ie2 on stem amily, a group o zinc nger–containing transcriptional
cells by angiopoietin 1 on niche cells. regulators that interact with the chromatin structure,
T e regulation o stem cell proli eration also appears contributing to the accessibility o groups o genes or
to change with age. In mice, the cyclin-dependent transcription. One member, Bmi-1, is important in
kinase inhibitor p16INK4a accumulates in stem cells in enabling hematopoietic stem cell sel -renewal through
older animals and is associated with a change in ve di - modi cation o cell cycle regulators such as the cyclin-
erent stem cell unctions, including cell cycling. Lower- dependent kinase inhibitors. In the absence o Bmi-1
ing expression o p16INK4a in older animals improves or o the transcriptional regulator, G -1, hematopoietic
stem cells decline in number and unction. In contrast,
dysregulation o Bmi-1 has been associated with leu-
kemia; it may promote leukemic stem cell sel -renewal
when it is overexpressed. Other transcription regulators
have also been associated with sel -renewal, particularly
homeobox, or “hox,” genes. T ese transcription actors
are named or their ability to govern large numbers o
genes, including those determining body patterning in
invertebrates. HoxB4 is capable o inducing extensive
sel -renewal o stem cells through its DNA-binding
moti . Other members o the hox amily o genes have
been noted to a ect normal stem cells, but they are
also associated with leukemia. External signals that
may inf uence the relative sel -renewal versus di eren-
tiation outcomes o stem cell cycling include speci c
Wnt ligands. Intracellular signal transducing interme-
diates are also implicated in regulating sel -renewal.
T ey include P EN, an inhibitor o the AK pathway,
and S A 5, both o which are downstream o activated
growth actor receptors and necessary or normal stem
cell unctions including sel -renewal, at least in mouse
models. T e connections between these molecules
remain to be de ned, and their role in physiologic regu-
lation o stem cell sel -renewal is still poorly understood.
CANCER IS SIMILAR TO AN O RGAN
WITH SELF-RENEWING CAPACITY
T e relationship o stem cells to cancer is an important
evolving dimension o adult stem cell biology. Cancer
may share principles o organization with normal tis-
sues. Cancer cells are heterogeneous even within a given
patient and may have a hierarchical organization o
cells with a base o stem-like cells capable o the signa-
ture stem cell eatures: sel -renewal and di erentiation.
T ese stem-like cells might be the basis or perpetuation
o the tumor and represent a slowly dividing, rare popu-
lation with distinct regulatory mechanisms, including
a relationship with a specialized microenvironment. A
subpopulation o sel -renewing cells has been de ned
or some, but not all, cancers. A more sophisticated
understanding o the stem cell organization o cancers
may lead to improved strategies or developing new
therapies or the many common and di cult-to-treat
types o malignancies that have been relatively re rac-
tory to interventions aimed at dividing cells.
Does the concept o cancer stem cells provide insight
into the cellular origin o cancer? T e act that some
cells within a cancer have stem cell–like properties
does not necessarily mean that the cancer arose in the
stem cell itsel . Rather, more mature cells could have 7
acquired the sel -renewal characteristics o stem cells.
Any single genetic event is unlikely to be su cient to
enable ull trans ormation o a normal cell to a rankly
C
H
malignant one. Rather, cancer is a multistep process,
A
P
T
and or the multiple steps to accumulate, the cell o
E
R
origin must be able to persist or prolonged periods. It
1
must also be able to generate large numbers o daughter
cells. T e normal stem cell has these properties and,
by virtue o its having intrinsic sel -renewal capability,
H
e
m
may be more readily converted to a malignant pheno-
a
t
type. T is hypothesis has been tested experimentally in
o
p
o
the hematopoietic system. aking advantage o the cell-
i
e
t
i
sur ace markers that distinguish hematopoietic cells o
c
S
t
varying maturity, stem cells, progenitors, precursors,
e
m
and mature cells can be isolated. Power ul trans orming
C
e
l
gene constructs were placed in these cells, and it was
l
s
ound that the cell with the greatest potential to pro-
duce a malignancy was dependent on the trans orming
gene. In some cases, it was the stem cell, but in others,
the progenitor cell unctioned to initiate and perpetuate
the cancer. T is shows that cells can acquire stem cell–
like properties in malignancy.
WHAT ELSE CAN HEMATO P O IETIC
STEM CELLS DO?
Some experimental data have suggested that hemato-
poietic stem cells or other cells mobilized into the circu-
lation by the same actors that mobilize hematopoietic
stem cells are capable o playing a role in healing the
vascular and tissue damage associated with stroke and
myocardial in arction. T ese data are controversial,
and the applicability o a stem cell approach to nonhe-
matopoietic conditions remains experimental. How-
ever, reprogramming technology o ers the potential or
using the readily obtained hematopoietic stem cell as a
source or cells with other capabilities.
T e stem cell, there ore, represents a true dual-edged
sword. It has tremendous healing capacity and is essen-
tial or li e. Uncontrolled, it can threaten the li e it main-
tains. Understanding how stem cells unction, the signals
that modi y their behavior, and the tissue niches that
modulate stem cell responses to injury and disease are
critical or more e ectively developing stem cell–based
medicine. T at aspect o medicine will include the use
o the stem cells and the use o drugs to target stem cells
to enhance repair o damaged tissues. It will also include
the care ul balance o interventions to control stem cells
where they may be dys unctional or malignant.
This page intentionally left blank
 SECTION II

CARDINAL
MANIFESTATIONS OF
HEMATOLOGIC DISEASE
 CH AP TER 2
ANEMIA AND POLYCYTHEMIA
Jo h n W. Ad am so n
HEMATO P O IESIS AND THE
P HYSIO LO GIC BASIS O F
RED CELL P RO DUCTIO N
Hematopoiesis is the process by which the ormed
elements o blood are produced. T e process is regu-
lated through a series o steps beginning with the hema-
topoietic stem cell. Stem cells are capable o producing
red cells, all classes o granulocytes, monocytes, plate-
lets, and the cells o the immune system. T e precise
molecular mechanism—either intrinsic to the stem
cell itsel or through the action o extrinsic actors—
by which the stem cell becomes committed to a given
lineage is not ully de ned. However, experiments in
mice suggest that erythroid cells come rom a common
erythroid/megakaryocyte progenitor that does not
develop in the absence o expression o the GA A-1
and FOG-1 ( riend o GA A-1) transcription actors
(Chap. 1). Following lineage commitment, hematopoi-
etic progenitor and precursor cells come increasingly
under the regulatory in uence o growth actors and
hormones. For red cell production, erythropoietin
(EPO) is the primary regulatory hormone. EPO is
required or the maintenance o committed erythroid
progenitor cells that, in the absence o the hormone,
undergo programmed cell death (apoptosis). T e reg-
ulated process o red cell production is erythropoiesis,
and its key elements are illustrated in Fig. 2-1.
In the bone marrow, the rst morphologically rec-
ognizable erythroid precursor is the pronormoblast.
T is cell can undergo our to ve cell divisions, which
result in the production o 16–32 mature red cells. With
increased EPO production, or the administration o
EPO as a drug, early progenitor cell numbers are ampli-
ed and, in turn, give rise to increased numbers o
erythrocytes. T e regulation o EPO production itsel is
linked to tissue oxygenation.
In mammals, O2 is transported to tissues bound to
the hemoglobin contained within circulating red cells.
10
■ Da n L. Lo n g o
T e mature red cell is 8 µm in diameter, anucleate, dis-
coid in shape, and extremely pliable in order to tra-
verse the microcirculation success ully; its membrane
integrity is maintained by the intracellular generation
o A P. Normal red cell production results in the daily
replacement o 0.8–1% o all circulating red cells in
the body, since the average red cell lives 100–120 days.
T e organ responsible or red cell production is called
the erythron. T e erythron is a dynamic organ made
up o a rapidly proli erating pool o marrow erythroid
precursor cells and a large mass o mature circulating
red blood cells. T e size o the red cell mass re ects
the balance o red cell production and destruction. T e
physiologic basis o red cell production and destruction
provides an understanding o the mechanisms that can
lead to anemia.
T e physiologic regulator o red cell production, the
glycoprotein hormone EPO, is produced and released
by peritubular capillary lining cells within the kidney.
T ese cells are highly specialized epithelial-like cells. A
small amount o EPO is produced by hepatocytes. T e
undamental stimulus or EPO production is the avail-
ability o O2 or tissue metabolic needs. Key to EPO
gene regulation is hypoxia-inducible actor (HIF)-1α. In
the presence o O2, HIF-1α is hydroxylated at a key pro-
line, allowing HIF-1α to be ubiquitinated and degraded
via the proteasome pathway. I O2 becomes limiting,
this critical hydroxylation step does not occur, allowing
HIF-1α to partner with other proteins, translocate to
the nucleus, and upregulate the expression o the EPO
gene, among others.
Impaired O2 delivery to the kidney can result rom
a decreased red cell mass (anemia), impaired O2 load-
ing o the hemoglobin molecule or a high O2 a nity
mutant hemoglobin (hypoxemia), or, rarely, impaired
blood ow to the kidney (renal artery stenosis). EPO
governs the day-to-day production o red cells, and
ambient levels o the hormone can be measured in the
plasma by sensitive immunoassays—the normal level
 an adequate supply o substrates or hemoglobin syn- 11
Iron fola te B12 thesis. A de ect in any o these key components can lead
Erythroid
ma rrow
to anemia. Generally, anemia is recognized in the labo-
Re d ce ll ma s s
Re d ce ll ratory when a patient’s hemoglobin level or hematocrit
de s truction is reduced below an expected value (the normal range).
Erythropoie tin
P la s ma T e likelihood and severity o anemia are de ned based
volume
on the deviation o the patient’s hemoglobin/hematocrit
Hb Conce ntra tion
Kidney
rom values expected or age- and sex-matched normal
tis s ue subjects. T e hemoglobin concentration in adults has a
Gaussian distribution. T e mean hematocrit value or

C
O 2 Cons umption He a rt

H
P O2
adult males is 47% (standard deviation, ±7%) and that

A
P
or adult emales is 42% (±5%). Any single hematocrit

T
E
Lungs

R
Ve s s e ls or hemoglobin value carries with it a likelihood o asso-

2
Atmos phe ric O 2 leve ls
ciated anemia. T us, a hematocrit o <39% in an adult
male or <35% in an adult emale has only about a 25%
FIGURE 2 -1
chance o being normal. Hematocrit levels are less use-

A
n
Th e p hysio lo g ic re g u la tio n o re d ce ll p ro d u ctio n b y tissu e

e
ul than hemoglobin levels in assessing anemia because

m
oxyg e n te n sio n . Hb, hemoglobin.

i
they are calculated rather than measured directly. Sus-

a
a
n
pected low hemoglobin or hematocrit values are more

d
P
being 10–25 U/L. When the hemoglobin concentration easily interpreted i previous values or the same patient

o
l
y
are known or comparison. T e World Health Organi-

c
alls below 100–120 g/L (10–12 g/dL), plasma EPO levels

y
t
h
increase in proportion to the severity o the anemia zation (WHO) de nes anemia as a hemoglobin level

e
m
(Fig. 2-2). In circulation, EPO has a hal -clearance time <130 g/L (13 g/dL) in men and <120 g/L (12 g/dL) in

i
a
o 6–9 h. EPO acts by binding to speci c receptors on women.
the sur ace o marrow erythroid precursors, inducing T e critical elements o erythropoiesis—EPO pro-
them to proli erate and to mature. With EPO stimula- duction, iron availability, the proli erative capacity o
tion, red cell production can increase our- to ve old the bone marrow, and e ective maturation o red cell
within a 1- to 2-week period, but only in the presence precursors—are used or the initial classi cation o anemia
o adequate nutrients, especially iron. T e unctional (see below).
capacity o the erythron, there ore, requires normal renal
production o EPO, a unctioning erythroid marrow, and
ANEMIA
CLINICAL PRESENTATION OF ANEMIA
10 4
Sig n s a n d sym p to m s
)
L
m
/
U
Anemia is most of en recognized by abnormal screening
m
(
10 3 laboratory tests. Patients less commonly present with
n
i
t
advanced anemia and its attendant signs and symptoms.
e
i
o
p
Acute anemia is due to blood loss or hemolysis. I blood
o
r
h
loss is mild, enhanced O2 delivery is achieved through
yt
10 2
r
e
changes in the O2–hemoglobin dissociation curve medi-
m
Norma l 9–26 mU/mL
u
ated by a decreased pH or increased CO2 (Bohr ef ect).
r
e
S
10 1 With acute blood loss, hypovolemia dominates the
clinical picture, and the hematocrit and hemoglobin
3 6 9 12 15 levels do not re ect the volume o blood lost. Signs o
He moglobin (g/dL) vascular instability appear with acute losses o 10–15%
FIGURE 2 -2 o the total blood volume. In such patients, the issue is
Eryt h ro p o ie t in (EPO) le ve ls in re sp o n se t o a n e m ia . When not anemia but hypotension and decreased organ per-
the hemoglobin level alls to 120 g/L (12 g/dL), plasma EPO lev- usion. When >30% o the blood volume is lost sud-
els increase logarithmically. In the presence o chronic kidney dis- denly, patients are unable to compensate with the
ease or chronic in ammation, EPO levels are typically lower than usual mechanisms o vascular contraction and changes
expected or the degree o anemia. As individuals age, the level in regional blood ow. T e patient pre ers to remain
o EPO needed to sustain normal hemoglobin levels appears to supine and will show postural hypotension and tachy-
increase. (From RS Hillman et al: Hematology in Clinical Practice, cardia. I the volume o blood lost is >40% (i.e., >2 L in
5th ed. New York, McGraw-Hill, 2010.) the average-sized adult), signs o hypovolemic shock
12 including con usion, dyspnea, diaphoresis, hypotension, Glucose-6-phosphate dehydrogenase (G6PD) de ciency
and tachycardia appear (Chap. 10). Such patients have and certain hemoglobinopathies are seen more commonly
signi cant de cits in vital organ per usion and require in those o Middle Eastern or A rican origin, including
immediate volume replacement. A rican Americans who have a high requency o G6PD
With acute hemolysis, the signs and symptoms de ciency. Other in ormation that may be use ul includes
depend on the mechanism that leads to red cell destruc- exposure to certain toxic agents or drugs and symptoms
tion. Intravascular hemolysis with release o ree hemo- related to other disorders commonly associated with ane-
globin may be associated with acute back pain, ree mia. T ese include symptoms and signs such as bleeding,
hemoglobin in the plasma and urine, and renal ailure. atigue, malaise, ever, weight loss, night sweats, and other
Symptoms associated with more chronic or progres-
S
systemic symptoms. Clues to the mechanisms o anemia
E
sive anemia depend on the age o the patient and the
C
may be provided on physical examination by ndings o
T
I
adequacy o blood supply to critical organs. Symptoms
O
in ection, blood in the stool, lymphadenopathy, spleno-
N
associated with moderate anemia include atigue, loss
I
megaly, or petechiae. Splenomegaly and lymphadenopa-
I
o stamina, breathlessness, and tachycardia (particu- thy suggest an underlying lymphoproli erative disease,
larly with physical exertion). However, because o the whereas petechiae suggest platelet dys unction. Past labo-
intrinsic compensatory mechanisms that govern the
C
ratory measurements are help ul to determine a time o
a
r
O2–hemoglobin dissociation curve, the gradual onset
d
i
onset.
n
o anemia—particularly in young patients—may not
a
l
In the anemic patient, physical examination may dem-
M
be associated with signs or symptoms until the anemia
a
onstrate a orce ul heartbeat, strong peripheral pulses, and
n
is severe (hemoglobin <70–80 g/L [7–8 g/dL]). When
i
f
e
a systolic “ ow” murmur. T e skin and mucous mem-
s
anemia develops over a period o days or weeks, the
t
a
branes may be pale i the hemoglobin is <80–100 g/L
t
i
total blood volume is normal to slightly increased, and
o
n
(8–10 g/dL). T is part o the physical examination should
s
changes in cardiac output and regional blood ow help
o
ocus on areas where vessels are close to the sur ace such
f
compensate or the overall loss in O2-carrying capacity.
H
e
as the mucous membranes, nail beds, and palmar creases.
m
Changes in the position o the O 2–hemoglobin dis-
a
I the palmar creases are lighter in color than the sur-
t
o
sociation curve account or some o the compensatory
l
rounding skin when the hand is hyperextended, the
o
g
response to anemia. With chronic anemia, intracellular
i
c
hemoglobin level is usually <80 g/L (8 g/dL).
D
levels o 2,3-bisphosphoglycerate rise, shif ing the dis-
i
s
e
sociation curve to the right and acilitating O2 unload- LABORATORYEVALUATION Table 2-1 lists the tests used in the
a
s
e
ing. T is compensatory mechanism can only maintain initial workup o anemia. A routine complete blood count
normal tissue O2 delivery in the ace o a 20–30 g/L (CBC) is required as part o the evaluation and includes
(2–3 g/dL) de cit in hemoglobin concentration. Finally, the hemoglobin, hematocrit, and red cell indices: the mean
urther protection o O2 delivery to vital organs is cell volume (MCV) in emtoliters, mean cell hemoglobin
achieved by the shunting o blood away rom organs (MCH) in picograms per cell, and mean concentration o
that are relatively rich in blood supply, particularly the hemoglobin per volume o red cells (MCHC) in grams per
kidney, gut, and skin. liter (non-SI: grams per deciliter). T e red cell indices are
Certain disorders are commonly associated with ane- calculated as shown in Table 2-2, and the normal variations
mia. Chronic in ammatory states (e.g., in ection, rheu- in the hemoglobin and hematocrit with age are shown in
matoid arthritis, cancer) are associated with mild to Table 2-3. A number o physiologic actors a ect the CBC,
moderate anemia, whereas lymphoproli erative disor- including age, sex, pregnancy, smoking, and altitude.
ders, such as chronic lymphocytic leukemia and certain High-normal hemoglobin values may be seen in men and
other B cell neoplasms, may be associated with auto- women who live at altitude or smoke heavily. Hemoglobin
immune hemolysis. elevations due to smoking re ect normal compensation
due to the displacement o O2 by CO in hemoglobin bind-
ing. Other important in ormation is provided by the retic-
ulocyte count and measurements o iron supply including
APPROACHTOTHEPATIENT: serum iron, total iron-binding capacity ( IBC; an indirect
Anemia measure o serum trans errin), and serum erritin. Marked
T e evaluation o the patient with anemia requires a alterations in the red cell indices usually re ect disorders o
care ul history and physical examination. Nutritional maturation or iron de ciency. A care ul evaluation o the
history related to drugs or alcohol intake and amily his- peripheral blood smear is important, and clinical laborato-
tory o anemia should always be assessed. Certain geo- ries of en provide a description o both the red and white
graphic backgrounds and ethnic origins are associated cells, a white cell di erential count, and the platelet count.
with an increased likelihood o an inherited disorder o In patients with severe anemia and abnormalities in red
the hemoglobin molecule or intermediary metabolism. blood cell morphology and/or low reticulocyte counts, a
TABLE 2 -1 TABLE 2 -3 13
LABORATORY TESTS IN ANEMIA DIAGNOSIS CHANGES IN NORMAL HEMOGLOBIN/HEMATOCRIT
I. Complete blood count (CBC) VALUES WITH AGE, SEX, AND PREGNANCY
A. Red blood cell count AGE/SEX HEMOGLOBIN, g /d L HEMATOCRIT, %
1. Hemoglobin
2. Hematocrit At birth 17 52
3. Reticulocyte count Childhood 12 36
B. Red blood cell indices Adolescence 13 40
1. Mean cell volume (MCV)
Adult man 16 (±2) 47 (±6)
2. Mean cell hemoglobin (MCH)
Adult woman 13 (±2) 40 (±6)

C
3. Mean cell hemoglobin concentration (MCHC)

H
(menstruating)

A
4. Red cell distribution width (RDW)

P
C. White blood cell count

T
Adult woman 14 (±2) 42 (±6)

E
R
1. Cell di erential (postmenopausal)

2
2. Nuclear segmentation o neutrophils During pregnancy 12 (±2) 37 (±6)
D. Platelet count
E. Cell morphology
So u rce : From RS Hillman et al: Hematology in Clinical Practice, 5th ed.

A
1. Cell size

n
New York, McGraw-Hill, 2010.

e
m
2. Hemoglobin content

i
a
3. Anisocytosis

a
n
4. Poikilocytosis hemoglobin synthesis (hypochromia). Automated cell coun-

d
P
5. Polychromasia ters describe the red cell volume distribution width (RDW).

o
l
y
II. Iron supply studies T e MCV (representing the peak o the distribution curve)

c
y
t
A. Serum iron

h
is insensitive to the appearance o small populations o

e
B. Total iron-binding capacity

m
macrocytes or microcytes. An experienced laboratory

i
a
C. Serum erritin
III. Marrow examination technician will be able to identi y minor populations o
A. Aspirate large or small cells or hypochromic cells be ore the red cell
1. M/E ratio a indices change.
2. Cell morphology
3. Iron stain Peripheral Blood Smear he peripheral blood smear pro-
B. Biopsy vides important in ormation about de ects in red cell
1. Cellularity production (Chap. 6). As a complement to the red cell
2. Morphology indices, the blood smear also reveals variations in cell size
(anisocytosis) and shape (poikilocytosis). he degree o
a
M/E ratio, ratio o myeloid to erythroid precursors. anisocytosis usually correlates with increases in the RDW
or the range o cell sizes. Poikilocytosis suggests a de ect
in the maturation o red cell precursors in the bone mar-
bone marrow aspirate or biopsy can assist in the diagnosis. row or ragmentation o circulating red cells. he blood
Other tests o value in the diagnosis o speci c anemias are smear may also reveal polychromasia—red cells that are
discussed in chapters on speci c disease states. slightly larger than normal and grayish blue in color on
T e components o the CBC also help in the classi ca- the Wright-Giemsa stain. hese cells are reticulocytes that
tion o anemia. Microcytosis is re ected by a lower than have been prematurely released rom the bone marrow,
normal MCV (<80), whereas high values (>100) re ect and their color represents residual amounts o ribosomal
macrocytosis. T e MCH and MCHC re ect de ects in RNA. hese cells appear in circulation in response to EPO
stimulation or to architectural damage o the bone marrow
( ibrosis, in iltration o the marrow by malignant cells, etc.)
that results in their disordered release rom the marrow.
TABLE 2 -2
he appearance o nucleated red cells, Howell-Jolly bodies,
RED BLOOD CELL INDICES
target cells, sickle cells, and others may provide clues to
INDEX NORMAL VALUE speci ic disorders (Figs. 2-3 to 2-11).
Mean cell volume (MCV) = (hematocrit × 90 ± 8 L Reticulocyte Count An accurate reticulocyte count is key to
10)/(red cell count × 106)
the initial classi cation o anemia. Reticulocytes are red
Mean cell hemoglobin (MCH) = 30 ± 3 pg cells that have been recently released rom the bone mar-
(hemoglobin × 10)/(red cell count × 106) row. T ey are identi ed by staining with a supravital dye
Mean cell hemoglobin concentration = 33 ± 2% that precipitates the ribosomal RNA (Fig. 2-12). T ese
(hemoglobin × 10)/hematocrit, or precipitates appear as blue or black punctate spots and can
MCH/MCV
be counted manually or, currently, by uorescent emission
14
S
E
C
T
I
O
N
I
I
FIGURE 2 -3 FIGURE 2 -6
No rm a l b lo o d sm e ar (Wrig ht sta in ). High-power f eld show- Ho we ll-Jo lly b o d ie s. In the absence o a unctional spleen,
C
a
ing normal red cells, a neutrophil, and a ew platelets. (From RS nuclear remnants are not culled rom the red cells and remain as
r
d
i
n
Hillman et al: Hematology in Clinical Practice, 5th ed. New York, small homogeneously staining blue inclusions on Wright stain.
a
l
McGraw-Hill, 2010.) (From RS Hillman et al: Hematology in Clinical Practice, 5th ed.
M
a
New York, McGraw-Hill, 2010.)
n
i
f
e
s
t
a
t
i
o
n
s
o
f
H
e
m
a
t
o
l
o
g
i
c
D
i
s
e
a
s
e
FIGURE 2 -4
Se ve re iro n -d e cie n cy a n e m ia . Microcytic and hypochromic FIGURE 2 -7
red cells smaller than the nucleus o a lymphocyte associated with Red cell changes in myelo b rosis. The le t panel shows a teardrop-
marked variation in size (anisocytosis) and shape (poikilocytosis). shaped cell. The right panel shows a nucleated red cell. These orms
(From RS Hillman et al: Hematology in Clinical Practice, 5th ed. can be seen in myelof brosis.
New York, McGraw-Hill, 2010.)

FIGURE 2 -8
FIGURE 2 -5 Ta rg e t ce lls. Target cells have a bull’s-eye appearance and are
Macrocytosis. Red cells are larger than a small lymphocyte and well seen in thalassemia and in liver disease. (From RS Hillman et al:
hemoglobinized. O ten macrocytes are oval shaped (macro-ovalocytes). Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)

FIGURE 2 -9
Re d ce ll ra g m e n t a t io n . Red cells may become ragmented
FIGURE 2 -1 2
in the presence o oreign bodies in the circulation, such as
Re t icu lo cyt e s. Methylene blue stain demonstrates residual RNA
mechanical heart valves, or in the setting o thermal injury. (From
in newly made red cells. (From RS Hillman et al: Hematology in
RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York,
Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)
McGraw-Hill, 2010.)
FIGURE 2 -1 0
Ure m ia . The red cells in uremia may acquire numerous regu-
larly spaced, small, spiny projections. Such cells, called burr cells
or echinocytes, are readily distinguishable rom irregularly spicu-
lated acanthocytes shown in Fig. 2-11.
FIGURE 2 -1 1
Sp u r ce lls. Spur cells are recognized as distorted red cells con-
taining several irregularly distributed thornlike projections. Cells
with this morphologic abnormality are also called acanthocytes.
(From RS Hillman et al: Hematology in Clinical Practice, 5th ed.
New York, McGraw-Hill, 2010.)
15
C
H
A
P
T
E
R
2
A
n
e
m
i
a
a
n
d
P
o
l
y
c
y
o dyes that bind to RNA. T is residual RNA is metabo-
t
h
e
lized over the rst 24–36 h o the reticulocyte’s li e span in
m
i
circulation. Normally, the reticulocyte count ranges rom
a
1 to 2% and re ects the daily replacement o 0.8–1.0% o
the circulating red cell population. A corrected reticulo-
cyte count provides a reliable measure o e ective red cell
production.
In the initial classi cation o anemia, the patient’s retic-
ulocyte count is compared with the expected reticulocyte
response. In general, i the EPO and erythroid marrow
responses to moderate anemia [hemoglobin <100 g/L
(10 g/dL)] are intact, the red cell production rate increases
to two to three times normal within 10 days ollowing
the onset o anemia. In the ace o established anemia, a
reticulocyte response less than two to three times normal
indicates an inadequate marrow response.
o use the reticulocyte count to estimate marrow
response, two corrections are necessary. T e rst correc-
tion adjusts the reticulocyte count based on the reduced
number o circulating red cells. With anemia, the percent-
age o reticulocytes may be increased while the absolute
number is unchanged. o correct or this e ect, the reticu-
locyte percentage is multiplied by the ratio o the patient’s
hemoglobin or hematocrit to the expected hemoglobin/
hematocrit or the age and sex o the patient (Table 2-4).
T is provides an estimate o the reticulocyte count cor-
rected or anemia. o convert the corrected reticulocyte
count to an index o marrow production, a urther correc-
tion is required, depending on whether some o the reticu-
locytes in circulation have been released rom the marrow
prematurely. For this second correction, the peripheral
blood smear is examined to see i there are polychromato-
philic macrocytes present.
T ese cells, representing prematurely released reticu-
locytes, are re erred to as “shif ” cells, and the relationship
16 TABLE 2 -4 TABLE 2 -5
CALCULATION OF RETICULOCYTE PRODUCTION NORMAL MARROW RESPONSE TO ANEMIA
INDEX
PRODUCTION RETICULOCYTE
Correction #1 for Anemia: HEMOGLOBIN INDEX COUNT
This correction produces the corrected reticulocyte count.
15 g/dL 1 50,000/µL
In a person whose reticulocyte count is 9%, hemoglobin 7.5 g/dL,
and hematocrit 23%, the absolute reticulocyte count = 11 g/dL 2.0–2.5 100–150,000/µL
9 × (7.5/15) [or × (23/45)] = 4.5% 8 g/dL 3.0–4.0 300–400,000/µL
Note. This correction is not done i the reticulocyte count is
reported in absolute numbers (e.g., 50,000/µL o blood)
S
Correction #2 for Longer Life of Prematurely Released
E
severity o anemia. In general, a correction o 2 is simply
C
Reticulocytes in the Blood:
T
I
used. An appropriate correction is shown in able 2-4. I
O
This correction produces the reticulocyte production index.
N
In a person whose reticulocyte count is 9%, hemoglobin polychromatophilic cells are not seen on the blood smear,
I
I
7.5 gm/dL, and hematocrit 23%, the reticulocyte the second correction is not required. T e now doubly
production index corrected reticulocyte count is the reticulocyte production
index, and it provides an estimate o marrow production
C
(7.5 / 15)(hemoglobin correction)
a
=9× = 2.25
r
relative to normal. In many hospital laboratories, the retic-
d
2(maturation time correction)
i
n
ulocyte count is reported not only as a percentage but also
a
l
M
in absolute numbers. I so, no correction or dilution is
a
n
required. A summary o the appropriate marrow response
i
f
between the degree o shif and the necessary shif correc-
e
s
to varying degrees o anemia is shown in Table 2-5.
t
a
tion actor is shown in Fig. 2-13. T e correction is neces-
t
i
Premature release o reticulocytes is normally due to
o
sary because these prematurely released cells survive as
n
s
increased EPO stimulation. However, i the integrity o
o
reticulocytes in circulation or >1 day, thereby providing a
f
H
alsely high estimate o daily red cell production. I poly- the bone marrow release process is lost through tumor
e
m
in ltration, brosis, or other disorders, the appearance
a
chromasia is increased, the reticulocyte count, already cor-
t
o
o nucleated red cells or polychromatophilic macrocytes
l
rected or anemia, should be divided again by 2 to account
o
g
should still invoke the second reticulocyte correction.
i
or the prolonged reticulocyte maturation time. T e sec-
c
D
T e shif correction should always be applied to a patient
i
ond correction actor varies rom 1 to 3 depending on the
s
e
with anemia and a very high reticulocyte count to pro-
a
s
e
vide a true index o e ective red cell production. Patients
Marrow Pe riphe ral
no rmo blas ts and blo o d with severe chronic hemolytic anemia may increase red
re tic ulo c yte s re tic ulo c yte s cell production as much as six- to seven old. T is measure
He mato c rit (%) (days ) (days ) alone con rms the act that the patient has an appropri-
45 3.5 1.0 ate EPO response, a normally unctioning bone marrow,
and su cient iron available to meet the demands or new
35 3.0 1.5 red cell ormation. I the reticulocyte production index is
<2 in the ace o established anemia, a de ect in erythroid
25 2.5 2.0
marrow proli eration or maturation must be present.
15 1.5 2.5 Tests of Iron Supply and Storage T e laboratory measure-
ments that re ect the availability o iron or hemoglobin
“S HIFT”
synthesis include the serum iron, the IBC, and the
corre ction fa ctor percent trans errin saturation. T e percent trans errin
saturation is derived by dividing the serum iron level
FIGURE 2 -1 3 (× 100) by the IBC. T e normal serum iron ranges rom 9
Co rre ct io n o t h e re t icu lo cyt e co u n t. To use the reticulocyte to 27 µmol/L (50–150 µg/dL), whereas the normal IBC is
count as an indicator o e ective red cell production, the reticulo- 54–64 µmol/L (300–360 µg/dL); the normal trans errin sat-
cyte percentage must be corrected based on the level o anemia uration ranges rom 25 to 50%. A diurnal variation in the
and the circulating li e span o the reticulocytes. Erythroid cells serum iron leads to a variation in the percent trans errin
take ~4.5 days to mature. At a normal hemoglobin, reticulocytes
saturation. T e serum erritin is used to evaluate total body
are released to the circulation with ~1 day le t as reticulocytes.
iron stores. Adult males have serum erritin levels that
However, with di erent levels o anemia, reticulocytes (and even
average ~100 µg/L, corresponding to iron stores o ~1 g.
earlier erythroid cells) may be released rom the marrow prema-
Adult emales have lower serum erritin levels averaging
turely. Most patients come to clinical attention with hematocrits
30 µg/L, re ecting lower iron stores (~300 mg). A serum
in the mid-20s, and thus a correction actor o 2 is commonly
used because the observed reticulocytes will live or 2 days in the
erritin level o 10–15 µg/L indicates depletion o body iron
circulation be ore losing their RNA. stores. However, erritin is also an acute-phase reactant
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vengeance. Maintenant que te voici ramené à Dieu, as-tu
complètement dépouillé le vieil homme ?
Lorsque tu profères cette redoutable demande, es-tu bien assuré
de pardonner aux autres le mal qu’ils te firent ? En un mot, leur
remets-tu leur dette comme tu supplies notre Père de te remettre la
tienne ? Je dois te demander cela car songe quelle serait ta faute si,
lorsque tu invoques la miséricorde divine, tu gardais, au fond de ton
cœur, du mauvais vouloir à l’égard d’autrui !
Il y eut un silence. Chériat, les mains jointes, s’interrogeait lui-
même. Cependant Robert remarqua que Charles attendait la
réponse. Il s’était à demi-tourné vers le lit et, le sourcil froncé, il
observait Chériat comme pour juger de son état d’esprit.
— Je sais, dit enfin Chériat, que je serais indigne de la bonté de
Dieu si, quand je le supplie de me pardonner mes égarements, je
conservais de l’animosité contre ceux qui les partagèrent. Les
souffrances méritées que j’endure m’apprirent que la douleur est la
loi du monde. Les illusionnés qui croient s’en affranchir en festoyant
leur égoïsme au dépens de leur semblables, je les haïssais naguère.
Aujourd’hui, je les plains car je n’ignore pas que, tôt ou tard, dans
cette vie ou dans l’autre, ils pâtiront en proportion du mal qu’ils
auront commis ou approuvé.
Non, poursuivit-il, les yeux pleins de larmes et la voix tremblante,
je ne puis plus haïr personne. J’ai trop besoin de l’indulgence divine
pour ne pas concevoir que quiconque vit dans le péché en a besoin
autant que moi. N’est-ce pas, ami, que mon orgueil est bien mort
puisque Dieu me fait cette grande grâce de pouvoir dire avec
sincérité : Pardonnez-nous nos offenses comme nous pardonnons à
ceux qui nous ont offensés ? C’est pourquoi je lui témoignerai ma
reconnaissance en employant le peu de jours qui me restent non
seulement à Lui demander qu’Il me reçoive à merci mais aussi qu’Il
éclaire les malheureux qui fuient sa Face adorable…
Robert se transfigurait d’allégresse pieuse à recueillir ces paroles
par où s’avérait le salut du pauvre malade.
 — Ah ! se disait-il, si elles pouvaient toucher le cœur de
Charles !…
Mais, celui-ci avait eu un mouvement de colère en entendant
Chériat proclamer la défaite de son orgueil. Il se détourna du lit et
fixa le plancher, devant lui, d’un air farouche.
Robert s’était agenouillé au chevet de Chériat.
L’un et l’autre se signèrent et, d’une inspiration spontanée, se
mirent à prier, à voix basse, pour leur ami perdu dans les ténèbres.
Tandis qu’ils appelaient sur lui la miséricorde du Seigneur,
Charles récapitulait, avec amertume et dérision, les propos des deux
croyants. Il tendait toutes les forces de son âme pour qu’elle rejetât
cette leçon de fraternité à l’égard d’autrui, d’humilité devant Dieu
qu’il venait de recevoir. Un instant, il avait été sur le point de fléchir ;
à présent encore, l’écho de l’Oraison Dominicale résonnait dans son
cœur. Mais il voulait que ce fût un bruit importun qu’il fallait se hâter
d’étouffer.
L’Évangile était près de lui, sur la table, ouvert au XIe chapitre de
Saint-Matthieu. Son regard s’y porta et il lut ceci :
Aimez vos ennemis, faites du bien à ceux qui vous haïssent et
priez pour ceux qui vous persécutent et vous calomnient, afin que
vous soyez les enfants de votre Père qui est dans les cieux, qui fait
lever son soleil sur les bons et les méchants et qui fait pleuvoir sur
les justes et les injustes.
— Encore le pardon ! murmura Charles qui sentait un étrange
courroux l’envahir de plus en plus. Il feuilleta quelques pages et
s’arrêta sur ce verset :
« Pierre, s’approchant du Seigneur, lui dit :
— Seigneur, combien de fois pardonnerai-je à mon frère, lorsqu’il
aura péché contre moi ? Sera-ce jusqu’à sept fois ?
Jésus lui dit :
— Je ne te dis pas jusqu’à sept fois, mais jusqu’à soixante-dix
fois sept fois… »
 Charles ferma le livre d’un geste de mépris, et le repoussa loin
de lui.
— Voilà donc leur religion, pensa-t-il — et sa bouche se crispait
de dédain — : Souffrir avec patience, se résigner, se soumettre et,
par surcroît, faire du bien à ceux qui vous outragent… Morale
d’esclaves ! Et à supposer que leur Dieu existe, n’y aurait-il pas de la
grandeur à braver les préceptes de servilité qu’il impose aux cœurs
assez lâches pour lui obéir ?
Il se leva. Il lui semblait que son âme entière se raidissait en une
attitude de révolte, cependant que les clairons de l’orgueil lui
chantaient aux oreilles une furieuse fanfare.
D’une voix éclatante il cria :
— Je ne servirai pas !…
Ah ! c’était le non serviam de Lucifer, le sombre entêtement de
l’archange déchu, lorsque, précipité dans l’abîme, il releva sa tête où
fumait encore la marque de la foudre et refusa de se courber sous la
Main qui le châtiait…
A cette clameur, Abry et Chériat tressaillirent. Ils se tournèrent du
côté de Charles et l’envisagèrent avec une stupéfaction craintive.
— Mon Dieu, que t’arrive-t-il ? demanda Robert.
Charles eut un rire sarcastique :
— Si je te le dis, tu ne me comprendras sans doute pas. Et
pourtant, je veux que tu le saches : je ne pardonne pas à mes
ennemis moi ; je ne m’incline pas devant ton Dieu, moi ; je hais ceux
qui consentent à subir sa tyrannie. Ah ! je cherchais qui frapper. Eh
bien, ce sera justement les adorateurs de ton Dieu, les serviles qui,
comme toi, maintiennent, par leur douceur exécrable, une société
que je voudrais faire voler en éclats…
Robert frémit. Mais ces phrases forcenées, si elles le terrifiaient,
ne le firent pas reculer. Il sentait l’âme de son ami en proie au plus
extrême péril et il n’eut qu’une idée : l’arrêter sur la pente effroyable
où il roulait.
Il fit un pas en avant :
 — Charles je t’en supplie, reviens à toi. Écoute-moi…
Mais l’autre, d’un geste coupant, le cloua sur place :
— Ne m’approche pas… Il y a un fossé entre nous, et ce fossé je
veux le remplir de sang… Ne m’approche pas, dis-je, je porte la
mort !
Et ce disant, il étreignait la bombe sur sa poitrine.
Chériat devina tout. Dressé d’épouvante, il s’écria :
— La bombe ! Il va jeter la bombe ; retiens-le…
Mais Charles avait gagné la porte. Du seuil, il se retourna et,
versant le feu par ses prunelles, il proféra : Oui, je vais jeter la
bombe.
Et savez-vous en quel endroit ? Sur l’autel même de ce Dieu dont
vous vous fabriquez un épouvantail. Nous verrons qui, de lui ou de
moi, sera le plus fort !…
Il sortit et, la seconde d’après, ils l’entendirent descendre
l’escalier quatre à quatre. Robert allait le suivre, le rattraper, lui
disputer l’engin, fût-ce au prix de sa propre existence. Mais Chériat,
tout suffoquant, venait de retomber sur l’oreiller. Une hémoptysie se
déclarait.
Robert courut au malade et lui prodiguant ses soins, tremblant
d’horreur et de désolation, il ne pouvait que répéter : Seigneur,
Seigneur, retenez son bras… Éclairez ce malheureux, il ne sait ce
qu’il fait !…
Et, à travers les hoquets lugubres qui lui soulevaient la poitrine,
Chériat disait :
— Mon Dieu, prenez-moi en rançon pour l’âme de cet infortuné ;
ne permettez pas que cette chose affreuse s’accomplisse…
 CHAPITRE XIV

En janvier, le jour se lève tard. Six heures sonnaient lorsque

Charles se précipita dans la rue ; le temps s’était radouci ; il dégelait ;
mais une ombre brumeuse se traînait encore sur la ville. Un vent
mou passait par rafales, faisait vaciller les flammes des réverbères
et appliquait de larges gouttes de pluie sur le visage brûlant du
possédé.
Il descendit d’abord, presque en courant, le boulevard Saint-
Michel, mû par la crainte que Robert le rejoignît et tentât de lui
enlever la bombe — ce qui serait certainement arrivé sans le
crachement de sang de Chériat.
— S’il me suit, grondait-il, s’il veut me barrer le chemin, c’est lui
que je frapperai…
Il traversa la chaussée où des voitures de laitiers trottaient à
grand tapage et, s’adossant à la grille du square de Cluny, il surveilla
le trottoir opposé où il croyait toujours apercevoir Robert. Mais il n’y
avait que des tâcherons et des ouvrières qui se hâtaient vers leur
travail.
Rassuré, il repartit d’un pas plus lent. Il se disait seulement :
— J’entrerai dans la première église qui sera ouverte et là, je
lancerai la bombe soit sur quelque prêtre, soit parmi les individus
stupides qui s’y agenouillent, soit, au hasard, à travers le chœur. Le
tout, c’est qu’elle éclate comme un défi à ce Dieu en qui l’humanité
place ses lâches espoirs et son amour encore plus lâche de la
servitude. Si ce Dieu est une chimère, eh bien je lui mettrai du plomb
dans l’aile. Si, par grand hasard, il existe, je l’aurai bravé dans sa
maison. Oui cela vaut mieux que de supprimer Legranpan, Jacobin
tyrannique, ou de vagues bourgeois à l’abreuvoir…
Après je me laisserai arrêter sans résistance, Car il importe que
j’explique mon acte.
A la pensée de ce qu’il allait faire, son cœur se gonfla d’orgueil. Il
lui sembla qu’il dominait son époque et il éprouva un atroce bien-être
à se sentir inébranlable dans sa résolution.
Il arriva au bas du boulevard. Au lieu de traverser la Seine, il prit
machinalement à droite, longea le parapet du quai, enfila le Petit-
Pont et déboucha sur le Parvis. La façade et les tours de Notre-
Dame surgirent devant lui, dans le brouillard. On venait d’entr’ouvrir
le portail de gauche.
— Ah ! voici le but, s’exclama-t-il. Sans tergiverser, il franchit le
seuil, poussa la porte à ressort de l’intérieur et pénétra dans la
cathédrale.
Quel profond silence, quel calme auguste, quelle obscurité sainte
à peine interrompue par la faible clarté de la lampe qui scintille au
grand autel et par la lueur de petits cierges allumés çà et là.
Le contraste était trop fort entre le recueillement sacré de
l’immense basilique et le tumulte de rumeurs homicides qui
remplissaient l’âme de Charles. Il en subit l’impression et se sentit
comme intimidé. Mais réagissant aussitôt, il traversa la nef et se mit
à suivre le bas-côté qui mène à la sacristie.
Il alla jusqu’à la chapelle où s’élève le groupe de Saint-Georges
terrassant le démon. Là, il s’arrêta et s’accotant à un pilier, il
regarda.
Un vieux prêtre, servi par un seul enfant de chœur, célébrait la
Messe à côté du tombeau de Monseigneur Darboy. Cinq ou six
femmes du peuple, inclinées sur leur prie-dieu, s’unissaient avec
ferveur au Saint-Sacrifice. Charles, les bras croisés, la lèvre
dédaigneuse, ne quittait pas des yeux l’officiant.
 Hésitait-il à l’imminence du crime ? — Point ; voici ce qu’il se
disait :
— Dans une minute, dès que ce vieil homme se retournera, je
lancerai la bombe. Et alors comme je jouirai de la panique de ces
sottes brebis laissées en détresse par leur Manitou !…
On commençait l’Offertoire. Le prêtre fit face aux fidèles, et les
mains ouvertes en signe de paix, il prononça :
— Que le Seigneur soit avec vous.
— Et avec ton esprit, murmurèrent l’enfant et les assistants.
Charles eut un geste pour saisir la bombe. Mais déjà le prêtre,
retourné vers le tabernacle, faisait l’offrande du pain et du vin.
— Après tout, se dit alors l’assassin, je n’ai pas besoin d’attendre
qu’il regarde de nouveau par ici… Assez de délais !
Il déboutonna son veston et tâta l’engin. Rien ne le retiendrait-il ?
— Au contraire, il avait la sensation qu’une invisible main lui poussait
le coude, tandis qu’une voix sardonique lui chuchotait :
— Va donc ! Va donc !…
Cependant le prêtre se purifiait les doigts et, juste comme
Charles mesurait la distance pour projeter la bombe, il récita le
verset tutélaire : Ne perdas cum impiis, Deus, animam meam, et
cum viris sanguinum vitam meam.
O Providence divine ; vous étiez là !
A ce moment, une étrange faiblesse fit retomber, désarmé, le
bras de l’homicide. Il y eut comme un mur d’airain qui se dressait
entre lui et l’autel. Il recula, balbutiant : Je ne peux pas !… Je ne
peux pas !… Ces pauvres femmes, cet enfant, ce vieillard en prière.
Oh ! non, c’est trop horrible. Je ne peux pas !…
Mais tout de suite, honteux d’avoir fléchi dans sa fureur, il se
donna un prétexte pour différer :
— Il n’y a pas assez de monde. Peut-être, tout à l’heure, y en
aura-t-il davantage. Je reviendrai…
 Il s’éloigna rebroussant vers la sortie. Alors la voix démoniaque
reprit d’un accent furibond !
— Couard, tu cherches à ruser avec ta poltronnerie et tu traites
les autres de lâches ! Allons, reviens sur tes pas, frappe, tu seras
semblable à ce Dieu que tu redoutes…
Sur cette incitation, l’orgueil raidit tous les muscles de Charles. Il
lui parut qu’un torrent de feu lui coulait dans les veines.
— Soit ! répondit-il, que mon destin s’accomplisse…
Quand il proféra ces mots, il était sur le point de repasser le
portail. L’écume aux lèvres, il fit volte-face et poussa violemment la
porte intérieure afin de rentrer dans l’église. Puis il lâcha le bouton
pour ressaisir la bombe. Mais, dans la même seconde, le battant
actionné par le ressort, revint sur lui et le frappa d’un coup sec, en
pleine poitrine.
Un éclair rougeâtre jaillit, une détonation formidable roula sous
les voûtes séculaires, puis une âcre fumée remplit la cathédrale
jusqu’à l’abside…
Les premiers qui accoururent relevèrent le cadavre affreusement
mutilé de Charles : le torse était déchiré depuis le cou jusqu’au bas-
ventre ; les viscères hachés pendaient dans une mare de sang. La
main qui avait tenu la bombe avait été arrachée et projetée dehors,
sur le Parvis. La figure, restée intacte, exprimait une angoisse infinie
et l’on eût dit qu’un cri de terreur effroyable demeurait figé sur la
bouche béante…
Ainsi, par un évident miracle de la Justice divine, le meurtre
s’était retourné contre celui qui appelait le meurtre sur autrui.
 ÉPILOGUE

L’attentat de Charles souleva une assez grande émotion dans

Paris.
Les fidèles, reconnaissant l’intervention de la Providence dans le
châtiment si prompt et si terrible de l’assassin, s’unirent pour rendre
grâces au Dieu d’équité qui a dit : « Je me suis réservé la
vengeance ».
Le peuple, qui garde du bon sens et des sentiments généreux
lorsque les sectaires qui l’exploitent ne le rendent point frénétique,
témoigna de l’horreur pour un assassin dont la barbarie avait failli
frapper des femmes sans défense. Les plus indulgents le plaignirent
comme un fou dont l’acte ne s’expliquait guère. D’autres — et ils
étaient nombreux — se sentirent troublés par les circonstances du
drame. Il se disait dans les ateliers :
— Pour sûr, c’est singulier qu’il se soit tué lui-même au moment
où il voulait chambarder Notre-Dame. Est-ce que, des fois, ce ne
seraient pas des blagues ce que racontent les calotins ? Y aurait-il
un Bon Dieu pour veiller sur nous ?
Cet état d’esprit prenant de l’extension, la Maçonnerie s’en
alarma et fit donner la presse athée. Divers journaux épiloguèrent à
l’infini sur les portes à ressort et le danger des explosifs maniés par
un agité. Le tout pour conclure à un hasard dont il fallait se féliciter
sans y reconnaître rien d’extraordinaire. Puis ils mirent les citoyens
en garde contre les manœuvres du « parti clérical » et ils insinuèrent
que les catholiques, lorsqu’ils affirmaient que la mort de Charles
prouvait, une fois de plus, l’existence du Surnaturel, méditaient de
rétablir l’Inquisition. Ensuite, ils couvrirent d’outrages le Cardinal-
archevêque qui s’était permis d’ordonner des prières expiatoires et
une cérémonie de purification de la Basilique où vint une foule
énorme. Bien entendu, ils rappelèrent, à ce propos, la révocation de
l’Édit de Nantes et la Saint-Barthélemy.
Enfin, pour faire entièrement diversion, ils organisèrent un défilé
des Loges devant la statue d’Étienne Dolet, ce précurseur dont la
libre-pensée alla jusqu’à l’uranisme.
Parmi les pauvres cervelles qui constituent ce que l’on baptise —
personne ne sait pourquoi — le grand monde, on éprouva d’abord
une frousse intense à la pensée que le meurtrier aurait pu jeter son
engin dans une paroisse élégante, à l’une de ces messes où les
gens du « dernier cri » font à Dieu l’honneur de venir s’ennuyer
pendant vingt minutes devant ses autels. Quelques caillettes chères
au Tout-Paris poussèrent des soupirs affectés et firent mine de
s’évanouir quand on parlait de Charles. Puis, comme un Juif fétide
mais fort millionnaire annonçait un grand bal, la « haute société » se
tourna toute vers un événement aussi considérable. On ne rêva plus
que de toilettes ébouriffantes et chacun se demanda s’il obtiendrait
la faveur d’une invitation à gigoter sous les regards chassieux de cet
Israélite.
L’explosion de la bombe ne surprit pas du tout Legranpan. Il
manda son chef de cabinet Lhiver et lui conta comment il avait
manqué, lui-même, d’être assassiné par le fils de Mandrillat. Puis,
songeant au désarroi où le Vénérable devait s’effondrer, il éclata de
ce rire en claquement de castagnettes archi-sèches dont il avait
coutume et dit :
— Du coup, voilà le banquet à l’eau, car vous comprenez bien,
Lhiver, que ce n’est pas le moment de repêcher ce pauvre Mandrillat
chu dans la mélasse par la faute de sa progéniture…
Mais ce qui importe, c’est d’exploiter la chose. Il faut détourner
l’attention des imbéciles de la Chambre qui espéraient se servir du
Maroc pour me flanquer à bas du pouvoir. Ah ! on dit qu’il y a des
fissures dans le Bloc : eh ! bien, nous allons les cimenter. Je fais
coffrer un certain nombre d’anarchistes et notamment les membres
du comité-directeur de la C. G. T. — Cela suscitera une interpellation
de l’Extrême-Gauche. Je monterai alors à la tribune : j’expliquerai
qu’en prenant cette mesure j’ai sauvé la République. Et je veux
devenir Pape si mes dindons radicaux et les bonnes poires du
Centre ne me votent pas, à une forte majorité, l’ordre du jour de
confiance que j’exigerai. Quant à ces messieurs de la Sociale, je
sais pertinemment, par les rapports de police, qu’ils ne sont pour
rien dans la stupide manifestation de Mandrillat junior. On les
relâchera donc dès que l’effet sera produit. S’ils braillent à
l’arbitraire, on leur collera une gratification pour leur Bourse du
travail ; cela leur fermera le bec…
Il en fut ainsi. Plusieurs révolutionnaires, dont Jourry, Sucre et
Greive, allèrent passer quelques jours à la Conciergerie. Le crime de
Charles les avait fort ennuyés car, comme tous les débitants de
drogues anarchistes, s’ils estimaient fort licite de prêcher l’impiété, le
vol et le massacre des « infâmes capitalistes », ils tremblaient dès
qu’un impatient de l’âge d’or promis par le socialisme appliquait
prématurément leur doctrine.
Charles ayant rompu avec eux, ils ne pouvaient se rendre
compte de l’inhumanité spéciale qui détermina le malheureux. C’est
pourquoi, sitôt remis en liberté, ils publièrent des articles où leur
ancien camarade était dénoncé, comme un agent provocateur que le
gouvernement avait soudoyé pour fournir un prétexte à leur
arrestation.
Le plus répugnant de tous fut Mandrillat.
Furieux et grotesque à la fois, il secouait sa femme qui se
permettait de verser quelques larmes, plutôt machinales, sur le
corps déchiré de leur enfant. Il lui défendit de prendre le deuil. Pour
le public, il se posa en Brutus et déclara aux reporters qui
assiégeaient sa porte que si son scélérat de fils avait survécu, il
l’aurait conduit de sa propre main à la guillotine.
 Cet héroïsme lui valut une batterie d’honneur au Grand-Orient.
Mais ce fut tout. Il fit tant de tapage que Legranpan, agacé de le voir
revenir sans cesse sur un incident dont nul ne voulait plus entendre
parler parce qu’il provoquait trop de réflexions désagréables, lui
ordonna, d’une façon fort impérieuse, de se taire.
Mandrillat obéit et, pour faire peau neuve, entreprit un voyage en
Allemagne. Il s’y aboucha avec quelques financiers de Berlin et de
Francfort qui désiraient introduire des valeurs véreuses sur le
marché français. Le résultat fructueux de cette villégiature le consola
bien vite du déboire qu’il venait de subir.
Cependant la police avait fait une perquisition dans l’appartement
de la place Médicis. Elle ne trouva naturellement rien qui pût la
mettre sur la piste d’un complot puisque Charles avait agi de lui-
même et s’était gardé de se confier à personne. Chériat et Robert
interrogés ne purent que rapporter la tristesse farouche de leur ami
depuis des semaines et la façon dont il s’enfuit, malgré leurs efforts,
le matin où la bombe éclata. On ne les inquiéta point, car il était de
toute évidence qu’ils n’encouraient pas de responsabilité dans un
crime dont, jusqu’au dernier moment, ils avaient ignoré la
préparation.
Le seul indice qu’on découvrit des projets de Charles fut un
papier où il avait tracé, d’une main fébrile, ces mots : « L’homme
libre écarte les dogmes, les lois et tout ce qui entrave son droit à la
révolte. Il ne croit qu’en lui-même. Il frappe pour se grandir et il reste
sourd aux plaintes de ses victimes. C’est ainsi qu’il devient le
surhomme… »
Et maintenant Robert Abry, assisté de Madame Viard, qui était
accourue auprès de son frère, s’empressait autour du malade dont
l’état s’était aggravé du fait de la scène terrible qui précéda la mort
de Charles.
Enfin, à force de soins, Chériat se sentit un peu mieux. Mais si
ses souffrances corporelles avaient diminué, son esprit restait tout
anxieux.
Fixant sur Robert un regard de détresse, il dit :
 — Mais comment, comment tout cela est-il arrivé ?… Comment
Charles a-t-il pu concevoir un dessein aussi épouvantable ?
— Ne parle pas, supplia la veuve, calme-toi, tu vas encore te
faire du mal…
— Eh bien je me tairai. Mais que Robert me rassure car je ne
comprends plus rien à rien et il me semble que je suis environné de
fantômes…
Robert était si profondément bouleversé qu’il ne réussit pas
d’abord à répondre. Dans son chagrin, il se demandait, lui aussi,
comment et pourquoi ? Et il se reprochait presque de n’avoir pas
deviné assez tôt le drame funèbre qui s’était déroulé dans l’âme de
son ami.
— Si j’avais insisté quand il vint rue d’Ulm, se disait-il, peut-être
m’aurait-il confié son affreux secret et aurais-je pu le fléchir… Il
courbait la tête, éperdu d’incertitude et se retenant pour ne pas
sangloter. Mais comme Chériat lui touchait le bras, d’un geste
suppliant, il fit un effort et dit d’une voix altérée :
— Avant tout, prions. Ce n’est qu’en sollicitant le secours d’En-
Haut que nous réussirons à échapper aux images sinistres qui nous
obsèdent.
— Oui, prions, répéta Mme Viard, qui s’agenouilla tandis que les
deux hommes joignaient les mains, prions la Sainte-Vierge. Jamais
nous n’avons eu plus besoin d’Elle puisqu’on la nomme, à juste titre,
la Consolatrice des affligés.
Par une inspiration spontanée, elle récita les litanies puis elle
proféra ce sublime appel à l’aide de la Grande-Auxiliatrice, le Sub
Tuum : Nous nous réfugions sous sa protection, Sainte Mère de
Dieu. Ne rejette pas la prière que nous t’adressons dans notre peine
excessive et garde-nous toujours de tout péril, ô Vierge de gloire et
de bénédiction…
A mesure qu’elle prononçait les saintes paroles, Robert se
rassérénait. Ainsi que bien d’autres fois, il vérifiait qu’on ne
s’adresse jamais en vain à Celle qui a reçu le pouvoir de réconforter
les cœurs trop éprouvés. La lumière se refit en lui et ce fut tout
enflammé d’une ardeur ineffable qu’à son tour, il récita le Memorare
de saint Bernard.
Quand il eut dit l’invocation finale : Noli, Mater Verbi, verba mea
despicere, sed audi, propitia et exaudi, son âme s’était reconquise.
De même, Chériat s’apaisait. Les ténèbres tragiques qui venaient
de descendre sur lui se dissipaient pour faire place à une aurore
angélique.
O Sainte Église, ce sont là les dictames que tu départis à tes
fidèles !…
— Ne prierons-nous pas aussi pour Charles, murmura-t-il, sa
pauvre âme, où est-elle à présent ?
— Certes approuva Robert, nous allons prier pour lui. Dieu est si
bon : je veux espérer qu’au moment suprême, il a permis que
l’infortuné ait une pensée de contrition.
— Et puis, reprit Chériat, rappelle-toi qu’il était charitable. Il m’a
recueilli mourant de misère. Presque tout son argent, il le donnait
aux pauvres… Louise Larbriselle peut en témoigner… Jusqu’au jour
où il devint si sombre et si méfiant, nul n’aurait pu le taxer de
perversité. Comme tant d’autres, comme moi-même avant que
Notre-Seigneur m’éclairât, il vivait dans l’erreur mais il était de bonne
foi. Où aurait-il appris à se garder du mal ? Ce n’est pas dans le
milieu où il fut élevé puisque, nous le savons, on s’est appliqué à lui
nourrir l’esprit d’athéisme et d’orgueil.
— Il m’a demandé de prier pour lui, dit Mme Viard en pleurant.
— Oui, conclut Robert, la Justice divine qui, seule, est infaillible,
pèsera tout cela dans sa balance. Mais ce qui me fait frissonner
c’est que je réfléchis qu’ils sont des milliers à présent, dans notre
pauvre pays, qui subissent une éducation analogue à celle de
Charles. On ne veut plus de Dieu ; on fait le vide dans les âmes.
Puis l’on s’étonne que le démon s’y installe à la place de ce Dieu
qu’on jette à la voirie parmi les outrages et les crachats… Je sais : il
est de mode de sourire lorsqu’un croyant affirme que le diable
s’empare de nous dès que nous nous détournons de l’Église.
 Pour expliquer les crimes qui se multiplient, la frénésie de
jouissance, l’inquiétude sans but qui possèdent tant de nos
contemporains, la Science, pauvre folle infatuée d’elle-même, bat les
buissons çà et là, bâtit cent systèmes, cent châteaux de sable
qu’elle n’édifie que pour les renverser la minute d’après et pour
courir à de nouvelles illusions. Des philosophies se hissent sur des
piédestaux branlants et affirment que l’homme n’est qu’une
mécanique instable mue par des forces aveugles et que le bonheur
consiste à satisfaire ses pulsions jusqu’à la satiété. On instaure le
règne de la Bête d’après cette maxime : « La vie est un cauchemar
entre deux néants. » Pour l’oublier régalons nos instincts !
Cependant le démon verse les ténèbres du désespoir dans l’âme
des sensitifs et des douloureux qu’une telle odieuse doctrine ne suffit
pas à contenter. La France est ivre d’impiété ; par suite le nombre ne
cesse de s’accroître de ceux qui, comme notre ami, tombent sous le
joug du Mauvais parce que nul ne les avertit que, seule, notre sainte
religion peut les en préserver. Hélas, ils se disent libres ; et on les
força d’ignorer qu’en rejetant, comme une lisière importune, la
sauvegarde de la foi, ils se soumettent au plus irrémissible des
esclavages : celui du péché.
Ah ! prions, prions pour Charles. Prions aussi pour la France,
supplions le Seigneur d’avoir pitié de nous.
Et suivi par la veuve et le malade, il dit humblement les versets
du De profundis :

« Des profondeurs de l’abîme, nous crions vers toi, Seigneur.

Seigneur, écoute notre voix.
« Que tes oreilles se rendent attentives à la voix de notre
déprécation.
« Si tu observes nos iniquités, Seigneur, qui de nous soutiendra
ton regard ?
« Mais parce que la miséricorde est en toi, Seigneur, j’espère à
cause de ta loi.
 « Mon âme se confie en ton verbe ; mon âme espère dans le
Seigneur.
« Depuis la vigile du matin jusqu’à la nuit, que ton peuple espère
en toi, Seigneur.
« Parce que la miséricorde appartient au Seigneur et qu’auprès
de lui la rédemption est abondante.
« Et lui-même rachètera son peuple de toutes les iniquités.
« Seigneur donne aux âmes des morts le repos éternel et fais
luire sur eux ta lumière sans fin.
« Qu’ils reposent en paix. — Ainsi soit-il. »

Tous trois s’embrassèrent. Puis Robert, debout et les yeux au

ciel, reprit :
— Seigneur, nous ne sommes rien sans ton secours. S’il est
dans tes desseins que nous périssions, que ta volonté s’accomplisse
et non la nôtre. Mais, ô mon Dieu, si pour sauver notre France qui se
détourne de ta Face, il est besoin de victimes expiatoires, nous voici
prêts à souffrir pour que ton Nom soit sanctifié, pour que ton règne
arrive.
Pour les folies et les péchés des égarés qui te défient, l’injure et
le sarcasme à la bouche, nous nous offrons à ta colère. Toi,
cependant, ramène-les dans tes voies ; distribue-leur le pain
suprasubstantiel : ta parole immuable.
Comme il nous fut prescrit par ton Fils, nous leur pardonnons,
sans arrière-pensée, sans restrictions vindicatives, les persécutions
qu’ils infligent à ton Église. De même, ne les traite pas d’après
l’énormité de leur ingratitude envers toi, mais considère leur
aveuglement.
Par l’incarnation de ton Fils, par ses souffrances et ses plaies,
par la Croix qui ne cesse d’étendre sur le monde ses bras
rédempteurs, par ta Sainte-Mère, refuge des pécheurs, appui des
malheureux, étoile du matin, arche de ton alliance avec nous, par les
mérites de tous les Saints qui combattirent et triomphèrent pour ta
gloire, accueille notre supplication ; fais cesser cette trop longue
tentation. Libère la France du démon d’orgueil qui l’opprime ; délivre-
nous du mal. Ainsi soit-il.
D’un même élan, tous trois répétèrent :
— O Dieu le Père, qui es la Justice, ô Dieu le Fils, qui es l’Amour,
ô Dieu le Saint-Esprit qui es la Grâce, Sainte-Trinité, un seul Dieu,
libère la France du démon qui l’opprime, délivre nous du mal…
Et longtemps, agenouillés côte à côte, ils demeurèrent en
oraison, selon l’esprit de la Sainte-Église catholique, en dehors de
laquelle il n’y a ni lumière, ni vérité, ni consolation, ni salut.

Benevolens lector, in nomine

Domini, ora pro scriptore.

Fin

Note. — L’auteur croit devoir rappeler que pour l’explosion qui termine le livre
par la mort de Charles, il n’a rien inventé.
En effet, les choses se passèrent exactement telles quelles à l’église de la
Madeleine en 1894.
L’auteur n’a fait que transposer l’événement à Notre-Dame.

Saint-Amand, Cher. — Imprimerie BUSSIÈRE.

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