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WILLIAMS M A N U A L O F
Hematology
1Oth Edition
NOTICE
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Williams
Manual of Hematology
Tenth Edition
Marshall A. Lichtman, MD
Professor Emeritus of Medicine; ( Hematology-Oncology )
and of Biochemistry and Biophysics
Dean Emeritus, School of Medicine and Dentistry; James P. Wdmot Cancer Institute
University of Rochester Medical Center
Rochester, New York
Kenneth Kausha risky, MD
Senior Vice President , Health Sciences
Dean , School of Medicine
SUNY Distinguished Professor
Stony Brook University
Stony Brook, New York
Josef T. Prchal, MD
Professor of Hematology and Malignant Hematology
Adjunct in tiejietics and Pathology
University of Utah St Huntsman Cancer Institute
Salt hake City, Utah
1. intend klinika VFN a Ustav patologickr fyziologie 1. LF School of Medicine
Universila Karlov , Prague, Grech Republic
Marcel M. Levi , MD, PhD
Professor of Medicine
Amsterdam University Medical Centers
University' of Amsterdam
Amsterdam, The Netherlands
Professor of Medicine
University' College london
London, United Kingdom
Linda J , Burns, MD
Consultant and Sr. Scientific Director
Center for International Blood and Marrow Transplant Research
Milwaukee, Wisconsin
David C, Llndl, FRCP, FRCPath, FM ?d So
Professor of Haematology
Cancer Program Director
UCL/ UCLH Biomedical Research Centre
University' College London
London, United Kingdom
Me
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CONTENTS
Preface
49 Classification and Clinical Manifestations of Polyclonal Lymphocyte and Plasma Cell Disorders
50 Lymphocytosis and Lymphocytopenia
51 Primary Immunodeficiency Syndrome
52 Hematologic Manifestations of the Acquired Immunodeficiency Syndrome
53 The Mononucleosis Syndromes
79 Hemophilia A and B
80 von Willebrand Disease
81 Hereditary Disorders of Fibrinogen
82 Inherited Deficiencies of Coagulation Factors II, V, VII, X, XI, and XIII and Combined Deficiencies of
Factor V and VIII and of Vitamin K–Dependent Factors
83 Antibody-Mediated Coagulation Factor Deficiencies
84 Hemostatic Dysfunction Related to Liver Diseases
85 The Antiphospholipid Syndrome
86 Disseminated Intravascular Coagulation
87 Fibrinolysis and Thrombolysis
The 10th edition of Williams Manual of Hematology follows soon after the publication of the new 10th
edition of the Williams Hematology textbook, as has been the custom for the last seven editions. The
Manual provides a condensation of the essential elements of 95 of the 140 chapters of the textbook,
chapters that are focused on describing hematologic diseases or broadly applicable therapeutic
approaches, such as hematopoietic stem cell transplantation, the pharmacology and toxicity of
antineoplastic drugs, and the application of genetically engineered chimeric antigen receptor T
lymphocytes. The Manual provides the clinician with a comprehensive precis of the critical elements of
diagnosis and management that is easily accessible and important to the care of patients. It is keyed to the
Williams Hematology textbook, allowing the physician to move to its more comprehensive coverage as
time and interest permit. We urge all readers to avail themselves of the richness of the full coverage
provided in the Williams Hematology 10th edition textbook.
Hematology is a discipline for which the impact of advances in genetics, immunology, molecular
biology, biotechnology, biomedical informatics, diagnostic imaging, and cytometry and the application of
these disciplines to experimental therapeutics have led to an astounding array of pharmaceutical agents,
including monoclonal antibodies, advancing our ability to treat successfully and, with increasing
frequency, to cure hematologic diseases. Perhaps the most dramatic of these accomplishments is the
advance in the treatment of chronic myelogenous leukemia (CML). At the time of the publication of the 1st
edition of Hematology in 1972 (to become Williams Hematology with the 5th edition), the 5-year
survival of patients with CML was approximately 20%. Today, study of patients consistently taking a
tyrosine kinase inhibitor has found that they have a 90% 5-year survival. Analysis has shown that the life
expectancy of patients with CML is within 3 years of the general population in all age categories.
Moreover, some patients may be cured, allowing them to stop the drug. This dramatic and profound
achievement and other parallel advances in the treatment of the leukemias, lymphomas, myeloma, and the
many nonmalignant, but consequential and often life-impairing or life-threatening, diseases of blood cells
and coagulation proteins is a testament to the advances flowing from the investment in biomedical
research.
This increase in knowledge is reflected in the 10th edition of Williams Hematology being 1024 pages
longer than the 1st edition (despite artful editing!); hence, the raison d’être for the Manual as an essential
guide for the clinician. The editors of the Manual have endeavored to bring to the reader information,
focused on pathogenesis, diagnosis, and management, in an organized and easy-to-use way, to assist the
clinician in the examining room, at the bedside, or when using telemedicine. The Manual has been an
important resource for clinicians preparing for certification examinations in hematology or other
disciplines requiring a knowledge of hematology because the information for patient diagnosis and
management is provided in a comprehensive document of manageable size and format and packed with
essential information.
We acknowledge the authors of the chapters in the 10th edition of Williams Hematology, who
provided the basis for the exposition of pathogenesis, diagnosis, and management in each chapter. We
have translated and condensed their current and state-of-the-art information for the users of the Manual.
We welcome David Linch, University College London, to the editorial board of the Williams Manual
(and textbook), thereby broadening its international perspective and reach. Its international import is
attested to by its having been translated into Chinese, Greek, Japanese, Portuguese, Russian, Spanish, and
Turkish in one recent edition or another.
We gratefully acknowledge Harriet Lebowitz for editorial development of the manuscript, the
administrative support of Jason Malley, and our production manager Richard Ruzycka, each at McGraw-
Hill Education; the valuable assistance of Susan M. Daley in Rochester who provided administrative
assistance in the preparation of the manuscript and the management of chapter flow; and Warishree Pant of
KnowledgeWorks Global Ltd. for the final composition of the book.
The care of a patient with a hematologic disorder begins with eliciting a medical history and
performing a thorough physical examination. Certain parts of the history and physical examination that are
of particular interest to the hematologist are presented here.
• Drugs and chemicals may induce or aggravate hematologic diseases; drug use or chemical exposure,
intentional or inadvertent, should be evaluated. One should inquire about professionally prescribed and
self-prescribed drugs, such as herbal remedies. Occupational exposures should be defined.
• Fever may result from hematologic disease or, more often, from an associated infection. Night sweats
suggest the presence of fever. They are especially prevalent in the lymphomas.
• Weight loss may occur in some hematologic diseases.
• Fatigue, malaise, lassitude, and weakness are common but nonspecific symptoms and may be the result
of anemia, fever, or muscle wasting associated with hematologic malignancy or neurologic
complications of hematologic disease.
• Symptoms or signs related to specific organ systems or regions of the body may arise because of
involvement in the basic disease process, such as spinal cord compression from a plasmacytoma,
ureteral or intestinal obstruction from abdominal lymphoma, or stupor from exaggerated
hyperleukocytosis in chronic myelogenous leukemia.
FAMILY HISTORY
• Hematologic disorders may be inherited as autosomal dominant, autosomal recessive, or X
chromosome–linked traits (see Williams Hematology, 10th ed, Chap. 10). The family history is crucial
to provide initial clues to inherited disorders and should include information relevant to the disease in
question in grandparents, parents, siblings, children, maternal uncles and aunts, and nephews. Careful
and repeated questioning is often necessary because some important details, such as the death of a
sibling in infancy, may be forgotten years later.
• Consanguinity should be considered in a patient who belongs to a population group prone to marrying
family members.
• Absence of a family history in a dominantly inherited disease may indicate a de novo mutation or
nonpaternity.
• Deviations from Mendelian inheritance may result from uniparental disomy (patient receives two copies
of a chromosome, or part of a chromosome, containing a mutation from one parent and no copies from
the other parent) or genetic imprinting (same abnormal gene inherited from mother has a different
phenotype than that inherited from father as a result of silencing or imprinting of one parent’s portion of
DNA) (see Williams Hematology, 10th ed, Chap. 10).
SEXUAL HISTORY
• One should obtain the history of the sexual preferences and practices of the patient.
PHYSICAL EXAMINATION
Special attention should be paid to the following aspects of the physical examination:
• Skin: cyanosis, ecchymoses, excoriation, flushing, jaundice, leg ulcers, nail changes, pallor, petechiae,
telangiectases, rashes (eg, lupus erythematosus, leukemia cutis, cutaneous T-cell lymphoma)
• Eyes: jaundice, pallor, plethora, retinal hemorrhages, exudates, or engorgement and segmentation of
retinal veins
• Mouth: bleeding, jaundice, mucosal ulceration, pallor, smooth tongue
• Lymph nodes: slight enlargement may occur in the inguinal region in healthy adults and in the cervical
region in children. Enlargement elsewhere, or moderate to marked enlargement in these regions, should
be considered abnormal
• Chest: sternal and/or rib tenderness
• Liver: enlargement
• Spleen: enlargement, splenic rub
• Joints: swelling, deformities
• Neurologic: abnormal mental state, cranial nerve abnormalities, peripheral nerve abnormalities, spinal
cord signs
LABORATORY EVALUATION
The blood should be evaluated, both quantitatively and qualitatively. This is usually achieved using
automated equipment.
• Normal blood cell values are presented in Table 1–4. Normal total leukocyte and differential leukocyte
counts are presented in Table 1–5.