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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

FIGURE 2 -1 4
No rm a l b o n e m a rro w. This is a low-power view o a section o
a normal bone marrow biopsy stained with hematoxylin and
eosin (H&E). Note that the nucleated cellular elements account
or ~40–50% and the at (clear areas) accounts or ~50–60% o the
area. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed.
New York, McGraw-Hill, 2010.)
and, in the presence o acute or chronic in ammation, may
rise several- old above baseline levels. As a rule, a serum
erritin >200 µg/L means there is at least some iron in tis-
sue stores.
Bone Marrow Examination A bone marrow aspirate and smear
or a needle biopsy can be use ul in the evaluation o some
patients with anemia. In patients with hypoproli erative
anemia and normal iron status, a bone marrow is indicated.
Marrow examination can diagnose primary marrow dis-
orders such as myelo brosis, a red cell maturation de ect,
or an in ltrative disease (Figs. 2-14 to 2-16). T e increase
or decrease o one cell lineage (myeloid vs erythroid)
FIGURE 2 -1 5
Eryth ro id hyp e rp la sia . This marrow shows an increase in the
raction o cells in the erythroid lineage as might be seen when a
normal marrow compensates or acute blood loss or hemolysis. The
myeloid/erythroid (M/E) ratio is about 1:1. (From RS Hillman et al:
Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)
17
C
H
A
P
T
E
R
2
FIGURE 2 -1 6
Mye lo id h yp e rp la sia . This marrow shows an increase in
A
n
the raction o cells in the myeloid or granulocytic lineage as
e
m
might be seen in a normal marrow responding to in ection. The
i
a
a
myeloid/erythroid (M/E) ratio is >3:1. (From RS Hillman et al: Hema-
n
d
tology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)
P
o
l
y
c
y
t
compared to another is obtained by a di erential count
h
e
m
o nucleated cells in a bone marrow smear (the myeloid/
i
a
erythroid [M/E] ratio). A patient with a hypoproli erative
anemia (see below) and a reticulocyte production index
<2 will demonstrate an M/E ratio o 2 or 3:1. In contrast,
patients with hemolytic disease and a production index >3
will have an M/E ratio o at least 1:1. Maturation disorders
are identi ed rom the discrepancy between the M/E ratio
and the reticulocyte production index (see below). Either
the marrow smear or biopsy can be stained or the presence
o iron stores or iron in developing red cells. T e storage
iron is in the orm o erritin or hemosiderin. On care ully
prepared bone marrow smears, small erritin granules can
normally be seen under oil immersion in 20–40% o devel-
oping erythroblasts. Such cells are called sideroblasts.
OTHER LABORATORY MEASUREMENTS Additional laboratory
tests may be o value in con rming speci c diagnoses. For
details of these tests and how they are applied in indi-
vidual disorders, see Chaps. 7 to 11.
DEFINITION AND CLASSIFICATION OF
ANEMIA
In itia l cla ssif ca tio n o a n em ia
T e unctional classi cation o anemia has three major
categories. T ese are (1) marrow production de ects
(hypoproli eration), (2) red cell maturation de ects (ine -
ective erythropoiesis), and (3) decreased red cell sur-
vival (blood loss/hemolysis). T e classi cation is shown
in Fig. 2-17. A hypoproli erative anemia is typically
seen with a low reticulocyte production index together
with little or no change in red cell morphology (a nor-
mocytic, normochromic anemia) (Chap. 7). Maturation
disorders typically have a slight to moderately elevated
18 ALGORITHM OF THE P HYS IOLOGIC CLAS S IFICATION OF ANEMIA Hyp o p ro li era tive a n em ia s
Ane mia At least 75% o all cases o anemia are hypoproli -
erative in nature. A hypoproli erative anemia re ects
absolute or relative marrow ailure in which the ery-
CBC, re ticulocyte
count throid marrow has not proli erated appropriately or
the degree o anemia. T e majority o hypoproli era-
tive anemias are due to mild to moderate iron de -
Index < 2.5 Index ≥ 2.5
ciency or in ammation. A hypoproli erative anemia
can result rom marrow damage, iron de ciency, or
S
Re d ce ll He molys is / inadequate EPO stimulation. T e last may re ect
E
C
morphology he morrha ge
impaired renal unction, suppression o EPO produc-
T
I
O
Blood los s
tion by in ammatory cytokines such as interleukin
N
Normocytic Micro or
I
1, or reduced tissue needs or O 2 rom metabolic dis-
I
normochromic ma crocytic Intrava s cula r
he molys is
ease such as hypothyroidism. Only occasionally is the
Me ta bolic de fe ct marrow unable to produce red cells at a normal rate,
C
Hypoprolife ra tive Ma tura tion dis orde r
and this is most prevalent in patients with renal ail-
a
Me mbra ne
r
d
a bnorma lity
i
ure. With diabetes mellitus or myeloma, the EPO de -
n
Ma rrow da ma ge Cytopla s mic de fe cts
a
l
• Infiltra tion/fibros is • Iron de ficie ncy He moglobinopa thy ciency may be more marked than would be predicted
M
• Apla s ia • Tha la s s e mia
a
by the degree o renal insu ciency. In general, hypo-
n
Iron de ficie ncy • S ide robla s tic Immune de s truction
i
f
a ne mia
e
proli erative anemias are characterized by normocytic,
s
S timula tion Fra gme nta tion
t
a
• Infla mma tion Nucle a r de fe cts normochromic red cells, although microcytic, hypo-
t
he molys is
i
o
• Me ta bolic de fe ct • Fola te de ficie ncy
n
• Re na l dis e a s e • Vita min B 12 de ficie ncy chromic cells may be observed with mild iron de -
s
o
• Drug toxicity
ciency or long-standing chronic in ammatory disease.
f
H
• Re fra ctory a ne mia
e
T e key laboratory tests in distinguishing between the
m
a
various orms o hypoproli erative anemia include the
t
o
FIGURE 2 -1 7
l
serum iron and iron-binding capacity, evaluation o
o
g
Th e p hysio lo g ic cla ssi ca tio n o a n e m ia . CBC, complete blood
i
c
renal and thyroid unction, a marrow biopsy or aspi-
D
count.
i
rate to detect marrow damage or in ltrative disease,
s
e
a
s
and serum erritin to assess iron stores. An iron stain
e
reticulocyte production index that is accompanied by
either macrocytic (Chap. 9) or microcytic (Chaps. 7, 8) o the marrow will determine the pattern o iron dis-
red cell indices. Increased red blood cell destruction tribution. Patients with the anemia o acute or chronic
secondary to hemolysis results in an increase in the in ammation show a distinctive pattern o serum
reticulocyte production index to at least three times iron (low), IBC (normal or low), percent trans er-
normal (Chap. 10), provided su cient iron is avail- rin saturation (low), and serum erritin (normal or
able. Hemorrhagic anemia does not typically result in high). T ese changes in iron values are brought about
production indices o more than 2.0–2.5 times normal by hepcidin, the iron regulatory hormone that is pro-
because o the limitations placed on expansion o the duced by the liver and is increased in in ammation
erythroid marrow by iron availability. (Chap. 7). A distinct pattern o results is noted in mild
In the rst branch point o the classi cation o ane- to moderate iron de ciency (low serum iron, high
mia, a reticulocyte production index >2.5 indicates IBC, low percent trans errin saturation, low serum
that hemolysis is most likely. A reticulocyte production erritin) (Chap. 7). Marrow damage by drugs, in ltra-
index <2 indicates either a hypoproli erative anemia tive disease such as leukemia or lymphoma, or marrow
or maturation disorder. T e latter two possibilities can aplasia is diagnosed rom the peripheral blood and
of en be distinguished by the red cell indices, by exami- bone marrow morphology. With in ltrative disease or
nation o the peripheral blood smear, or by a marrow brosis, a marrow biopsy is required.
examination. I the red cell indices are normal, the
anemia is almost certainly hypoproli erative in nature. Ma tura tio n d iso rd ers
Maturation disorders are characterized by ine ective
red cell production and a low reticulocyte production T e presence o anemia with an inappropriately low
index. Bizarre red cell shapes—macrocytes or hypo- reticulocyte production index, macro- or microcytosis
chromic microcytes—are seen on the peripheral blood on smear, and abnormal red cell indices suggests a mat-
smear. With a hypoproli erative anemia, no erythroid uration disorder. Maturation disorders are divided into
hyperplasia is noted in the marrow, whereas patients two categories: nuclear maturation de ects, associated
with ine ective red cell production have erythroid with macrocytosis, and cytoplasmic maturation de ects,
hyperplasia and an M/E ratio <1:1. associated with microcytosis and hypochromia usually
 rom de ects in hemoglobin synthesis. T e inappropri-
ately low reticulocyte production index is a re ection
o the ine ective erythropoiesis that results rom the
destruction within the marrow o developing eryth-
roblasts. Bone marrow examination shows erythroid
hyperplasia.
Nuclear maturation de ects result rom vitamin
B12 or olic acid de ciency, drug damage, or myelo-
dysplasia. Drugs that inter ere with cellular DNA syn-
thesis, such as methotrexate or alkylating agents, can
produce a nuclear maturation de ect. Alcohol, alone, is
also capable o producing macrocytosis and a variable
degree o anemia, but this is usually associated with
olic acid de ciency. Measurements o olic acid and
vitamin B12 are critical not only in identi ying the spe-
ci c vitamin de ciency but also because they re ect di -
erent pathogenetic mechanisms (Chap. 9).
Cytoplasmic maturation de ects result rom severe
iron de ciency or abnormalities in globin or heme syn-
thesis. Iron de ciency occupies an unusual position
in the classi cation o anemia. I the iron-de ciency
anemia is mild to moderate, erythroid marrow proli -
eration is blunted and the anemia is classi ed as hypo-
proli erative. However, i the anemia is severe and
prolonged, the erythroid marrow will become hyper-
plastic despite the inadequate iron supply, and the ane-
mia will be classi ed as ine ective erythropoiesis with a
cytoplasmic maturation de ect. In either case, an inap-
propriately low reticulocyte production index, micro-
cytosis, and a classic pattern o iron values make the
diagnosis clear and easily distinguish iron de ciency
rom other cytoplasmic maturation de ects such as the
thalassemias. De ects in heme synthesis, in contrast to
globin synthesis, are less common and may be acquired
or inherited. Acquired abnormalities are usually associ-
ated with myelodysplasia, may lead to either a macro-
or microcytic anemia, and are requently associated
with mitochondrial iron loading. In these cases, iron
is taken up by the mitochondria o the developing ery-
throid cell but not incorporated into heme. T e iron-
encrusted mitochondria surround the nucleus o the
erythroid cell, orming a ring. Based on the distinctive
nding o so-called ringed sideroblasts on the marrow
iron stain, patients are diagnosed as having a sidero-
blastic anemia—almost always re ecting myelodyspla-
sia. Again, studies o iron parameters are help ul in the
di erential diagnosis o these patients.
Blo o d lo ss/h em o lytic a n em ia
In contrast to anemias associated with an inappropri-
ately low reticulocyte production index, hemolysis is
associated with red cell production indices ≥2.5 times
normal. T e stimulated erythropoiesis is re ected in the
blood smear by the appearance o increased numbers
o polychromatophilic macrocytes. A marrow exami- 19
nation is rarely indicated i the reticulocyte production
index is increased appropriately. T e red cell indices are
typically normocytic or slightly macrocytic, re ecting
the increased number o reticulocytes. Acute blood loss
is not associated with an increased reticulocyte produc-
tion index because o the time required to increase EPO
production and, subsequently, marrow proli eration.
Subacute blood loss may be associated with modest
reticulocytosis. Anemia rom chronic blood loss pres-
C
H
ents more of en as iron de ciency than with the picture
A
P
T
o increased red cell production.
E
R
T e evaluation o blood loss anemia is usually not di -
2
cult. Most problems arise when a patient presents with
an increased red cell production index rom an episode
A
o acute blood loss that went unrecognized. T e cause o
n
e
the anemia and increased red cell production may not
m
i
a
be obvious. T e con rmation o a recovering state may
a
n
require observations over a period o 2–3 weeks, during
d
P
o
which the hemoglobin concentration will rise and the
l
y
c
reticulocyte production index all (Chap. 10).
y
t
h
Hemolytic disease, while dramatic, is among the least
e
m
i
common orms o anemia. T e ability to sustain a high
a
reticulocyte production index re ects the ability o the
erythroid marrow to compensate or hemolysis and, in
the case o extravascular hemolysis, the e cient recy-
cling o iron rom the destroyed red cells to support red
cell production. With intravascular hemolysis, such as
paroxysmal nocturnal hemoglobinuria, the loss o iron
may limit the marrow response. T e level o response
depends on the severity o the anemia and the nature o
the underlying disease process.
Hemoglobinopathies, such as sickle cell disease and
the thalassemias, present a mixed picture. T e reticu-
locyte index may be high but is inappropriately low or
the degree o marrow erythroid hyperplasia (Chap. 8).
Hemolytic anemias present in di erent ways. Some
appear suddenly as an acute, sel -limited episode o
intravascular or extravascular hemolysis, a presentation
pattern of en seen in patients with autoimmune hemo-
lysis or with inherited de ects o the Embden-Meyerho
pathway or the glutathione reductase pathway. Patients
with inherited disorders o the hemoglobin molecule or
red cell membrane generally have a li elong clinical his-
tory typical o the disease process. T ose with chronic
hemolytic disease, such as hereditary spherocytosis,
may actually present not with anemia but with a com-
plication stemming rom the prolonged increase in red
cell destruction such as symptomatic bilirubin gall-
stones or splenomegaly. Patients with chronic hemoly-
sis are also susceptible to aplastic crises i an in ectious
process interrupts red cell production.
T e di erential diagnosis o an acute or chronic
hemolytic event requires the care ul integration o
amily history, the pattern o clinical presentation,
20 and—whether the disease is congenital or acquired— Of en patients with polycythemia are detected through
care ul examination o the peripheral blood smear. Pre- an incidental nding o elevated hemoglobin or hema-
cise diagnosis may require more specialized laboratory tocrit levels. Concern that the hemoglobin level may
tests, such as hemoglobin electrophoresis or a screen be abnormally high is usually triggered at 170 g/L
or red cell enzymes. Acquired de ects in red cell sur- (17 g/dL) or men and 150 g/L (15 g/dL) or women.
vival are of en immunologically mediated and require a Hematocrit levels >50% in men or >45% in women
direct or indirect antiglobulin test or a cold agglutinin may be abnormal. Hematocrits >60% in men and
titer to detect the presence o hemolytic antibodies or >55% in women are almost invariably associated with
complement-mediated red cell destruction (Chap. 10). an increased red cell mass. Given that the machine
that quantitates red cell parameters actually measures
S
E
hemoglobin concentrations and calculates hematocrits,
C
T
I
TREATMENT Anemia hemoglobin levels may be a better index.
O
N
Features o the clinical history that are use ul in the
I
I
An overriding principle is to initiate treatment o mild to di erential diagnosis include smoking history; current
moderate anemia only when a speci c diagnosis is made. living at high altitude; or a history o congenital heart
Rarely, in the acute setting, anemia may be so severe that red disease, sleep apnea, or chronic lung disease.
C
a
r
cell trans usions are required be ore a speci c diagnosis is Patients with polycythemia may be asymptomatic or
d
i
n
available. Whether the anemia is o acute or gradual onset, the experience symptoms related to the increased red cell
a
l
M
selection o the appropriate treatment is determined by the mass or the underlying disease process that leads to the
a
n
documented cause(s) o the anemia. Of en, the cause o the increased red cell mass. T e dominant symptoms rom
i
f
e
s
anemia is multi actorial. For example, a patient with severe an increased red cell mass are related to hyperviscosity
t
a
t
i
rheumatoid arthritis who has been taking anti-in ammatory and thrombosis (both venous and arterial), because the
o
n
s
drugs may have a hypoproli erative anemia associated with blood viscosity increases logarithmically at hematocrits
o
f
>55%. Mani estations range rom digital ischemia to
H
chronic in ammation as well as chronic blood loss associ-
e
m
ated with intermittent gastrointestinal bleeding. In every Budd-Chiari syndrome with hepatic vein thrombosis.
a
t
o
circumstance, it is important to evaluate the patient’s iron Abdominal vessel thromboses are particularly common.
l
o
g
status ully be ore and during the treatment o any anemia. Neurologic symptoms such as vertigo, tinnitus, head-
i
c
D
Transfusion is discussed in Chap. 12; iron therapy is dis- ache, and visual disturbances may occur. Hypertension
i
s
e
cussed in Chap. 7; treatment of megaloblastic anemia is is of en present. Patients with polycythemia vera may
a
s
e
discussed in Chap. 9; treatment of other entities is dis- have aquagenic pruritus and symptoms related to hepa-
cussed in their respective chapters (sickle cell anemia, tosplenomegaly. Patients may have easy bruising, epi-
Chap. 8; hemolytic anemias, Chap. 10; aplastic anemia and staxis, or bleeding rom the gastrointestinal tract. Peptic
myelodysplasia, Chap. 11). ulcer disease is common. Patients with hypoxemia may
T erapeutic options or the treatment o anemias have develop cyanosis on minimal exertion or have head-
expanded dramatically during the past 30 years. Blood com- ache, impaired mental acuity, and atigue.
ponent therapy is available and sa e. Recombinant EPO as an T e physical examination usually reveals a ruddy
adjunct to anemia management has trans ormed the lives o complexion. Splenomegaly avors polycythemia vera as
patients with chronic renal ailure on dialysis and reduced the diagnosis (Chap. 13). T e presence o cyanosis or
trans usion needs o anemic cancer patients receiving chemo- evidence o a right-to-lef shunt suggests congenital heart
therapy. Eventually, patients with inherited disorders o glo- disease presenting in the adult, particularly tetralogy o
bin synthesis or mutations in the globin gene, such as sickle Fallot or Eisenmenger’s syndrome. Increased blood vis-
cell disease, may bene t rom the success ul introduction o cosity raises pulmonary artery pressure; hypoxemia
targeted genetic therapy. can lead to increased pulmonary vascular resistance.
ogether, these actors can produce cor pulmonale.
Polycythemia can be spurious (related to a decrease
P O LYCYTHEMIA in plasma volume; Gaisbock’s syndrome), primary,
or secondary in origin. T e secondary causes are all
Polycythemia is de ned as an increase in the hemoglo- associated with increases in EPO levels: either a physi-
bin above normal. T is increase may be real or only ologically adapted appropriate elevation based on tis-
apparent because o a decrease in plasma volume (spu- sue hypoxia (lung disease, high altitude, CO poisoning,
rious or relative polycythemia). T e term erythrocytosis high-a nity hemoglobinopathy) or an abnormal over-
may be used interchangeably with polycythemia, but production (renal cysts, renal artery stenosis, tumors
some draw a distinction between them: erythrocytosis with ectopic EPO production). A rare amilial orm o
implies documentation o increased red cell mass, polycythemia is associated with normal EPO levels but
whereas polycythemia re ers to any increase in red cells. hyperresponsive EPO receptors due to mutations.

APPROACHTOTHEPATIENT:
Polycythemia
As shown in Fig. 2-18, the rst step is to document the
presence o an increased red cell mass using the prin-
ciple o isotope dilution by administering 51Cr-labeled
autologous red blood cells to the patient and sampling
blood radioactivity over a 2-h period. I the red cell mass
is normal (<36 mL/kg in men, <32 mL/kg in women),
21
the patient has spurious or relative polycythemia. I the
red cell mass is increased (>36 mL/kg in men, >32 mL/kg
in women), serum EPO levels should be measured. I EPO
levels are low or unmeasurable, the patient most likely
has polycythemia vera. A mutation in JAK2 (Val617Phe),
a key member o the cytokine intracellular signaling path-
way, can be ound in 90–95% o patients with polycy-
themia vera. Many o those without this particular JAK2
mutation have mutations in exon 12. As a practical matter,

C
ew centers assess red cell mass in the setting o an

H
A
increased hematocrit. T e short workup is to measure

P
T
AN APPROACH TO DIAGNOS ING P ATIENTS WITH P OLYCYTHEMIA EPO levels, check or JAK2 mutation, and per orm an

E
R
abdominal ultrasound to assess spleen size. ests that sup-

2
Incre a s e d hct or hgb

norma l port the diagnosis o polycythemia vera include elevated

Me a s ure RBC ma s s Dx: Re la tive white blood cell count, increased absolute basophil count,

A
e rythrocytos is and thrombocytosis.

n
e
e leva te d

m
I serum EPO levels are elevated, one needs to distin-

i
a
low Confirm
guish whether the elevation is a physiologic response

a
Me a s ure s e rum Dx: Polycythe mia JAK2

n
EP O leve ls

d
ve ra muta tion to hypoxia or related to autonomous EPO production.

P
o
e leva te d Patients with low arterial O2 saturation (<92%) should be

l
y
c
y
low urther evaluated or the presence o heart or lung dis-

t
Me a s ure a rte ria l

h
Dia gnos tic eva lua tion for

e
O 2 s a tura tion he a rt or lung dis e a s e, ease, i they are not living at high altitude. Patients with

m
e.g., COP D, high a ltitude,

i
a
norma l AV or intra ca rdia c s hunt normal O2 saturation who are smokers may have elevated
no EPO levels because o CO displacement o O2. I car-
s moke r? Me a s ure he moglobin boxyhemoglobin (COHb) levels are high, the diagnosis is
O 2 a ffinity
ye s
norma l
“smoker’s polycythemia.” Such patients should be urged
incre a s e d to stop smoking. T ose who cannot stop smoking require
Me a s ure norma l phlebotomy to control their polycythemia. Patients with
ca rboxyhe moglobin Dx: O 2 a ffinity
leve ls he moglobinopa thy normal O2 saturation who do not smoke either have an
abnormal hemoglobin that does not deliver O2 to the
e leva te d S e a rch for tumor a s s ource of EP O
IVP /re na l ultra s ound (re na l Ca or cys t) tissues (evaluated by nding elevated O2–hemoglobin
Dx: S moke r’s CT of he a d (ce re be lla r he ma ngioma ) a nity) or have a source o EPO production that is not
polycythe mia CT of pe lvis (ute rine le iomyoma )
CT of a bdome n (he pa toma ) responding to the normal eedback inhibition. Further
workup is dictated by the di erential diagnosis o EPO-
producing neoplasms. Hepatoma, uterine leiomyoma, and
FIGURE 2 -1 8
renal cancer or cysts are all detectable with abdominopel-
An a p p ro a ch t o t h e d if e re n t ia l d ia g n o sis o p a t ie n ts wit h
vic computed tomography scans. Cerebellar hemangiomas
a n e le va t e d h e m o g lo b in (p o ssib le p o lycyt h e m ia ). AV, atrio-
may produce EPO, but they present with localizing neu-
ventricular; COPD, chronic obstructive pulmonary disease; CT,
computed tomography; EPO, erythropoietin; hct, hematocrit; hgb, rologic signs and symptoms rather than polycythemia-
hemoglobin; IVP, intravenous pyelogram; RBC, red blood cell. related symptoms.
 CH AP TER 3
BLEEDING AND THROMBOSIS
Ba rb ara A. Ko n kle
T e human hemostatic system provi es a natural bal-
ance between procoagulant an anticoagulant orces. T e
procoagulant orces inclu e platelet a hesion an aggre-
gation an brin clot ormation; anticoagulant orces
inclu e the natural inhibitors o coagulation an brino-
lysis. Un er normal circumstances, hemostasis is regu-
late to promote bloo ow; however, it is also prepare
to clot bloo rapi ly to arrest bloo ow an prevent
exsanguination. A er blee ing is success ully halte ,
the system remo els the amage vessel to restore nor-
mal bloo ow. T e major components o the hemostatic
system, which unction in concert, are (1) platelets an
other orme elements o bloo , such as monocytes an
re cells; (2) plasma proteins (the coagulation an bri-
nolytic actors an inhibitors); an (3) the vessel wall.
STEP S O F NO RMAL HEMO STASIS
PLATELET PLUG FORMATION
On vascular injury, platelets a here to the site o injury,
usually the enu e vascular intimal sur ace. Platelet
a hesion is me iate primarily by Von Willebran ac-
tor (VWF), a large multimeric protein present in both
plasma an the extracellular matrix o the suben othe-
lial vessel wall, which serves as the primary “molecular
glue,” provi ing su cient strength to withstan the
high levels o shear stress that woul ten to etach
them with the ow o bloo . Platelet a hesion is also
acilitate by irect bin ing to suben othelial collagen
through speci c platelet membrane collagen receptors.
Platelet a hesion results in subsequent platelet acti-
vation an aggregation. T is process is enhance an
ampli e by humoral me iators in plasma (e.g., epi-
nephrine, thrombin); me iators release rom activate
platelets (e.g., a enosine iphosphate, serotonin); an
vessel wall extracellular matrix constituents that come
in contact with a herent platelets (e.g., collagen, VWF).
22
Activate platelets un ergo the release reaction, ur-
ing which they secrete contents that urther promote
aggregation an inhibit the naturally anticoagulant
en othelial cell actors. During platelet aggregation
(platelet-platelet interaction), a itional platelets are
recruite rom the circulation to the site o vascular
injury, lea ing to the ormation o an occlusive platelet
thrombus. T e platelet plug is anchore an stabilize
by the eveloping brin mesh.
T e platelet glycoprotein (Gp) IIb/IIIa (αIIbβ3) com-
plex is the most abun ant receptor on the platelet sur-
ace. Platelet activation converts the normally inactive
Gp IIb/IIIa receptor into an active receptor, enabling
bin ing to brinogen an VWF. Because the sur ace o
each platelet has about 50,000 Gp IIb/IIIa–bin ing sites,
numerous activate platelets recruite to the site o vas-
cular injury can rapi ly orm an occlusive aggregate by
means o a ense network o intercellular brinogen
bri ges. Because this receptor is the key me iator o
platelet aggregation, it has become an ef ective target or
antiplatelet therapy.
FIBRIN CLOT FORMATION
Plasma coagulation proteins (clotting factors) normally cir-
culate in plasma in their inactive orms. T e sequence
o coagulation protein reactions that culminate in the
ormation o brin was originally escribe as a water-
fall or a cascade. wo pathways o bloo coagulation
have been escribe in the past: the so-calle extrinsic,
or tissue actor, pathway an the so-calle intrinsic, or
contact activation, pathway. We now know that coagu-
lation is normally initiate through tissue actor ( F)
exposure an activation through the classic extrinsic
pathway but with critically important ampli cation
through elements o the classic intrinsic pathway, as illus-
trate in Fig. 3-1. T ese reactions take place on phos-
pholipi sur aces, usually the activate platelet sur ace.
Coagulation testing in the laboratory can re ect other
 23
Ve s s e l IX
injury
IX
T
F VIIIa
VIIa
IXa XIa
X

TFP I
X
XI

C
H
A
P
T
Va

E
Xa II

R
3
(Prothrombin)
Thrombin (IIa )

B
l
e
Fibrinoge n Fibrin

e
d
i
n
g
FIGURE 3 -1

a
n
Co a g u la t io n is in it ia te d b y t issu e a ct o r TF e xp o su re , Once the TF/FVIIa/FXa complex is ormed, tissue actor pathway

d
T
which, with actor (F) VIIa, activates FIX and FX, which in turn, with inhibitor (TFPI) inhibits the TF/FVIIa pathway, making coagulation

h
r
o
FVIII and FV as co actors, respectively, results in thrombin orma- dependent on the ampli cation loop through FIX/FVIII. Coagula-

m
b
tion and subsequent conversion o brinogen to brin. Throm- tion requires calcium (not shown) and takes place on phospholipid

o
s
i
s
bin activates FXI, FVIII, and FV, ampli ying the coagulation signal. sur aces, usually the activated platelet membrane.

in uences ue to the arti cial nature o the in vitro sys- A D E D

tems use (see below).
T e imme iate trigger or coagulation is vascular Thrombin Fibrin a s s e mbly
amage that exposes bloo to F that is constitutively
expresse on the sur aces o suben othelial cellular com-
D E D D E D D E D
ponents o the vessel wall, such as smooth muscle cells B
an broblasts. F is also present in circulating micropar- D E D D E D D E D
ticles, presumably she rom cells inclu ing monocytes
an platelets. F bin s the serine protease actor VIIa; the Fibrin
Fa ctor XIIIa cros s -linking
complex activates actor X to actor Xa. Alternatively, the
complex can in irectly activate actor X by initially con- D E D D E D D E D
verting actor IX to actor IXa, which then activates ac- C
tor X. T e participation o actor XI in hemostasis is not D E D D E D D E D
epen ent on its activation by actor XIIa but rather on
its positive ee back activation by thrombin. T us, ac-
P la s min Clot lys is
tor XIa unctions in the propagation an ampli cation,
rather than in the initiation, o the coagulation casca e.
Factor Xa can be orme through the actions o D D D E
either the F/ actor VIIa complex or actor IXa (with
actor VIIIa as a co actor) an converts prothrombin to FIGURE 3 -2
thrombin, the pivotal protease o the coagulation sys- Fib rin o rm a t io n a n d d isso lu t io n . A Fibrinogen is a trinodu-
tem. T e essential co actor or this reaction is actor Va. lar structure consisting o two D domains and one E domain.
Like the homologous actor VIIIa, actor Va is pro uce Thrombin activation results in an ordered lateral assembly o pro-
by thrombin-in uce limite proteolysis o actor V. to brils B with noncovalent associations. Factor XIIIa cross-links
T rombin is a multi unctional enzyme that converts the D domains on adjacent molecules C. Fibrin and brinogen
soluble plasma brinogen to an insoluble brin matrix. (not shown) lysis by plasmin occurs at discrete sites and results
Fibrin polymerization involves an or erly process o in intermediary brin(ogen) degradation products (not shown).
intermolecular associations (Fig. 3-2). T rombin also d-Dimers are the product o complete lysis o brin D, maintain-
activates actor XIII ( brin-stabilizing actor) to actor ing the cross-linked D domains.
24 XIIIa, which covalently cross-links an thereby stabi- XII
lizes the brin clot.
T e assembly o the clotting actors on activate cell TF
XI
membrane sur aces greatly accelerates their reaction VII VIIa XIIa
rates an also serves to localize bloo clotting to sites o IX
vascular injury. T e critical cell membrane components,
VIIa /TF XIa
aci ic phospholipi s, are not normally expose on rest- TFP I
ing cell membrane sur aces. However, when platelets,
monocytes, an en othelial cells are activate by vas- IXa
cular injury or in ammatory stimuli, the procoagulant
S
VIIIa
E
hea groups o the membrane anionic phospholipi s
C
T
I
become translocate to the sur aces o these cells or
O
N
release as part o microparticles, making them avail- X Xa AT
I
I
able to support an promote the plasma coagulation PC
Va
reactions. PS
C
a
r
PT Th
d
i
n
a
l
M
ANTITHRO MBOTIC MECHANISMS
a
n
Fibrinoge n Fibrin FDP
i
f
e
Several physiologic antithrombotic mechanisms act in
s
t
a
t
concert to prevent clotting un er normal circumstances.
i
P la s min
o
n
T ese mechanisms operate to preserve bloo ui -
s
o
PA
f
ity an to limit bloo clotting to speci c ocal sites o
H
P la s minoge n
e
vascular injury. En othelial cells have many antithrom-
m
a
botic ef ects. T ey pro uce prostacyclin, nitric oxi e,
t
o
l
FIGURE 3 -3
o
an ectoADPase/CD39, which act to inhibit platelet
g
i
Site s o a ct io n o th e o u r m a jo r p hysio lo g ic a n t it h ro m -
c
bin ing, secretion, an aggregation. En othelial cells
D
i
b o tic p a t h wa ys: antithrombin (AT); protein C/S (PC/PS); tissue
s
pro uce anticoagulant actors inclu ing heparan pro-
e
a
actor pathway inhibitor (TFPI); and the brinolytic system, con-
s
teoglycans, antithrombin, F pathway inhibitor, an
e
sisting o plasminogen, plasminogen activator (PA), and plasmin.
thrombomo ulin. T ey also activate brinolytic mecha- PT, prothrombin; Th, thrombin; FDP, brin(ogen) degradation
nisms through the pro uction o tissue plasminogen products. (Modi ed rom BAKonkle, AI Scha er, in DP Zipes et al [eds]:
activator 1, urokinase, plasminogen activator inhibitor, Braunwald’s Heart Disease, 7th ed. Philadelphia, Saunders, 2005.)
an annexin-2. T e sites o action o the major physi-
ologic antithrombotic pathways are shown in Fig. 3-3.
Antithrombin (or antithrombin III) is the major en othelial cells places it in proximity to the throm-
plasma protease inhibitor o thrombin an the other bin-thrombomo ulin complex, thereby enhancing
clotting actors in coagulation. Antithrombin neutral- its activation e ciency. Activate protein C acts as an
izes thrombin an other activate coagulation ac- anticoagulant by cleaving an inactivating activate ac-
tors by orming a complex between the active site o tors V an VIII. T is reaction is accelerate by a co ac-
the enzyme an the reactive center o antithrombin. tor, protein S, which, like protein C, is a glycoprotein
T e rate o ormation o these inactivating complexes that un ergoes vitamin K– epen ent posttranslational
increases by a actor o several thousan in the pres- mo i cation. Quantitative or qualitative e ciencies
ence o heparin. Antithrombin inactivation o thrombin o protein C or protein S, or resistance to the action
an other activate clotting actors occurs physiologi- o activate protein C by a speci c mutation at its tar-
cally on vascular sur aces, where glycosoaminoglycans, get cleavage site in actor Va ( actor V Lei en), lea to
inclu ing heparan sul ates, are present to catalyze these hypercoagulable states.
reactions. Inherite quantitative or qualitative e cien- issue actor pathway inhibitor ( FPI) is a plasma
cies o antithrombin lea to a li elong pre isposition to protease inhibitor that regulates the F-in uce extrin-
venous thromboembolism. sic pathway o coagulation. FPI inhibits the F/ actor
Protein C is a plasma glycoprotein that becomes an VIIa/ actor Xa complex, essentially turning of the
anticoagulant when it is activate by thrombin. T e F/ actor VIIa initiation o coagulation, which then
thrombin-in uce activation o protein C occurs physi- becomes epen ent on the “ampli cation loop”
ologically on thrombomo ulin, a transmembrane pro- via actor XI an actor VIII activation by throm-
teoglycan-bin ing site or thrombin on en othelial cell bin. FPI is boun to lipoprotein an can also be
sur aces. T e bin ing o protein C to its receptor on release by heparin rom en othelial cells, where it
is boun to glycosaminoglycans, an rom platelets.
T e heparin-me iate release o FPI may play a role
in the anticoagulant ef ects o un ractionate an low-
molecular-weight heparins.
THE FIBRINOLYTIC SYSTEM
Any thrombin that escapes the inhibitory ef ects o the
physiologic anticoagulant systems is available to con-
vert brinogen to brin. In response, the en ogenous
brinolytic system is then activate to ispose o intra-
vascular brin an thereby maintain or reestablish the
patency o the circulation. Just as thrombin is the key
protease enzyme o the coagulation system, plasmin is
the major protease enzyme o the brinolytic system,
acting to igest brin to brin egra ation pro ucts.
T e general scheme o brinolysis an its control is
shown in Fig. 3-4.
T e plasminogen activators, tissue type plasminogen
activator (tPA) an the urokinase-type plasminogen
activator (uPA), cleave the Arg560-Val561 bon o plas-
minogen to generate the active enzyme plasmin. T e
lysine-bin ing sites o plasmin (an plasminogen) per-
mit it to bin to brin, so that physiologic brinolysis is
“ brin speci c.” Both plasminogen (through its lysine-
bin ing sites) an tPA possess speci c a nity or brin
an thereby bin selectively to clots. T e assembly o
a ternary complex, consisting o brin, plasminogen,
an tPA, promotes the localize interaction between
plasminogen an tPA an greatly accelerates the rate o
plasminogen activation to plasmin. Moreover, partial
UPA P la s minoge n
tPA
PAI P la s min
Thrombin
α 2 P I-P la s min
FDP s
FIGURE 3 -4
A sch e m a t ic d ia g ra m o t h e f b rin o lyt ic syst e m . Tissue plas-
minogen activator (tPA) is released rom endothelial cells, binds
the brin clot, and activates plasminogen to plasmin. Excess brin
is degraded by plasmin to distinct degradation products (FDPs).
Any ree plasmin is complexed with α2-antiplasmin (α 2Pl). PAI,
plasminogen activator inhibitor; UPA, urokinase-type plasmino-
gen activator.
egra ation o brin by plasmin exposes new plasmin- 25
ogen an tPA-bin ing sites in carboxy-terminus lysine
resi ues o brin ragments to enhance these reactions
urther. T is creates a highly e cient mechanism to
generate plasmin ocally on the brin clot, which then
becomes plasmin’s substrate or igestion to brin eg-
ra ation pro ucts.
Plasmin cleaves brin at istinct sites o the brin
molecule, lea ing to the generation o characteris-
tic brin ragments uring the process o brinolysis
C
H
(Fig. 3-2). T e sites o plasmin cleavage o brin are
A
P
the same as those in brinogen. However, when plas-
T
E
R
min acts on covalently cross-linke brin, d- imers are
3
release ; hence, - imers can be measure in plasma
as a relatively speci c test o brin (rather than brino-
gen) egra ation. d-Dimer assays can be use as sen-
B
l
e
sitive markers o bloo clot ormation an have been
e
d
i
n
vali ate or clinical use to exclu e the iagnosis o
g
a
eep venous thrombosis (DV ) an pulmonary embo-
n
d
lism in selecte populations. In a ition, d- imer mea-
T
h
r
surement can be use to strati y patients, particularly
o
m
women, or risk o recurrent venous thromboembo-
b
o
s
lism (V E) when measure 1 month a er iscontinu-
i
s
ation o anticoagulation given or treatment o an initial
i iopathic event. d-Dimer levels may be elevate in the
absence o V E in el erly people.
Physiologic regulation o brinolysis occurs primarily
at three levels: (1) plasminogen activator inhibitors
(PAIs), speci cally PAI-1 an PAI-2, inhibit the physio-
logic plasminogen activators; (2) the thrombin-activatable
brinolysis inhibitor ( AFI) limits brinolysis; an
(3) α2-antiplasmin inhibits plasmin. PAI-1 is the pri-
mary inhibitor o tPA an uPA in plasma. AFI cleaves
the N-terminal lysine resi ues o brin, which ai in
localization o plasmin activity. α2-Antiplasmin is the
main inhibitor o plasmin in human plasma, inactivating
any non brin clot-associate plasmin.
APPROACHTOTHEPATIENT:
Bleeding and Thrombosis
CLINICALPRESENTATION Disor ers o hemostasis may be ei-
ther inherite or acquire . A etaile personal an amily
history is key in etermining the chronicity o symptoms
an the likelihoo o the isor er being inherite , as well
as provi ing clues to un erlying con itions that have con-
tribute to the blee ing or thrombotic state. In a ition,
the history can give clues as to the etiology by etermining
(1) the blee ing (mucosal an /or joint) or thrombosis (ar-
terial an /or venous) site an (2) whether an un erlying
blee ing or clotting ten ency was enhance by another
me ical con ition or the intro uction o me ications or
ietary supplements.
26
History of Bleeding A history o blee ing is the most Easy bruising an menorrhagia are common com-
important pre ictor o blee ing risk. In evaluating a plaints in patients with an without blee ing isor ers.
patient or a blee ing isor er, a history o at-risk situa- Easy bruising can also be a sign o me ical con itions in
tions, inclu ing the response to past surgeries, shoul be which there is no i enti able coagulopathy; instea , the
assesse . Does the patient have a history o spontaneous con itions are cause by an abnormality o bloo vessels
or trauma/surgery-in uce blee ing? Spontaneous hem- or their supporting tissues. In Ehlers-Danlos syn rome,
arthroses are a hallmark o mo erate an severe actor there may be posttraumatic blee ing an a history o joint
VIII an IX e ciency an , in rare circumstances, o other hyperextensibility. Cushing’s syn rome, chronic steroi
clotting actor e ciencies. Mucosal blee ing symptoms use, an aging result in changes in skin an subcutaneous
S
are more suggestive o un erlying platelet isor ers or Von tissue, an subcutaneous blee ing occurs in response to
E
C
Willebran isease (VWD), terme disorders of primary minor trauma. T e latter has been terme senile purpura.
T
I
O
hemostasis or platelet plug formation. Disor ers af ecting Epistaxis is a common symptom, particularly in chil-
N
I
primary hemostasis are shown in Table 3-1. ren an in ry climates, an may not re ect an un er-
I
A blee ing score has been vali ate as a tool to pre- lying blee ing isor er. However, it is the most common
ict patients more likely to have type 1 VWD (Interna- symptom in here itary hemorrhagic telangiectasia an
C
tional Society on T rombosis an Haemostasis Blee ing in boys with VWD. Clues that epistaxis is a symptom o
a
r
d
i
Assessment ool [www.isth.org/resource/resmgr/ssc/isth-ssc_ an un erlying blee ing isor er inclu e lack o seasonal
n
a
l
bleeding_assessment.pdf]). T is is most use ul tool in variation an blee ing that requires me ical evaluation
M
a
exclu ing the iagnosis o a blee ing isor er, an thus or treatment, inclu ing cauterization. Blee ing with erup-
n
i
f
e
avoi ing unnecessary testing. One stu y oun that a tion o primary teeth is seen in chil ren with more severe
s
t
a
low blee ing score (≤3) an a normal activate partial blee ing isor ers, such as mo erate an severe hemo-
t
i
o
n
thromboplastin time (aP ) ha 99.6% negative pre ic- philia. It is uncommon in chil ren with mil blee ing
s
o
tive value or the iagnosis o VWD. Blee ing symptoms isor ers. Patients with isor ers o primary hemosta-
f
H
e
that appear to be more common in patients with blee ing sis (platelet a hesion) may have increase blee ing a er
m
a
isor ers inclu e prolonge blee ing with surgery, ental ental cleanings an other proce ures that involve gum
t
o
l
proce ures an extractions, an /or trauma, menorrha- manipulation.
o
g
i
c
gia or postpartum hemorrhage, an large bruises (o en Menorrhagia is e ne quantitatively as a loss o >80 mL
D
i
escribe with lumps). o bloo per cycle, base on the quantity o bloo loss
s
e
a
s
require to pro uce iron- e ciency anemia. A complaint
e
o heavy menses is subjective an has a poor correla-
TABLE 3 -1 tion with excessive bloo loss. Pre ictors o menorrhagia
PRIMARY HEMOSTATIC (PLATELET PLUG) inclu e blee ing resulting in iron- e ciency anemia or
DISORDERS a nee or bloo trans usion, passage o clots >1 inch
Defects of Platelet Adhesion in iameter, an changing a pa or tampon more than
Von Willebrand disease
hourly. Menorrhagia is a common symptom in women
Bernard-Soulier syndrome (absence or dys unction o platelet with un erlying blee ing isor ers an is reporte in
Gp Ib-IX-V) the majority o women with VWD, women with actor
Defects of Platelet Aggregation XI e ciency, an symptomatic carriers o hemophilia.
Women with un erlying blee ing isor ers are more
Glanzmann’s thrombasthenia (absence or dys unction o
platelet glycoprotein [Gp] IIb/IIIa) likely to have other blee ing symptoms, inclu ing blee -
A brinogenemia ing a er ental extractions, postoperative blee ing, an
Defects of Platelet Secretion
postpartum blee ing, an are much more likely to have
menorrhagia beginning at menarche than women with
Decreased cyclooxygenase activity
menorrhagia ue to other causes.
Drug-induced (aspirin, nonsteroidal anti-in ammatory
agents, thienopyridines) Postpartum hemorrhage (PPH) is a common symptom
Inherited in women with un erlying blee ing isor ers. In women
Granule storage pool de ects with type 1 VWD an symptomatic carriers o hemophilia
Inherited A in whom levels o VWF an actor VIII usually normal-
Acquired ize uring pregnancy, PPH may be elaye . Women with a
Nonspeci c inherited secretory de ects
history o PPH have a high risk o recurrence with subse-
Nonspeci c drug ef ects
Uremia quent pregnancies. Rupture o ovarian cysts with intraab-
Platelet coating (e.g., paraprotein, penicillin) ominal hemorrhage has also been reporte in women
Defect of Platelet Coagulant Activity
with un erlying blee ing isor ers.
onsillectomy is a major hemostatic challenge, because
Scott’s syndrome
intact hemostatic mechanisms are essential to prevent
 TABLE 3 -2 27
excessive blee ing rom the tonsillar be . Blee ing may
HERBAL SUPPLEMENTS ASSOCIATED WITH
occur early a er surgery or a er approximately 7 ays
INCREASED BLEEDING
postoperatively, with loss o the eschar at the operative
Herbs with Potential Antiplatelet Activity
site. Similar elaye blee ing is seen a er colonic polyp
resection. Gastrointestinal (GI) blee ing an hematuria Ginkgo (Ginkgo biloba L.)
are usually ue to un erlying pathology, an proce ures Garlic (Allium sativum)
Bilberry (Vaccinium myrtillus)
to i enti y an treat the blee ing site shoul be un er- Ginger (Gingiber of cinale)
taken, even in patients with known blee ing isor ers. Dong quai (Angelica sinensis)
VWD, particularly types 2 an 3, has been associate with Fever ew (Tanacetum parthenium)

C
angio ysplasia o the bowel an GI blee ing. Asian ginseng (Panax ginseng)

H
A
Hemarthroses an spontaneous muscle hematomas American ginseng (Panax quinque olius)

P
T
Siberian ginseng/eleuthero (Eleutherococcus senticosus)

E
are characteristic o mo erate or severe congenital ac-

R
Turmeric (Circuma longa)
tor VIII or IX e ciency. T ey can also be seen in mo -

3
Meadowsweet (Filipendula ulmaria)
erate an severe e ciencies o brinogen, prothrombin, Willow (Salix spp.)
an actors V, VII, an X. Spontaneous hemarthroses
Coumarin-Containing Herbs

B
occur rarely in other blee ing isor ers except or severe

l
e
e
Motherwort (Leonurus cardiaca)

d
VWD, with associate actor VIII levels <5%. Muscle an

i
n
Chamomile (Matricaria recutita, Chamaemelum mobile)

g
so tissue blee s are also common in acquire actor VIII

a
Horse chestnut (Aesculus hippocastanum)

n
e ciency. Blee ing into a joint results in severe pain an

d
Red clover (Tri olium pratense)

T
h
swelling, as well as loss o unction, but is rarely associ- Fenugreek (Trigonella oenum-graecum)

r
o
m
ate with iscoloration rom bruising aroun the joint.

b
o
Li e-threatening sites o blee ing inclu e blee ing into the

oropharynx, where blee ing can obstruct the airway, into
the central nervous system, an into the retroperitoneum.
Central nervous system blee ing is the major cause o
blee ing-relate eaths in patients with severe congenital
actor e ciencies.
Prohemorrhagic Effects of Medications and Dietary Supplements
Aspirin an other nonsteroi al anti-in lammatory rugs
(NSAIDs) that inhibit cyclooxygenase 1 impair primary
hemostasis an may exacerbate blee ing rom another
cause or even unmask a previously occult mil blee ing
isor er such as VWD. All NSAIDs, however, can pre-
cipitate GI blee ing, which may be more severe in patients
with un erlying blee ing isor ers. he aspirin e ect on
platelet unction as assesse by aggregometry can persist
or up to 7 ays, although it has requently returne to
normal by 3 ays a ter the last ose. he e ect o other
NSAIDs is shorter, as the inhibitor e ect is reverse
when the rug is remove . hienopyri ines (clopi ogrel
an prasugrel) inhibit ADP-me iate platelet aggregation
an , like NSAIDs, can precipitate or exacerbate blee ing
symptoms.
Many herbal supplements can impair hemostatic unc-
tion (Table 3-2). Some are more convincingly associate
with a blee ing risk than others. Fish oil or concentrate
omega-3 atty aci supplements impair platelet unction.
T ey alter platelet biochemistry to pro uce more PGI3, a
more potent platelet inhibitor than prostacyclin (PGI2),
an more thromboxane A3, a less potent platelet activa-
tor than thromboxane A2. In act, iets naturally rich in
omega-3 atty aci s can result in a prolonge blee ing time
an abnormal platelet aggregation stu ies, but the actual
associate blee ing risk is unclear. Vitamin E appears to
s
i
s
inhibit protein kinase C–me iate platelet aggregation
an nitric oxi e pro uction. In patients with unexplaine
bruising or blee ing, it is pru ent to review any new me i-
cations or supplements an iscontinue those that may be
associate with blee ing.
Underlying Systemic Diseases That Cause or Exacerbate a Bleeding
Tendency Acquire blee ing isor ers are commonly sec-
on ary to, or associate with, systemic isease. he clini-
cal evaluation o a patient with a blee ing ten ency must
there ore inclu e a thorough assessment or evi ence o
un erlying isease. Bruising or mucosal blee ing may
be the presenting complaint in liver isease, severe renal
impairment, hypothyroi ism, paraproteinemias or amy-
loi osis, an con itions causing bone marrow ailure. All
coagulation actors are synthesize in the liver, an hepatic
ailure results in combine actor e iciencies. his is o ten
compoun e by thrombocytopenia rom splenomegaly
ue to portal hypertension. Coagulation actors II, VII, IX,
an X an proteins C, S, an Z are epen ent on vitamin
K or posttranslational mo i ication. Although vitamin
K is require in both procoagulant an anticoagulant
processes, the phenotype o vitamin K e iciency or the
war arin e ect on coagulation is blee ing.
T e normal bloo platelet count is 150,000–450,000/µL.
T rombocytopenia results rom ecrease pro uction,
increase estruction, an /or sequestration. Although
the blee ing risk varies somewhat by the reason or the
thrombocytopenia, blee ing rarely occurs in isolate
thrombocytopenia at counts <50,000/µL an usually not
until <10,000–20,000/µL. Coexisting coagulopathies, as
is seen in liver ailure or isseminate coagulation; in ec-
tion; platelet-inhibitory rugs; an un erlying me ical
28
con itions can all increase the risk o blee ing in the DV increases per eca e, with an approximate inci ence
thrombocytopenic patient. Most proce ures can be per- o 1/100,000 per year in early chil hoo to 1/200 per year
orme in patients with a platelet count o 50,000/µL. among octogenarians. Family history is help ul in eter-
T e level nee e or major surgery will epen on the mining i there is a genetic pre isposition an how strong
type o surgery an the patient’s un erlying me ical state, that pre isposition appears to be. A genetic thrombophilia
although a count o approximately 80,000/µL is likely that con ers a relatively small increase risk, such as being
su cient. a heterozygote or the prothrombin G20210A or actor V
Lei en mutation, may be a minor eterminant o risk in
HISTORYOF THROMBOSIS T e risk o thrombosis, like that o
an el erly in ivi ual un ergoing a high-risk surgical pro-
blee ing, is in uence by both genetic an environmental
S
ce ure. As illustrate in Fig. 3-5, a thrombotic event usu-
E
in uences. T e major risk actor or arterial thrombosis is
C
ally has more than one contributing actor. Pre isposing
T
I
atherosclerosis, whereas or venous thrombosis, the risk
O
actors must be care ully assesse to etermine the risk
N
actors are immobility, surgery, un erlying me ical con i-
I
o recurrent thrombosis an , with consi eration o the
I
tions such as malignancy, me ications such as hormonal
patient’s blee ing risk, etermine the length o anticoagu-
therapy, obesity, an genetic pre ispositions. Factors that
lation. Similar consi eration shoul be given in etermin-
increase risks or venous an or both venous an arterial
C
ing the nee , i any, to test the patient an amily members
a
r
thromboses are shown in Table 3-3.
d
i
or thrombophilias.
n
T e most important point in a history relate to venous
a
l
M
thrombosis is etermining whether the thrombotic event LABORATORYEVALUATION Care ul history taking an clinical
a
n
was i iopathic (meaning there was no clear precipitat- examination are essential components in the assessment
i
f
e
s
ing actor) or was a precipitate event. In patients with- o blee ing an thrombotic risk. he use o laboratory
t
a
t
i
out un erlying malignancy, having an i iopathic event is
o
n
s
the strongest pre ictor o recurrence o V E. In patients
o
f
who have a vague history o thrombosis, a history o
H
e
m
being treate with war arin suggests a past DV . Age is an
a
OCP us e
k
t
s
important risk actor or venous thrombosis—the risk o
o
i
Le g in ca s t
r
l
o
c
g
i
HRT us e
t
i
o
c
b
DVT
D
m
i
s
o
e
r
Thrombos is
h
a
T
s
e
TABLE 3 -3 S urge ry
RISK FACTORS FOR THROMBOSIS
VENOUS VENOUS AND ARTERIAL

Inherited Inherited
Factor V Leiden Homocystinuria
Prothrombin G20210A Dys brinogenemia
Antithrombin de ciency Mixed (inherited and
Protein C de ciency acquired) Le id e n
Fa c to r V
Protein S de ciency Hyperhomocysteinemia
Elevated actor VIII
Acquired
Acquired Malignancy Age
Age Antiphospholipid antibody
Previous thrombosis syndrome FIGURE 3 -5
Immobilization Hormonal therapy Th ro m b o t ic risk o ve r t im e . Shown schematically is an indi-
Major surgery Polycythemia vera vidual’s thrombotic risk over time. An underlying actor V Leiden
Pregnancy and puerperium Essential thrombocythemia mutation provides a “theoretically” constant increased risk. The
Hospitalization Paroxysmal nocturnal
Obesity thrombotic risk increases with age and, intermittently, with oral
hemoglobinuria
In ection contraceptive (OCP) or hormone replacement therapy (HRT) use;
Thrombotic thrombocytope-
APC resistance, nongenetic other events may increase the risk urther. At some point, the
nic purpura
Smoking Heparin-induced cumulative risk may increase to the threshold or thrombosis and
Unknown a thrombocytopenia result in deep venous thrombosis (DVT). Note: The magnitude
Elevated actor II, IX, XI Disseminated intravascular and duration o risk portrayed in the gure are meant or example
Elevated TAFI levels coagulation only and may not precisely re ect the relative risk determined
Low levels o TFPI by clinical study. (From BA Konkle, A Scha er, in DP Zipes et al [eds]:
a
Unknown whether risk is inherited or acquired.
Braunwald’s Heart Disease, 7th ed. Philadelphia, Saunders, 2005;
Abbrevia tions: APC, activated protein C; TAFI, thrombin-activatable modi ed with permission rom FR Rosendaal: Venous thrombosis:
brinolysis inhibitor; TFPI, tissue actor pathway inhibitor. Amulticausal disease. Lancet 353:1167, 1999.)
 aPTT 29
tests o coagulation complement, but cannot substitute or,
clinical assessment. No test exists that provi es a global
assessment o hemostasis. he blee ing time has been HMWK
PT
use to assess blee ing risk; however, it oes not pre ict
PK
blee ing risk with surgery an it is not recommen e or
this in ication. he PFA-100, an instrument that measures FXII FVII
platelet- epen ent coagulation un er low con itions, is
FXI
more sensitive an speci ic or VWD than the blee ing
time; however, it is not sensitive enough to rule out mil FIX

C
blee ing isor ers. PFA-100 closure times are prolonge in

H
A
patients with some, but not all, inherite platelet isor ers. FVIII

P
T
E
Also, its utility in pre icting blee ing risk has not been FX

R
etermine .

3
FV
For routine preoperative an preproce ure testing, an
abnormal prothrombin time (P ) may etect liver is- Prothrombin (FII)

B
ease or vitamin K e ciency that ha not been previously

l
e
e
Fibrinoge n (FI)

d
appreciate . Stu ies have not con rme the use ulness

i
n
g
o an aP in preoperative evaluations in patients with

a
n
a negative blee ing history. T e primary use o coagula-

d
T
h
tion testing shoul be to con rm the presence an type

r
o
m
o blee ing isor er in a patient with a suspicious clinical FIGURE 3 -6

b
o
history. Co a g u la t io n a ct o r a ct ivit y tested in the activated partial

Because o the nature o coagulation assays, proper
sample acquisition an han ling is critical to obtaining
vali results. In patients with abnormal coagulation assays
who have no blee ing history, repeat stu ies with atten-
tion to these actors requently results in normal values.
Most coagulation assays are per orme in so ium citrate
anticoagulate plasma that is recalci e or the assay.
Because the anticoagulant is in liqui solution an nee s
to be a e to bloo in proportion to the plasma volume,
incorrectly lle or ina equately mixe bloo collection
tubes will give erroneous results. Vacutainer tubes shoul
be lle to >90% o the recommen e ll, which is usu-
ally enote by a line on the tube. An elevate hemato-
crit (>55%) can result in a alse value ue to a ecrease
plasma-to-anticoagulant ratio.
Screening Assays he most commonly use screening tests
are the P , aP , an platelet count. he P assesses the
actors I ( ibrinogen), II (prothrombin), V, VII, an X
(Fig. 3-6). he P measures the time or clot ormation o the
citrate plasma a ter recalci ication an a ition o throm-
boplastin, a mixture o F an phospholipi s. he sensi-
tivity o the assay varies by the source o thromboplastin.
he relationship between e ects in secon ary hemostasis
( ibrin ormation) an coagulation test abnormalities is
shown in Table 3-4. o a just or this variability, the over-
all sensitivity o i erent thromboplastins to re uction
o the vitamin K– epen ent clotting actors II, VII, IX,
an X in anticoagulation patients is now expresse as the
International Sensitivity In ex (ISI). An inverse relation-
ship exists between ISI an thromboplastin sensitivity. he
international normalize ratio (INR) is then etermine
base on the ormula: INR = (P patient/P normal mean)ISI.
s
i
s
thromboplastin time (aPTT) in red and prothrombin time (PT) in
green, or both. F, actor; HMWK, high-molecular-weight kinino-
gen; PK, prekallikrein.
T e INR was evelope to assess stable anticoagulation
ue to re uction o vitamin K– epen ent coagulation ac-
tors; it is commonly use in the evaluation o patients with
liver isease. Although it oes allow comparison between
laboratories, reagent sensitivity as use to etermine the
ISI is not the same in liver isease as with war arin anti-
coagulation. In a ition, progressive liver ailure is asso-
ciate with variable changes in coagulation actors; the
egree o prolongation o either the P or the INR only
roughly pre icts the blee ing risk. T rombin generation
has been shown to be normal in many patients with mil
to mo erate liver ys unction. Because the P only mea-
sures one aspect o hemostasis af ecte by liver ys unc-
tion, we likely overestimate the blee ing risk o a mil ly
elevate INR in this setting.
T e aP assesses the intrinsic an common coagula-
tion pathways; actors XI, IX, VIII, X, V, an II; brino-
gen; prekallikrein; high-molecular-weight kininogen; an
actor XII (Fig. 3-6). T e aP reagent contains phospho-
lipi s erive rom either animal or vegetable sources that
unction as a platelet substitute in the coagulation path-
ways an inclu es an activator o the intrinsic coagulation
system, such as nonparticulate ellagic aci or the particu-
late activators kaolin, celite, or micronize silica.
T e phospholipi composition o aP reagents varies,
which in uences the sensitivity o in ivi ual reagents to
clotting actor e ciencies an to inhibitors such as hepa-
rin an lupus anticoagulants. T us, aP results will vary
30 TABLE 3 -4
plasma an patient plasma are mixe in a 1:1 ratio, an the
HEMOSTATIC DISORDERS AND COAGULATION TEST
aP or P is etermine imme iately an a er incuba-
ABNORMALITIES
tion at 37°C or varying times, typically 30, 60, an /or 120
Pro lo n g e d Activate d Pa rtia l Th ro m b o p la stin Tim e a PTT
min. With isolate actor e ciencies, the aP will cor-
No clinical bleeding—↓ actor XII, high-molecular-weight rect with mixing an stay correcte with incubation. With
kininogen, prekallikrein aP prolongation ue to a lupus anticoagulant, the mix-
Variable, but usually mild, bleeding—↓ actor XI, mild ↓ actor
ing an incubation will show no correction. In acquire
VIII and actor IX
Frequent, severe bleeding—severe de ciencies o actors VIII neutralizing actor antibo ies, notably an acquire actor
and IX VIII inhibitor, the initial assay may or may not correct
S
Heparin and direct thrombin inhibitors imme iately a er mixing but will prolong or remain
E
C
prolonge with incubation at 37°C. Failure to correct with
T
Pro lo n g e d Pro t h ro m b in Tim e PT
I
O
mixing can also be ue to the presence o other inhibitors
N
Factor VII de ciency
I
or inter ering substances such as heparin, brin split pro -
I
Vitamin K de ciency—early
War arin anticoagulation ucts, an paraproteins.
Direct Xa inhibitors (rivaroxaban, apixaban)
Specific Factor Assays Decisions to procee with speci c
C
a
Pro lo n g e d a PTT a n d PT
r
clotting actor assays will be in uence by the clinical
d
i
n
Factor II, V, X, or brinogen de ciency
a
situation an the results o coagulation screening tests.
l
M
Vitamin K de ciency—late
Precise iagnosis an ef ective management o inherite
a
n
Direct thrombin inhibitors
i
an acquire coagulation e ciencies necessitate quan-
f
e
s
Pro lo n g e d Th ro m b in Tim e
t
titation o the relevant actors. When blee ing is severe,
a
t
i
Heparin or heparin-like inhibitors
o
speci c assays are urgently require to gui e appropriate
n
s
Direct thrombin inhibitors (e.g., dabigatran, argatroban, therapy. In ivi ual actor assays are usually per orme
o
f
bivalirudin)
H
as mo i cations o the mixing stu y, where the patient’s
e
Mild or no bleeding—dys brinogenemia
m
plasma is mixe with plasma e cient in the actor being
a
Frequent, severe bleeding—a brinogenemia
t
o
stu ie . T is will correct all actor e ciencies to >50%,
l
o
Pro lo n g e d PT a n d /o r a PTT No t Co rre cte d wit h Mixin g
g
thus making prolongation o clot ormation ue to a ac-
i
c
wit h No rm a l Pla sm a
D
tor e ciency epen ent on the actor missing rom the
i
s
Bleeding—speci c actor inhibitor
e
a e plasma.
a
s
No symptoms, or clotting and/or pregnancy loss—lupus
e
anticoagulant Testing for Antiphospholipid Antibodies Antibo ies to phos-
Disseminated intravascular coagulation
Heparin or direct thrombin inhibitor
pholipi s (car iolipin) or phospholipi -bin ing proteins
(β2-microglobulin an others) are etecte by enzyme-
Ab n o rm a l Clo t So lu b ilit y
linke immunosorbent assay (ELISA). When these anti-
Factor XIII de ciency bo ies inter ere with phospholipi - epen ent coagulation
Inhibitors or de ective cross-linking
tests, they are terme lupus anticoagulants. T e aP has
Ra p id Clo t Lysis variability sensitivity to lupus anticoagulants, epen ing in
De ciency o α2-antiplasmin or plasminogen activator inhibitor 1 part on the aP reagents use . An assay using a sensitive
Treatment with brinolytic therapy reagent has been terme an LA-PTT. T e ilute Russell
viper venom test ( RVV ) an the tissue thromboplastin
inhibition ( I) test are mo i cations o stan ar tests
rom one laboratory to another, an the normal range in with the phospholipi reagent ecrease , thus increasing
the laboratory where the testing occurs shoul be use in the sensitivity to antibo ies that inter ere with the phos-
the interpretation. Local laboratories can relate their aP pholipi component. T e tests, however, are not speci c or
values to the therapeutic heparin anticoagulation by cor- lupus anticoagulants, because actor e ciencies or other
relating aP values with irect measurements o heparin inhibitors will also result in prolongation. Documentation
activity (anti-Xa or protamine titration assays) in samples o a lupus anticoagulant requires not only prolongation o
rom heparinize patients, although correlation between a phospholipi - epen ent coagulation test but also lack o
these assays is o en poor. T e aP reagent will vary in correction when mixe with normal plasma an correc-
sensitivity to in ivi ual actor e ciencies an usually tion with the a ition o activate platelet membranes or
becomes prolonge with in ivi ual actor e ciencies o certain phospholipi s (e.g., hexagonal phase).
30–50%.
Other Coagulation Tests T e thrombin time anthe rep-
Mixing Studies Mixing stu ies are use to evaluate a pro- tilase time measure brinogen conversion to brin an
longe aP or, less commonly P , to istinguish between are prolonge when the brinogen level is low (usually
a actor e ciency an an inhibitor. In this assay, normal <80–100 mg/ L) or qualitatively abnormal, as seen in

inherite or acquire ys brinogenemias, or when brin/
brinogen egra ation pro ucts inter ere. T e thrombin
time, but not the reptilase time, is prolonge in the pres-
ence o heparin. T e thrombin time is marke ly prolonge
in the presence o the irect thrombin inhibitor, abi-
gatran; a ilute thrombin time can be use to assess rug
activity. Measurement o anti– actor Xa plasma inhibitory
activity is a test requently use to assess low-molecular-
weight heparin (LMWH) levels, as a irect measurement o
31
an testing can be per orme at least 3 weeks later. As a
sensitive marker o coagulation activation, the quantitative
d- imer assay, rawn 4 weeks a er stopping anticoagula-
tion, can be use to strati y risk o recurrent thrombosis in
patients who have an i iopathic event.
Measures of Platelet Function T e blee ing time has been
use to assess blee ing risk; however, it has not been oun
to pre ict blee ing risk with surgery, an it is not recom-

C
un ractionate heparin (UFH) activity, or to assess activity men e or use or this in ication. T e PFA-100 an simi-

H
A
o the new irect Xa inhibitors rivaroxaban or apixaban. lar instruments that measure platelet- epen ent coagula-

P
T
tion un er ow con itions are generally more sensitive an

E
Drug in the patient sample inhibits the enzymatic conver-

R
sion o an Xa-speci c chromogenic substrate to colore speci c or platelet isor ers an VWD than the blee ing

3
pro uct by actor Xa. Stan ar curves are create using time; however, ata are insu cient to support their use to
multiple concentrations o rug an are use to calculate pre ict blee ing risk or monitor response to therapy, an

B
the concentration o anti-Xa activity in the patient plasma. they will be normal in some patients with platelet isor ers

l
e
e
or mil VWD. When they are use in the evaluation o a

d
i
n
Laboratory Testing for Thrombophilia Laboratory assays to patient with blee ing symptoms, abnormal results, as with

g
a
etect thrombophilic states inclu e molecular iagnostics

n
the blee ing time, require speci c testing, such as VWF

d
T
an immunologic an unctional assays. T ese assays vary assays an /or platelet aggregation stu ies. Because all o

h
r
o
in their sensitivity an speci city or the con ition being these “screening” assays may miss patients with mil blee -

m
b
teste . Furthermore, acute thrombosis, acute illnesses, ing isor ers, urther stu ies are nee e to e ne their role

o
s
i
in ammatory con itions, pregnancy, an me ications

s
in hemostasis testing.
af ect levels o many coagulation actors an their inhibi- For classic platelet aggregometry, various agonists
tors. Antithrombin is ecrease by heparin an in the are a e to the patient’s platelet-rich plasma an plate-
setting o acute thrombosis. Protein C an S levels may let aggregation is measure . ests o platelet secretion in
be increase in the setting o acute thrombosis an are response to agonists can also be measure . T ese tests are
ecrease by war arin. Antiphospholipi antibo ies are af ecte by many actors, inclu ing numerous me ica-
requently transiently positive in acute illness. esting or tions, an the association between minor e ects in aggre-
genetic thrombophilias shoul , in general, only be per orme gation or secretion in these assays an blee ing risk is not
when there is a strong amily history o thrombosis an clearly establishe .
results woul af ect clinical ecision making.
Because thrombophilia evaluations are usually per-
orme to assess the nee to exten anticoagulation, test-
Ac kn o w l ed g men t
ing shoul be per orme in a stea y state, remote rom the
Robert I. Handin, MD, contributed this chapter in the
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 CHAPTER XII.
at her chariot wheels.
Captain Standish did not wait to be asked to dinner. He made his
appearance at Little Yafford Park within a few days of his first visit.
This time he rode over, and his hack was a thing to wonder at.
‘I’m blest if he ain’t the first bit of horseflesh we’ve had inside these
stables!’ exclaimed Mr. Piper’s coachman, who affected to despise
the pair of bays for which his master had given three hundred
guineas.
Mr. Piper was enjoying himself among his friends at Great Yafford.
There was a club in that commercial town, at which Mr. Timperley
and Mr. Porkman and their associates assembled daily to read the
newspapers and discuss the money market. They were all strong
politicians, and talked of politics as well as of the Stock Exchange,
but they contemplated all public events from one standpoint. What
would be the effect on the money market? How would this crisis in
France, or this artful move on the part of Russia, or this pretty piece
of business at Vienna affect the demand for cotton? Would
Palmerston’s last great speech steady the price of consols?
Mr. Piper went to his club oftener now-a-days than he had gone in
the first Mrs. Piper’s time. Bella was making him a man of fashion, as
he complained sometimes, with a fatuous delight in his young wife’s
frivolities. She would drive him into Great Yafford in her pony
carriage in the morning, do an hour’s shopping at Banbury’s, or get a
new novel at the circulating library, and fetch him in the afternoon in
her barouche, after making two or three calls on the commercial
aristocracy; for what is the use of having fine clothes, if you cannot
show them to somebody, or a carriage and pair if you cannot keep it
standing before somebody’s door? Bella heartily despised the
Porkmans, Timperleys, Wigzells, and all their set; but she was by
nature an actress, and must have a stage and an audience of some
kind.
Thus it happened that Mr. Piper was at his club, and that Bella
received Captain Standish alone. It was a lovely afternoon, the lawn
was steeped in sunshine, the flower-beds were almost too dazzling
to be looked at, the roses were in their midsummer glory. Bella
received her visitor in the garden. She was fond of sitting out of
doors. She liked to see the width and grandeur of her domain, the
fallow deer grouped gracefully in the distance, the cool shadows of
beech and oak, the tall elms yonder where the rooks had built for the
last century. Perhaps she knew that she looked her prettiest in the
garden, sitting in a low basket chair, in the shade of spreading lime
branches.
It was just the afternoon for archery. There was not a breath of
wind to blow the arrows about. The noble old beeches shaded the
long stretch of sward where the targets had been set up, and made it
possible for an enthusiastic toxophilite to endure the midsummer
heat. Bella made quite light of it.
‘I adore the summer,’ she said, when Captain Standish expressed
his fear that she might find archery too great an exertion, with the
thermometer at seventy-five in the shade. ‘I think I must belong to
the cat family, I so enjoy basking in the sun.’
‘So do I,’ said the captain, who looked as fresh and cool as if he
had just come out of a water-cure establishment; ‘and I detest the
people who go about the world mopping themselves and grumbling
at the heat on every decent summer day.’
Bella blushed. Mr. Piper had an unpleasant way of mopping his
face with a brown and yellow bandanna on warm afternoons. She
felt that there must be many habits of his that would jar on Captain
Standish’s nerves, if ever they came to be intimate.
The lesson was delightful. The captain was a first-rate master, and
after about an hour’s hard work Bella’s arrows began to fly straight to
the target, instead of taking a slanting direction and losing
themselves under the beeches. This was something gained. Once
she went within half an inch of the gold. And then, when her arm
began to ache desperately and she was obliged to give up, Captain
Standish took her bow, and in the easiest way in the world, just like
that famous marksman who drew his bow at a venture, shot three
arrows in the gold, in the neatest little triangle.
‘I could write my name on the target,’ he said. ‘It’s the simplest
thing in life when you’re used to it.’
Bella looked at her watch. Half-past four o’clock. How the
afternoon had flown! She had promised to call for her husband at his
club, and the carriage had been ordered for four. She explained her
engagement to Captain Standish, who apologized for having
detained her so long.
‘I was so pleased with your progress that I forgot all about time,’
he said. ‘May I come to-morrow—a little earlier? I want you to beat
the Miss Porkmans next Thursday. You will be shooting on Thursday,
I suppose?’
‘Yes, I dare say, if they come. I find archery a great relief on my
Thursday afternoons. It is something for people to do. There is so
little to talk about in the country. You must find it very trying, Captain
Standish.’
The captain shrugged his shoulders.
‘I’m used to country quarters,’ he said. ‘And then in the very
depths of Bœotia there are always bright exceptions. But candidly, I
don’t care much for what people call society. I like to choose my
friends, and when I have chosen them I am an enthusiast in
friendship. Now pray put on your bonnet, and don’t let Mr. Piper be
kept waiting through my indiscretion in staying so long. I’ll go round
to the stable for my horse. May I ride beside your carriage part of the
way, if I don’t make too much dust?’
Bella blushed and sparkled at the idea. To have this fine flower of
the army, this glass of fashion and mould of form riding beside her
barouche was an honour to boast of when next she met the
Porkmans. He had never ridden at their chariot wheels. Cæsar’s
triumph when he brought home Vercingetorix was not grander than
this.
Bella leaned back in her carriage, holding up the daintiest lace-
flounced parasol, just big enough to shelter the tip of her nose, while
the captain’s sleek bay trotted at her side, and arched his neck, and
sniffed the air, and gave himself resentful airs at being forced to suit
his pace to the jog-trot of the over-fed carriage horses. They passed
along the village street, under the cloudless blue, and Bella felt that
the eye of the world—her little world—was upon them. Miss Coyle
was clipping her solitary standard rose tree as they went by, and
stopped, scissors in hand, to stare at them. Cyril Culverhouse was
just coming out of his garden gate, with a black book under his arm.
Clementina and Flora Scratchell were flattening their noses against
the parlour window as usual. That vision of sisterly noses always
greeted Bella as she passed. This time she took care to be looking
another way. She did not want Captain Standish to know that her
‘people’ lived in the shabbiest house in the village.
The captain was far too good a horseman to keep up that ‘‘ammer,
‘ammer, on the ‘ard ‘igh road,’ of which the traditional cockney
complained. There were plenty of grassy bits by the wayside where
he was able to save his horse’s feet—stretches of open down on
which he could indulge himself with a gallop. Sometimes he dropped
behind and walked his horse for a mile or so, and then startled Bella
by descending upon her suddenly from some grassy height, fresh
and cool, and riding with a rein as light as a silken thread.
‘What a lovely horse that is!’ exclaimed Bella. ‘He seems able to
do anything.’
‘He was able to throw most of his riders before I got him,’
answered the captain; ‘but he’s tame enough now.’
There was a roll in the animal’s eye, and a liberal display of white,
which went far to confirm this account of his antecedents.
Captain Standish was riding beside the carriage when they
entered that newly-built suburb where the plutocracy of Great Yafford
had built their habitations. They passed the Porkmans’ Grange, with
its red walls, Tudor casements, and impossible gables, the Timperley
Manor House, with its Norman sugar-loaf towers, and the Wigzells’
Italian Gothic Villa, all white stucco, terraced walks and scarlet
geraniums. Bella, like Cæsar, felt that her triumph was complete.
Captain Standish only left her at the door of the club-house.
‘Well, little woman,’ cried Mr. Piper, when he came tumbling into
the barouche, with his white beaver hat at the back of his head, and
his brown and yellow bandanna on active service. ‘You haven’t kept
me waiting—no, not at all, neither.’
Bella told him all about Captain Standish’s visit. She was radiant
with this small social success.
‘Didn’t I tell you that I’d introduce you into tip-top society, old
woman?’ exclaimed Mr. Piper. ‘You shall hold your own with the best
of ’em. I’ll spare no expense till I see you at the top of the tree. We
must give a dinner party next week, and we’ll have Timperley, and
Wigzell, and the whole boiling.’
‘Captain Standish is always meeting them at Great Yafford. Don’t
you think we’d better ask the Dulcimers—and some of the Little
Yafford people?’ suggested Bella.
‘Well, have it your own way, my dear. I like to have the Vicar’s legs
under my mahogany. It looks respectable.’
Bella sent out her invitations for that day fortnight, carefully
excluding the manufacturing element. She impressed on Mr. Piper
that he was to give no accidental invitations. His impulsive hospitality
must not be allowed to spoil this particular party, as in Bella’s
opinion, at least, it had spoiled previous parties, by the interpolation
of ineligible guests.
‘Above all things let there be no Mr. Chumney,’ said Bella,
authoritatively.
‘Chumney’s enjoying himself at Whitby,’ replied Mr. Piper, ‘and
don’t want to be beholden to you for a dinner; but if you expect me to
forget that Chumney’s father was the first man that ever gave me a
week’s wages, you’ll find yourself disappointed. I’d take a knife and
cut my heart out, if I thought it was capable of such base ingratitude.’
 ‘You may remember Mr. Chumney’s father as much as you like,
but you needn’t always be talking of him, and of the time when you
were glad to earn twelve shillings a week,’ remonstrated Bella.
‘There’s no use in harping upon such things.’
‘Yes, there is,’ answered Mr. Piper, ‘it shows that prosperity hasn’t
made me proud.’
Mrs. Piper called at the Vicarage next day to ensure the
acceptance of her invitation. Mrs. Dulcimer had seen Captain
Standish riding by the Vicarage gate, in attendance on Bella’s
barouche, and had heard about that ride of his from ever so many
people already.
‘I don’t wonder people talk about him,’ said Mrs. Dulcimer. ‘He sits
his horse splendidly, and there’s a wonderful style about him. One
can see at a glance that he has always mixed in the best society.’
‘I hope you and Mr. Dulcimer can come to meet him on
Wednesday week,’ said Bella.
‘Is he really coming to you?’
‘I’ve asked him.’
‘Oh, but he is so very exclusive. I hear he is quite difficult to get.
He is not at all fond of visiting. He shoots and hunts a great deal,
they say, but doesn’t care for balls or parties.’
‘I think he will come,’ said Bella. ‘Colonel O’Shaughnessy brought
him to us last Thursday, and he seemed quite to take to—Mr. Piper.’
‘And he was giving you a lesson in archery, Miss Coyle told me.
You must be very careful, my dear. I thought you were just a little
imprudent to let him ride by your carriage yesterday. A man of that
kind would get you talked about in no time.’
‘My dear Mrs. Dulcimer, I don’t the least mind being talked about.’
‘Bella!’
‘In fact, I rather like it.’
 ‘Bella! I don’t think I could endure my existence if I thought that
people talked about me,’ cried Mrs. Dulcimer, solemnly. ‘Of course,
in my case it would be particularly awful. A vicar’s wife is like
Cæsar’s.’
‘Cæsar had so many wives,’ said Bella. ‘He could hardly expect all
of them to be respectable.’
‘My dear,’ exclaimed Mrs. Dulcimer, her whole countenance
suddenly illuminated, ‘I have such a splendid idea.’
Bella looked anything but delighted.
‘What is it, dear Mrs. Dulcimer?’
‘What a husband Captain Standish would make for your sister
Clementina! My dear, he is the very man for her. A man of high
family—rolling in money—young—handsome. What a chance for
that poor girl!’
‘My dear Mrs. Dulcimer, do you imagine that any man of high
family would choose a wife out of my father’s house?’
‘But he need not see her in her father’s house—at any rate not till
he is so deeply in love that he will not care a straw whether her
family are rich or poor. He will see her at the Park—elegantly
dressed—with you. He will only think of her as your sister. And if he
were to propose I feel sure that Mr. Piper would do something
handsome for her. He is the soul of generosity. You know that, Bella.’
‘He is very generous, but I cannot expect him to give all my sisters
fortunes.’
‘Not all of them, dear. No, of course not;—but he would give
Clementina something, if she were going to make such a match as
that. A man in his position would willingly make some sacrifice to
have Captain Standish for his brother-in-law. Only think, Lady
Emmeline Standish would be your—something-in-law. It would be so
nice for you to have people of high family belonging to you. It would
give you the entrée to county society.’
‘It would be very nice, I dare say,’ said Bella, not elated by this
brilliant perspective, ‘but it is just the most unlikely thing to come to
pass. A man so run after as Captain Standish has been is not likely
to fall in love with Clementina.’
‘I am not so sure of that,’ said Mrs. Dulcimer, sagely. ‘More
wonderful things have happened within my knowledge. Clementina
is a very pretty girl, almost as pretty as you, Bella. She has your
complexion. I hope you’ve invited her for Wednesday week.’
‘No, indeed I have not. It doesn’t do to be overrun by one’s family
always. You see I could scarcely ask Tina without asking papa and
mamma; and that is quite out of the question.’
‘You might have her to stay with you,’ suggested Mrs. Dulcimer.
‘She would help to amuse your step-daughters.’
Elizabeth Fry and Mary Wolstencroft were coming home for their
summer vacation in a few days, a return acutely dreaded by Bella.
‘Well, dear Mrs. Dulcimer, perhaps you are right. It might be as
well to have Clementina.’
She could not be more in the way than those two troublesome
step-daughters, Bella thought.
‘If you have your sister with you it will prevent people making
disagreeable remarks when Captain Standish calls on you,’ said
Mrs. Dulcimer. ‘It must be so awkward for a young woman like you to
receive a gentleman, when your husband is out.’
‘Captain Standish is not quite a dragon,’ replied Bella, laughing. ‘I
am not afraid of him.’
‘My dear, I am told he is a very fascinating man,’ said Mrs.
Dulcimer, ‘and that is the worst kind of dragon for a young married
woman. He certainly ought to marry Clementina, and if you and I
exercise a little diplomacy I believe he will do it. Look at your
position. I feel proud of that. If it hadn’t been for me you might have
never been Mrs. Piper. Poor Mr. Piper might never have repeated his
offer if I had not encouraged him.’
‘You are all that is kind and good,’ said Bella, inwardly rebelling
against this patronage and interference.
 ‘Now go and invite your sister to stay with you, dear. And see that
she is becomingly dressed. And you can polish her up a little in the
next fortnight. Clementina sadly wants polish. She has never had
your opportunities, you know.’
 CHAPTER XIII.
playing with fire.
Captain Standish accepted Mrs. Piper’s invitation. He rode over to
answer her note in person; and to give her another lesson in archery.
This time Clementina was with her and shared in the lesson. Captain
Standish had no objection to teach two pretty girls instead of one,
but he preferred Mrs. Piper, as the prettier and more fascinating of
the two. She possessed a great superiority too, in his eyes, as a
married woman. It was the rule of this great man’s life, when he
condescended to flirtation, to flirt with a married woman. No harm
could come of it to himself. There was always the risk of the husband
being made uncomfortable; but that was a detail. Captain Standish
was not afraid of making a husband jealous, or even unhappy; but
he was very much afraid of compromising himself by flirtation with a
single woman, who might be absurd enough to expect him to marry
her, and whose friends might make themselves disagreeable if he
declined to do so.
He was therefore the very last man to walk into the silken snare
that Mrs. Dulcimer had set for him. He was kind and courteous to
Clementina, who was ready to ‘worship him’ or to ‘rave about him’—
in the Porkman phraseology—at a moment’s notice; but he reserved
his tender attentions, his thrilling looks and lowered tones, for Bella,
for whom the sweet poison, the social deadly nightshade of an
unprincipled man’s flatteries had already too great a charm. Of the
extent of the captain’s influence over her mind Bella herself was not
yet aware. Indeed, she believed herself hardened against any such
influence by the counter poison of a previous love. She had loved
once, and loved unhappily, and therefore could never love again.
This she firmly believed, and, secure in this belief, walked blindfold
into danger. Her pleasure in the captain’s society she ascribed to the
triumph of parading him before the astonished eyes of Little Yafford,
the delight of lording it over the Porkmans, the fact that Captain
Standish was the fashion.
The dinner party was a success. It was made up of the élite of
Little Yafford and the surrounding neighbourhood—people who had
‘places’ of twenty to thirty acres, and who were altogether the next
best thing to county families—Mr. and Mrs. Dulcimer, Colonel
O’Shaughnessy, and Captain Standish. Clementina looked her
prettiest, and was complimented on her likeness to her sister.
‘Bella,’ said the Vicar’s wife in a confidential tone, when the ladies
were alone after dinner. ‘You are doing a noble thing for your sister.
In my opinion Captain Standish is struck with her already.’
‘You are sanguine, dear Mrs. Dulcimer,’ answered Bella, smiling. ‘I
have not seen him particularly attentive to her.’
‘Perhaps not, but he has been particularly attentive to you. He
would naturally begin in that way.’
Bella was not quite clear upon this point; she had little faith in Mrs.
Dulcimer’s judgment. Were not the most miserable hours of her life,
her one inexcusable sin, referable to that lady’s mistake? But she
found it rather agreeable to have Clementina as a companion. The
girl was grateful, and willing to be useful, and was not in the way.
Mrs. Dulcimer was so elated at the prospect of another brilliant
match, to be brought about by her agency, that, towards the end of
the evening, she took Mr. Piper into her confidence.
‘Charming man, Captain Standish, isn’t he?’ she asked.
‘I’ve ‘eard that remark made a good many times, mum,’ he
answered, candidly, ‘but as far as my individual opinion goes I don’t
see anything remarkable about the captain that should single him out
from the ruck of military men. Perhaps his hair is cropped a trifle
closer, and his whiskers neater trimmed. I don’t deny either that
there’s a junny serquaw, as my wife calls it, about the cut of his
clothes, and that he has a high way with him, as if we were all upon
a lower level, which I believe is uncommonly taking for some people,
though I can’t say I ever was took by that kind of thing myself. I like a
man who is my superior and yet takes care not to remind me of it. I
can feel the superiority of that kind of man. I don’t want it put before
me.’
Mrs. Dulcimer looked disappointed.
‘He is of a very high family,’ she said, ‘and enormously rich.’
‘That’s always a satisfaction to one’s mind, mum.’
‘Now don’t you think it would be a very grand thing if he were to
marry your sister-in-law Clementina?’
Mr. Piper was not enthusiastic.
‘She might like it, Mrs. Dulcimer,’ he said. ‘That’s just according to
her feelings. But it’s no business of mine to find husbands for my
wife’s sisters.’
This was disheartening, but Mrs. Dulcimer was not going to
renounce her project because Mr. Piper looked coldly upon it.
Clementina stayed at the Park, and Bella enriched her with a great
many dresses and other adornments of which she was beginning to
be tired, or which were of a fashion that had become too general for
a fine lady’s wear. Generosity in a person of Bella’s stamp is only
another word for extravagance. Bella would have as soon
contemplated cutting off her right hand as giving away anything she
wanted herself. These gifts to Tina necessitated the purchase of new
things, and already the second Mrs. Piper had begun to get into
debt, and to feel that she had bills which must be paid next year, or
at some more definite period. The three hundred a year which Mr.
Piper had settled upon her in the fulness of his heart, as an all-
sufficing income for dress and pocket money, was not nearly enough
to supply the manifold wants of a young woman who had been
brought up in poverty. Bella wanted everything, for everything was
new to her. She ran riot in laces, and silks, and velvets, bric-à-brac
for her boudoir, dainty stationery, devotional books, which were
seldom read, but which looked well on her dressing-table, parasols,
fans, slippers, albums, everything of the costliest. She was surprised
to find how soon her ready money had melted away, and almost
afraid to calculate how deeply she was in debt. But the burden
weighed lightly upon her. It would be easy to get Mr. Piper to give her
a cheque, when things got desperate. He might be surprised,
perhaps, that she had not managed her allowance better; but he
would not have the strength of mind to refuse her the money.
One day poor Mrs. Scratchell ventured to ask her daughter for a
little help. The tax-gatherer was pressing, and ‘father’ had nothing
put aside for the taxes.
‘Oh, mamma,’ cried Bella, ‘what has he done with Mr. Harefield’s
five hundred pounds? That ought to have set him up for life.’
‘My dear child, you must remember, surely. Father acted with the
greatest prudence, and invested his legacy safely in railway shares.
It brings us twenty-seven pounds a year. It doesn’t make a large
addition, you see, and last year was so expensive. Bread was a
penny dearer than it has been for ten years, and potatoes were
dreadfully scarce. Altogether things have got behindhand with us
——’
‘I never knew them to be beforehand,’ sighed Bella.
‘But it’s a great comfort to see you so splendidly established. I’m
sure I feel a thrill whenever I enter this house and think, “This is my
daughter’s. My child is the mistress of it all.” I feel almost as Esther’s
relations must have felt when they saw her sitting beside the king.
And now, dear, if you could let me have ten pounds——’
‘My dear mother, I haven’t ten shillings. Look, here’s my purse.
You can count the silver, if you like.’
She handed Mrs. Scratchell a toy of mother-o’-pearl and gold,
lined with rose-hued silk.
‘Oh, Bella, have you spent all your last half-year’s income?’
‘Every sixpence, except what you see there.’
‘My love, you must have been very extravagant—after such a
trousseau as you had to start with.’
‘Why, mamma, there were lots of things forgotten in my trousseau.
And then the fashions are always changing, and I have given my
sisters such heaps of things. I dare say I have been extravagant in
that particular. I am sure I have dressed Tina from head to foot.’
‘You have been very good, dear; but I so counted on you for the
taxes. I thought a ten pound note would be nothing to you.’
‘That was a tremendous mistake. I assure you that for actual ready
money I have been worse off since I have been Mr. Piper’s wife than
I was as his governess. There are so many demands upon my
purse. But if I can do anything next Christmas——’
‘Thank you, dear. We must get on somehow, I suppose. We
always have struggled through our difficulties, and I suppose we
always shall, thanks to Providence; but it’s a wearing life.’
The young Pipers came home for their holidays, and ran riot
amidst the splendours and luxuries that Bella had introduced into the
sober old house. These young people liked Bella better as a
stepmother than they had liked her as a governess. She was very
indulgent, so long as they did not spoil the furniture, or annoy her
with too much of their society. She gave the girls fine dresses, and
allowed them to share all her gaieties. She let the boys ride her
ponies, when she did not want to use them. In a word she was a
model stepmother, and everybody praised her, except Miss Coyle,
who never praised anybody, and Mr. Chumney, who generally
reserved his opinion as something too valuable to be parted with
except under strongest pressure.
So the briefly glorious summer hurried by, and Bella lived only for
pleasure, and to be flattered and followed by Captain Standish. She
went to a great many parties among the Wigzell, Timperley, and
Porkman section of society, and to a few among the professional
classes and landed gentry, which latter were not so splendid as the
mercantile entertainments, in the matter of eating and drinking, and
were not much more lively; for whereas the Porkmans and
Timperleys talked of nothing but money-making, the landed gentry
had a language of their own which Bella, clever as she was, had yet
to learn. Captain Standish was teaching her a great deal. Under his
tuition she had learned to look down upon her fellow-creatures as an
inferior set of beings, ‘mostly fools,’ to regard mental culture as a
process only valuable to schoolmasters, college dons, clergymen,
doctors, lawyers, and that altogether subordinate race which has to
earn its bread by the sweat of its brains, to think of money as a
stepping-stone to social importance, the pleasure of the present
moment as the one vital consideration, the future as an unknown
quantity, not worth serious thought.
This was the code of ethics which Bella learned from Captain
Standish, but before all and above all he taught her to despise her
husband, her husband’s children, and her husband’s surroundings,
from the lordly Timperley, swelling with the importance of the biggest
mills in the district, to the unpretending Chumney, living in modest
retirement upon an annuity of ninety pounds, the result of his
laborious existence.
Of this gradual corruption of his wife’s mind honest Ebenezer
Piper had no suspicion. Her manner and conduct to him of late had
been unexceptionable. The deeper and stronger that feeling of
contemptuous aversion grew in the secret depths of her heart, the
more carefully did she regulate her outward seeming. She had never
appeared sweeter, fairer, or more guileless in her husband’s eyes
than when she was most inclined to betray him. Vivien herself, that
supreme type of falsehood in woman, employed no finer art against
the enchanter Merlin than Bella used to guard herself from the
hazard of discovery.
She knew herself false to the core, not quite a subject for the
divorce court, but a creature whose good angel had long left her,
shuddering and abhorrent.
Mr. Piper had not forgotten Mrs. Dulcimer’s ideas about Captain
Standish and Clementina, and when he saw the captain and sister-
in-law together he was inclined to believe that there might be some
foundation for that inveterate matchmaker’s fancy. The captain had a
knack of being particularly attentive to Tina under Mr. Piper’s eye.
And now autumn was approaching, the russet corn was cut in the
wide shadowless fields, the ploughman’s white horses were seen
moving slowly along the upland ridges, against a cool gray sky.
 Captain Standish went up into the wildest part of the moors for a
fortnight’s grouse-shooting, and to everybody’s surprise came back
to Great Yafford in three days.
He rode over to the Park on the afternoon of his return, and found
Bella alone, yawning over a novel. She started and dropped her
book when the footman announced him, and changed from pale to
red, and red to pale again.
‘You did not expect to see me so soon,’ said the captain, keeping
her little cold hand in his.
‘No,’ she faltered, unable to say more.
‘You thought I should be able to endure a fortnight’s life without
you. I was fool enough to think so too—and made all my
arrangements for staying away till the 27th. But three days were
quite enough. How pale and tired you look!’
‘I have had nothing to do, and I suppose that is the most tiring
thing in the world. Tina has gone home. I did not want Mr. Piper to
think that she was going to live here always.’
‘What does it matter what he thinks?’ said Captain Standish, with
his supercilious smile. ‘Mr. Piper was only created to be useful to you
and your relations. And so you have missed—Tina.’
‘I have been very dull.’
‘If you knew how desolate my life was in those three days you
would pity me,’ said the captain, tenderly. ‘Yes, Isabel, you would pity
me for being so weak that I cannot live without you, so miserably
placed that I am obliged to hide my love.’
And then Captain Standish went on to tell his story; the old, old
story, the familiar melody, subject to such endless variations, such
kaleidoscopic distinctions without difference, and always coming to
the same thing in the end. ‘We might have been happy had
Providence willed it. Let us defy Providence, fling honour to the
winds, and be happy in spite of fate.’
He talked and pleaded for a long time, and Bella listened with
lowered eyelids, and lowered head, and let her hand lie locked in his,
and did not answer his specious arguments by one straight
outspoken denial. She paltered with this tempter, as she had
paltered with temptation all her life, always choosing the road she
liked best. She said neither yes nor no. It was an awful thing that he
was asking her to do. No more nor less than to surrender honour,
social status, everything for his sake, to go to Italy with him, and live
a gay, unfettered life there, among people who, according to his
showing, would be willing to accept her as his wife. He painted the
picture of that ideal Italian life so vividly that all the hideousness of
his proposal was lost sight of under that bright colouring.
‘Remember, dearest, I shall have my sacrifice to make too,’ he
said. ‘I must leave the army. And I shall almost break my poor
mother’s heart, for she has plans for my marriage which she has
cherished ever since I was at Eton. But I could sacrifice a great deal
more than that for your sake.’
‘Do not talk of it any more,’ said Bella, in a frightened voice. ‘It is
too awful. I like you—yes,’ as he drew her face round to him so that
her eyes reluctantly met his,—‘yes, very much. I hardly think’—
falteringly and in tears—‘I could go on living if you went away, and I
were not to see you any more; but what you are asking is horrible—
to defy everybody—to give up everything—to be pointed at and
spoken of as something utterly lost and wretched—a thing to be
spurned by other women—women who are my inferior in everything
—except that one wicked act. Why, my very housemaids would look
down upon me. No, I could not be so degraded. I could not sink so
low.’
‘I see,’ said Captain Standish. ‘You love yourself and your good
name better than you love me. You were not ashamed to sell
yourself to Piper. The world applauds that kind of bargain. But you
are not generous enough to give yourself to the man you love.’
He had let go her hand, and was walking with long quick steps
backwards and forwards across the deep bay, like a lion in a cage.
Bella thought there was something grand and noble about him in this
lofty rage. She loved him all the more for the hard things he said to
her, since his hard speeches proved the intensity of his love.
 ‘You are very cruel,’ she said, piteously.
‘I am very much in earnest. I thought to find in you something
better and grander than the shallow conventional woman of society
who only plays with hearts, who wants to walk through the deep
waters of passion without wetting her feet. You talk of sinking very
low—of degradation. Where is the degradation in the life I offer you
—the fair sweet unfettered life that poets have loved ever since the
world began?’
‘You would be tired of an idle life in Italy,’ said Bella.
‘With you, no. But we could wander about. We should not be tied
to one spot. I would take you to Algiers—Morocco. We could ride
over that strange land together—and when we had used up the Old
World we would be off to the New. I would take you across the Rocky
Mountains. I would make you my comrade and companion—a hardy
traveller—a dead shot. You should be no slavish English wife, sitting
at home while your husband enjoyed his life. No, love, you should
share every sport I had, hunt with me—shoot—fish—row—ride with
me. I would not have a pleasure in life that you could not share.’
The picture was full of charm for a woman who, in her eagerness
to enjoy life, had already almost exhausted the pleasures of
humdrum existence. Bella felt that this would indeed be the
beginning of a new life; this would be to drain to the dregs the cup of
youth and gladness. And then worldly pride for once took the shape
of a good angel, and pointed to the view from that wide bay-window,
the Park and deer, the avenue of goodly elms, the grandeur and
importance of her position as Mrs. Piper. Was she to surrender all
this, and give up her name to be a byeword and a reproach into the
bargain? No, she had hearkened too long to the tempter, but she
was not weak enough for this.
‘You must never speak to me of this again,’ she exclaimed. ‘I will
try to think there has been no serious meaning in what you have
said. Let us both forget it.’
‘I shall not forget it,’ said the captain, ‘but if you tell me to keep
silence I will obey. I would do anything rather than live out of your
society.’
‘If you ever repeat what you have said this afternoon, our
friendship will be ended.’
‘Anything sooner than that.’
He took the little hand again and kissed it tenderly. So there was a
kind of compact between them. He was to go on adoring her, but
was to say nothing about it.
Captain Standish rode back to Great Yafford in excellent humour.
He had considerably embellished the fact of his return, in his
conversation with Mrs. Piper. He had come back because the
weather had been abominable, and the birds hardly visible behind a
dense curtain of driving rain. Three days of such uncomfortable sport
had been quite enough for the captain.
‘Poor little thing,’ he mused, as he walked his horse, after a
swinging galop over a grassy waste, ‘how very weak she is! I am
glad she doesn’t want me to run away with her. It would be
uncommonly inconvenient. But when a man has flirted as
desperately as I have a woman expects him to say something
serious. She’s really very pretty—quite the most fascinating little
thing I’ve met for a long time. And if she were single—all things
being equal—I don’t think I should object to marry her.’
 CHAPTER XIV.
a turn of fortune’s wheel.
Cyril Culverhouse lived his useful life, full of thought and care for
others, honoured, beloved, but with a deep and settled sadness at
his heart. He could not forget the woman he loved, he could not
forgive himself for having doubted her. Both their lives were blighted
by that mistake; and yet, looking back, he knew that he had tried to
do his duty. Love seemed a snare of Satan, and he had cut himself
free from its meshes. But after that meeting in the churchyard all his
doubts vanished, his judgment wavered no longer. There is a power
in simple truth, when we meet it face to face, that is stronger than all
reasoning upon a chain of possibilities.
He was convinced for ever of her guiltlessness, in the hour when
he believed her irrevocably lost to him. Could he ever forget that
meeting—that one despairing kiss—the sight of her lying at his feet
among the rank grass that grows on graves? And she had confessed
her love for him, by flying from a loveless marriage.
Could he follow her?—search this wide world for her? How small a
penance would it be to wander over all the earth for her sake! But he
felt he had no right to pursue her. He had wronged her too deeply to
persecute her by a pursuit which no sign from her invited. It was for
her to make that sign—it was for her to pity and pardon him.
‘Let me go on doing my duty,’ he said to himself, ‘and if it is God’s
will that I am to be happy in that way, happiness will come to me.
Yes, it will come some day, when I least look for it, as the angels
came to Abraham.’
So he went on with his simple unpretending life, working with a
quiet earnestness which achieved wonders. It was one of his chief
gifts to do all things quietly. He worked almost as silently as the
bounteous fertilizing sun.