Williams Manual of Hematology - eBook

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

Ninth Edition

Marshall A. Lichtman, MD
Professor of Medicine (Hematology-Oncology)
and of Biochemistry and Biophysics
James P. Wilmot Cancer Institute
University of Rochester Medical Center
Rochester, New York

Kenneth Kaushansky, 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 Medicine, of Pathology, and of Genetics
Division of Hematology
University of Utah
Salt Lake City, Utah
First Faculty of Medicine
Charles University
Prague, Czech Republic

Marcel M. Levi, MD, PhD

Professor of Medicine
Dean, Faculty of Medicine
Academic Medical Center
University of Amsterdam
Amsterdam, The Netherlands

Linda J. Burns, MD
Professor of Medicine
Division of Hematology, Oncology, and Transplantation
University of Minnesota
Minneapolis, Minnesota

James O. Armitage, MD
The Joe Shapiro Professor of Medicine
Division of Oncology and Hematology
 University of Nebraska Medical Center
Omaha, Nebraska

New York Chicago San Francisco Athens London Madrid Mexico City
Milan New Delhi Singapore Sydney Toronto
Williams Manual of Hematology, Ninth Edition

Copyright © 2017 by McGraw-Hill Education. All rights reserved. Printed in China. Except as permitted under the United States
Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by an means, or stored in a data
base or retrieval system, without the prior written permission of the publisher.

123456789 DSS 21 20 19 18 17 16

ISBN 978-1-259-64247-0
MHID 1-259-64247-X

eISBN 978-1-259-64257-9
eMHID 1-259-64257-7

This book was set in Times LT Std by Cenveo® Publisher Services.

The editors were Karen Edmonson and Harriet Lebowitz.
The production supervisor was Richard Ruzycka.
Project management was provided by Sonam Arora, Cenveo Publisher Services.
The cover designer was Dreamit, Inc.
The interior designer was Eve Siegel.
RR Donnelley/Shenzhen was printer and binder.

This book is printed on acid-free paper.

Library of Congress Cataloging-in-Publication Data

Names: Lichtman, Marshall A., editor.

Title: Williams manual of hematology / [edited by] Marshall A. Lichtman … [and 5 others].
Other titles: Manual of hematology
Description: Ninth edition. | New York : McGraw-Hill Education, [2017] | Abridgement of: Williams hematology / editors, Kenneth
Kaushansky, Marshall A. Lichtman, Josef T. Prchal, Marcel Levi, Oliver W. Press, Linda J. Burns, Michael A. Caligiuri. Ninth
edition. 2015. | Includes bibliographical references and index.
Identifiers: LCCN 2016011463| ISBN 9781259642470 (pbk. : alk. paper) | ISBN
125964247X (pbk. : alk. paper)
Subjects: | MESH: Hematologic Diseases | Handbooks
Classification: LCC RC633 | NLM WH 39 | DDC 616.1/5—dc23 LC record available at
http://lccn.loc.gov/2016011463

International Edition ISBN 978-1-259-92147-6; MHID 1-259-92147-6.

Copyright © 2017. Exclusive rights by McGraw-Hill Education for manufacture and export. This book cannot be re-exported from
the country to which it is consigned by McGraw-Hill Education. The International Edition is not available in North America.

McGraw-Hill Education books are available at special quantity discounts to use as premiums and sales promotions or for use in
corporate training programs. To contact a representative, please visit the Contact Us pages at www.mhprofessional.com.
 CONTENTS

Preface

PART I INITIAL CLINICAL EVALUATION

1 Approach to the Patient

PART II DISORDERS OF RED CELLS

2 Classification of Anemias and Polycythemias

3 Aplastic Anemia: Acquired and Inherited
4 Pure Red Cell Aplasia
5 Anemia of Chronic Disease
6 Anemia of Endocrine Disorders
7 Congenital Dyserythropoietic Anemias
8 Folate, Cobalamin, and Megaloblastic Anemias
9 Iron-Deficiency Anemia and Iron Overload
10 Anemia Resulting from Other Nutritional Deficiencies
11 Hereditary and Acquired Sideroblastic Anemias
12 Anemia Resulting from Marrow Infiltration
13 Erythrocyte Membrane Disorders
14 Hemolytic Anemia Related to Red Cell Enzyme Defects
15 The Thalassemias
16 The Sickle Cell Diseases and Related Disorders
17 Hemoglobinopathies Associated with Unstable Hemoglobin
18 Methemoglobinemia and Other Dyshemoglobinemias
19 Fragmentation Hemolytic Anemia
20 Hemolytic Anemia Resulting from a Chemical or Physical Agent
21 Hemolytic Anemia Resulting from Infectious Agents
22 Hemolytic Anemia Resulting from Warm-Reacting Antibodies
23 Cryopathic Hemolytic Anemia
24 Drug-Induced Hemolytic Anemia
25 Alloimmune Hemolytic Disease of the Newborn
26 Hypersplenism and Hyposplenism
27 Polyclonal Polycythemias (Primary and Secondary)
28 The Porphyrias

PART III DISORDERS OF GRANULOCYTES

29 Classification and Clinical Manifestations of Neutrophil Disorders

30 Neutropenia and Neutrophilia
31 Disorders of Neutrophil Functions
32 Eosinophils and Related Disorders
33 Basophils, Mast Cells, and Related Disorders

PART IV DISORDERS OF MONOCYTES AND MACROPHAGES

34 Classification and Clinical Manifestations of Monocytes and Macrophages

35 Monocytosis and Monocytopenia
36 Inflammatory and Malignant Histiocytosis
37 Gaucher Disease and Related Lysosomal Storage Diseases

PART V PRINCIPLES OF THERAPY FOR NEOPLASTIC HEMATOLOGIC DISORDERS

38 Pharmacology and Toxicity of Antineoplastic Drugs

39 Principles of Hematopoietic Cell Transplantation

PART VI THE CLONAL MYELOID DISORDERS

40 Classification and Clinical Manifestations of the Clonal Myeloid Disorders

41 Polycythemia Vera
42 Essential (Primary) and Familial Thrombocythemia
43 Paroxysmal Nocturnal Hemoglobinuria
44 Myelodysplastic Syndromes (Clonal Cytopenias and Oligoblastic Myelogenous Leukemia)
45 The Acute Myelogenous Leukemias
46 The Chronic Myelogenous Leukemias
47 Primary Myelofibrosis

PART VII THE POLYCLONAL LYMPHOID DISEASES

48 Classification and Clinical Manifestations of Polyclonal Lymphocyte and Plasma Cell Disorders
49 Lymphocytosis and Lymphocytopenia
50 Primary Immunodeficiency Syndrome
51 Hematological Manifestations of the Acquired Immunodeficiency Syndrome
52 The Mononucleosis Syndromes

PART VIII THE CLONAL LYMPHOID AND PLASMA CELL DISEASES

53 Classification and Clinical Manifestations of the Malignant Lymphoid Disorders

54 The Acute Lymphocytic Leukemias
55 Chronic Lymphocytic Leukemia and Related Diseases
56 Hairy Cell Leukemia
57 Large Granular Lymphocytic Leukemia
58 General Considerations of Lymphoma: Epidemiology, Etiology, Heterogeneity, and Primary Extranodal Disease
59 Hodgkin Lymphoma
60 Diffuse Large B-Cell Lymphoma and Related Diseases
61 Follicular Lymphoma
62 Mantle Cell Lymphoma
63 Marginal Zone B-Cell Lymphoma
64 Burkitt Lymphoma
65 Cutaneous T-Cell Lymphoma
66 Mature T-Cell and Natural Killer Cell Lymphomas
67 Essential Monoclonal Gammopathy
68 Myeloma
69 Macroglobulinemia
70 Heavy-Chain Diseases
71 Amyloidosis

PART IX DISORDERS OF PLATELETS AND HEMOSTASIS

72 Clinical Manifestations, Evaluation, and Classification of Disorders of Hemostasis

73 Thrombocytopenia
74 Reactive (Secondary) Thrombocytosis
75 Hereditary Platelet Disorders
76 Acquired Platelet Disorders
77 The Vascular Purpuras

PART X DISORDERS OF COAGULATION PROTEINS

78 Hemophilia A and B
79 von Willebrand Disease
80 Hereditary Disorders of Fibrinogen
81 Inherited Deficiencies of Coagulation Factors II, V, V + VIII, VII, X, XI, and XIII
82 Antibody-Mediated Coagulation Factor Deficiencies
83 Hemostatic Dysfunction Related to Liver Diseases
84 The Antiphospholipid Syndrome
85 Disseminated Intravascular Coagulation
86 Fibrinolysis and Thrombolysis

PART XI THROMBOSIS AND ANTITHROMBOTIC THERAPY

87 Principles of Antithrombotic Therapy

88 Hereditary Thrombophilia
89 Venous Thromboembolism
90 Antibody-Mediated Thrombotic Disorders: Thrombotic Thrombocytopenic Purpura and Heparin-Induced Thrombocytopenia

PART XII TRANSFUSION AND HEMAPHERESIS

91 Red Cell Transfusion

92 Transfusion of Platelets
93 Therapeutic Hemapheresis

Table of Normal Values

Index
 PREFACE

Williams Manual of Hematology provides a convenient and easily navigable précis of the
epidemiology, etiology, pathogenesis, diagnostic criteria, differential diagnosis, and therapy of
blood cell and coagulation protein disorders. The 93 chapters in the Manual are a distillation of
the disease- and therapy-focused chapters of the ninth edition of Williams Hematology. The
Manual is a handbook, but it is comprehensive. It is organized into 12 parts, paralleling the ninth
edition of Williams Hematology, yet of a size that permits it to serve as a companion to the
physician in the hospital or clinic. It can be used as a hard copy carried in one’s coat pocket or,
more deftly, as an app on one’s smart phone or tablet.
We have included chapters on the classification of red cell, neutrophil, monocyte, lymphocyte,
and platelet disorders and of diseases of coagulation proteins to provide a framework for
considering the differential diagnosis of syndromes that are not readily apparent. Also included
are numerous tables that contain diagnostic and therapeutic information relevant to the diseases
discussed. Detailed chapters describing the features of individual myeloid and lymphoid
malignancies provide a guide to diagnosis, staging, and management. Chapters on the
manifestations, diagnostic criteria, and therapy of hereditary and acquired thrombophilia consider
the role hematologists play in diagnosing and managing this important mechanism of disease.
Descriptions of diseases of red cells, neutrophils, monocytes, macrophages, lymphocytes,
platelets, and coagulation proteins and their management leave no gaps and meet the needs of the
busy hematologist, internist, or pediatrician. In addition, this handbook is very useful for
advanced practice professionals, medical and pediatric residents and subspecialty fellows, and
medical or nursing students because of its succinct clinical focus on diagnosis and management.
For many tables reproduced in the Manual, the reader can find explicit citations documenting
those entries in the concordant chapter in the ninth edition of Williams Hematology. In addition,
where helpful, images of blood or marrow cell abnormalities or external manifestations of
disease are included. Each chapter ends with an acknowledgment of the authors of the relevant
chapter in the ninth edition of Williams Hematology, including the chapter title and number for
easy cross-reference to that comprehensive text.
The publisher prints a caution in the Manual that admonishes readers to verify drug doses,
routes of administration, timing of doses, and duration of administration and to check the
contraindications and adverse effects of drugs used to treat the diseases described. We
reemphasize that these often complex diseases require direct participation and close supervision
of an experienced diagnostician and therapist. This oversight should be provided by a person who
is able to individualize therapy depending on the nature of the expression of the primary
hematological disease, the patient’s physiological age, and the presence of coincidental medical
conditions, among other factors.
The authors acknowledge the valuable assistance of Marie Brito at Stony Brook University,
Kim Arnold at the University of Nebraska, and, notably, Susan Daley at the University of
Rochester, who entered tables and figures into the chapters, managed the administrative
requirements in the preparation of the Manual, and coordinated communication among the six of
us and McGraw-Hill. We also acknowledge the encouragement and support of Karen Edmonson,
Senior Content Acquisitions Editor, and Harriet Lebowitz, Senior Project Development Editor, at
the Medical Publishing Division, McGraw-Hill Education.

Marshall A. Lichtman, Rochester, New York

Kenneth Kaushansky, Stony Brook, New York
Josef T. Prchal, Salt Lake City, Utah
Marcel M. Levi, Amsterdam, The Netherlands
Linda J. Burns, Minneapolis, Minnesota
James O. Armitage, Omaha, Nebraska
PART I
INITIAL CLINICAL EVALUATION
CHAPTER 1
Approach to the Patient

FINDINGS THAT MAY LEAD TO A HEMATOLOGY CONSULTATION

Table 1–1 lists abnormalities that often require an evaluation by a hematologist.

TABLE 1–1 FINDINGS THAT MAY LEAD TO A HEMATOLOGY CONSULTATION

Decreased hemoglobin concentration (anemia)
Increased hemoglobin concentration (polycythemia)
Elevated serum ferritin level
Leukopenia or neutropenia
Immature granulocytes or nucleated red cells in the blood
Pancytopenia
Granulocytosis: neutrophilia, eosinophilia, basophilia, or mastocytosis
Monocytosis
Lymphocytosis
Lymphadenopathy
Splenomegaly
Hypergammaglobulinemia: monoclonal or polyclonal
Purpura
Thrombocytopenia
Thrombocytosis
Exaggerated bleeding: spontaneous or trauma related
Prolonged partial thromboplastin or prothrombin coagulation times
Venous thromboembolism
Thrombophilia
Obstetrical adverse events (eg, recurrent fetal loss, stillbirth, and HELLP* syndrome)
*Hemolytic anemia, elevated liver enzymes, and low platelet count.
Source: Williams Hematology, 9th ed, Chap. 1, Table 1–1.

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.

HISTORY OF THE PRESENT ILLNESS

Estimation of the “performance status” helps establish the degree of disability and permits
assessment of the effects of therapy (Tables 1–2 and 1–3).
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.

TABLE 1–2 CRITERIA OF PERFORMANCE STATUS (KARNOFSKY SCALE)

Able to carry on normal activity; no special care is needed.
100% Normal; no complaints, no evidence of disease
90% Able to carry on normal activity; minor signs or symptoms of disease
80% Normal activity with effort; some signs or symptoms of disease
Unable to work; able to live at home, care for most personal needs; a varying amount of assistance is needed.
70% Cares for self; unable to carry on normal activity or to do active work
60% Requires occasional assistance but is able to care for most personal needs
50% Requires considerable assistance and frequent medical care
Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly.
40% Disabled; requires special care and assistance
30% Severely disabled; hospitalization is indicated though death not imminent
20% Very sick; hospitalization necessary; active supportive treatment necessary
10% Moribund; fatal processes progressing rapidly
0% Dead
Source: Williams Hematology, 9th ed, Chap. 1, Table 1–2.

TABLE 1–3 EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS

Grade Activity
0 Fully active; able to carry on all predisease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary
nature (eg, light housework, office work)
2 Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than
50% of waking hours
3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours
4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5 Dead
Source: Williams Hematology, 9th ed, Chap. 1, Table 1–3.

FAMILY HISTORY
 Hematologic disorders may be inherited as autosomal dominant, autosomal recessive, or X
chromosome–linked traits (see Williams Hematology, 9th 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, 9th ed, Chap. 12).

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.
Hemoglobin concentration and red cell count are measured directly by automated instruments.
Packed cell volume (hematocrit) is derived from the product of erythrocyte count and the
mean red cell volume. It may also be measured directly by high-speed centrifugation of
anticoagulated blood.
Both the hemoglobin and the hematocrit are based on whole blood and are, therefore,
dependent on plasma volume. If a patient is severely dehydrated, the hemoglobin and
hematocrit will appear higher than if the patient were normovolemic; if the patient is fluid
overloaded, those values will be lower than their actual level when normovolemic.
Mean (red) cell volume (MCV), mean (red) cell hemoglobin (MCH), and mean (red) cell
hemoglobin concentration (MCHC) are determined directly in automated cell analyzers. They
may also be calculated by using the following formulas:

The units are femtoliters (fL).

Mean cell hemoglobin (MCH) is calculated as follows:

The units are picograms (pg) per cell.

Mean corpuscular hemoglobin concentration (MCHC) is calculated as follows:

The units are grams of hemoglobin per deciliter (g/dL) of erythrocytes, or a percentage.
The MCH may decrease or increase as a reflection of decreases or increases in red cell
volume as well as actual increases or decreases in red cell hemoglobin concentration. The
MCHC controls for those changes in red cell size, providing a more reliable measurement of
hemoglobin concentration of red cells.
Red cell distribution width (RDW) is calculated by automatic counters and reflects the
variability in red cell size. The term “width” in RDW is misleading; it is a measure of the
coefficient of variation of the volume of the red cells, and not the diameter. It is expressed as a
percent.
RDW = (Standard deviation of MCV ÷ mean MCV) × 100
— Normal values are 11% to 14% of 1.0.
— The presence of anisocytosis may be inferred from an elevated RDW value.
Reticulocyte index. This variable is derived from the reticulocyte count and gives an estimate
of the marrow response to anemia reflecting the red cell production rate.
— The normal marrow with adequate iron availability can increase red cell production two to
three times acutely and four to six times over a longer period of time.
— The reticulocyte index is used to determine if anemia is more likely the result of decreased
red cell production or accelerated destruction in the circulation (hemolysis).
— By convention, hemolysis should be considered if the reticulocyte index is more than two
times the basal value of 1.0.
— This calculation assumes (1) the red cell life span is ~100 days; (2) a normal reticulocyte
is identifiable in the blood with supravital staining for 1 day; (3) the red cell life span is
finite and the oldest 1% of red cells are removed and replaced each day; and (4) a
reticulocyte count of 1% in an individual with a normal red cell count represents the
normal red cell production rate per day thus, 1 is the basal reticulocyte index.
— The reticulocyte index provides the incidence of new red cells released per day as an
estimate of marrow response to anemia.
Consider a patient with a red cell count of 2 × 1012/L and a reticulocyte count of 15%. The
reticulocyte index is calculated as follows:
— Corrected reticulocyte percent = observed reticulocyte percent × observed red cell
count/normal red cell count. Calculation for patient values in this example = 15 × 2.0/5.0 =
6. This adjustment corrects the percent of reticulocytes for the decreased red cells in an
anemic person. This calculation provides the prevalence of reticulocytes, but we want to
know the incidence of reticulocytes (per day).
— In anemia, under the influence of elevated erythropoietin, reticulocytes do not mature in the
marrow for 3 days and then circulate for 1 day before they degrade their ribosomes and
cannot be identified as such. Reticulocytes are released prematurely and thus may be
identifiable in the circulation for 2 or 3 days and not reflect new red cells delivered that
day, as in the normal state.
— The corrected reticulocyte percent must be adjusted for premature release of reticulocytes.
This is done by dividing the corrected reticulocyte percent by a factor related to the
severity of anemia from 1.5 to 3. In practice, the value 2 is usually used as an
approximation.
— Thus, the corrected reticulocyte percent of 6 ÷ 2 results in a reticulocyte index of three
times the basal value, indicating the anemia is hemolytic.
Enumeration of erythrocytes, leukocytes, and platelets can be performed by manual methods by
using diluting pipettes, a specially designed counting chamber, and a light microscope, but an
electronic method provides much more precise data and is now used nearly universally for
blood cell counts.
Leukocyte differential count can be obtained from stained blood films prepared on glass
slides. Automated techniques may be used for screening purposes, in which case abnormal
cells are called out and examined microscopically by an experienced observer. Normal values
for specific leukocyte types in adults are given in Table 1–5. The identifying features of the
various types of normal leukocytes are shown in Figure 1–1 and are detailed in Williams
Hematology, 9th ed, Chap. 2; Chap. 60; Chap. 67; Chap. 73.
Electronic methods that provide rapid and accurate classification of leukocyte types based
largely on the physical properties of the cells have been developed and are in general use as
described in Williams Hematology, 9th ed, Chap. 2.
Properly stained blood films also provide important information on the morphology of
erythrocytes and platelets as well as leukocytes.
 Examination of the blood film may reflect the presence of a number of diseases of the blood.
These are listed in Table 1–6.

FIGURE 1–1 Images from a normal blood film showing major leukocyte types. The red cells are normocytic (normal size) and
normochromic (normal hemoglobin content) with normal shape. The scattered platelets are normal in frequency and morphology.
Images are taken from the optimal portion of the blood film for morphologic analysis. A. A platelet caught sitting in the biconcavity
of the red cell in the preparation of the blood film—a segmented (polymorphonuclear) neutrophil and in the inset, a band neutrophil.
This normal finding should not be mistaken for a red cell inclusion. B. A monocyte. C. A small lymphocyte. D. A large granular
lymphocyte. Note that it is larger than the lymphocyte in C with an increased amount of cytoplasm containing scattered eosinophilic
granules. E. An eosinophil. Virtually all normal blood eosinophils are bilobed and filled with relatively large (compared to the
neutrophil) eosinophilic granules. F. Basophil and in inset a basophil that was less degranulated during film preparation, showing
relatively large basophilic granules. The eosinophilic and basophilic granules are readily resolvable by light microscopy (×1000),
whereas the neutrophilic granules are not resolvable, but in the aggregate impart a faint tan coloration to the neutrophil cytoplasm,
quite distinctly different from the blue-gray cytoplasmic coloring of the monocyte and lymphocyte. (Source: Williams Hematology,
9th ed, Chap. 2, Figure 2–4.)

TABLE 1–4 BLOOD CELL VALUES IN A NORMAL POPULATION

Men Women Either

White cell count,* × 109/L blood 7.8 (4.4–11.3)+

Red cell count, × 1012/L blood 5.21 (4.52–5.90) 4.60 (4.10–5.10)
Hemoglobin, g/dL blood 15.7 (14.0–17.5)++ 13.8 (12.3–15.3)++
Hematocrit (Volume of packed red cells as a ratio 0.46 (0.42–0.50) 0.40 (0.36–0.45)
to a volume of blood)
Mean cell volume, fL/red cell 88.0 (80.0–96.1)
Mean cell hemoglobin, pg/red cell 30.4 (27.5–33.2)
Mean cell hemoglobin concentration, g/dL red cell 34.4 (33.4–35.5)
Red cell distribution width, CV (%) 13.1 (11.5–14.5)
Platelet count, × 109/L blood 311 (172–450)

*The International Committee for Standardization in Hematology recommends that SI units be used as follows: white cell count,
number × 109/L; red cell count, number × 1012/L; and hemoglobin, g/dL (dL = deciliter). The hematocrit (packed cell volume) is
given as a numerical proportion, for example, 0.41, without designated units. Units of liter (of red cells) per liter (of blood) are
implied. Mean cell volume is given as femtoliters (fL), mean cell hemoglobin as picograms (pg), and mean corpuscular hemoglobin
concentration as g/dL. Platelets are reported as number × 109/L. CV = coefficient of variation.
+The mean and reference intervals (normal range) are given. Because the distribution curves may be non-Gaussian, the reference
interval is the nonparametric central 95% confidence interval. Results are based on 426 normal adult men and 212 normal adult
women, with studies performed on the Coulter Model S-Plus IV. The normal intervals in this table may vary somewhat in different
laboratories and in populations with varying ethnic distributions. For example, the mean neutrophil count in persons of African
descent is approximately 1.5 × 109/L below that for individuals of European descent of similar sex and age. This difference also
decreases the total leukocyte count in Americans of African descent by a similar concentration.
++The hemoglobin level of individuals of African descent is approximately 1.0 g/dL below that for individuals of European descent
of similar sex and age.

TABLE 1–5 REFERENCE RANGES FOR LEUKOCYTE COUNT, DIFFERENTIAL COUNT, AND
HEMOGLOBIN CONCENTRATION IN CHILDREN*

TABLE 1–6 DISEASES IN WHICH EXAMINATION OF THE BLOOD FILM CAN SUGGEST OR
CONFIRM THE DISORDER
Disease Findings on Blood Film
Immune hemolytic anemia Spherocytes, polychromatophilia, erythrocyte agglutination, erythrophagocytosis
Hereditary spherocytosis Spherocytes, polychromatophilia
Hereditary elliptocytosis Elliptocytes
Hereditary ovalocytosis Ovalocytes
Hemoglobin C disease Target cells, spherocytes
Hemoglobin S disease Sickle cells
Hemoglobin SC
Thalassemia minor (alpha or beta)
Thalassemia major (alpha or beta)
Iron deficiency
Lead poisoning
Vitamin B12 or folic acid deficiency
Myeloma, macroglobulinemia
Malaria, babesiosis, others
Consumptive coagulopathy
Mechanical hemolysis
Severe infection
Infectious mononucleosis
Agranulocytosis
Allergic reactions
Chronic lymphocytic leukemia
Chronic myelogenous leukemia
Oligoblastic myelogenous leukemia
(refractory anemia with excess blast cells,
myelodysplasia)
Clonal cytopenias (myelodysplasia)
Acute leukemia
Thrombocytopenia
Thrombocytosis or thrombocythemia
Target cells, sickle cells
Microcytosis, target cells, teardrop cells, basophilic stippling, other misshapen cells
Microcytosis, target cells, basophilic stippling, teardrop cells, other misshapen cells
(often more exaggerated than minor form)
Microcytosis, hypochromia, absence of basophilic stippling
Basophilic stippling
Macrocytosis, with oval macrocytes, hypersegmented neutrophils
Pathologic rouleaux formation
Parasites in the erythrocytes
Fragmented red cells (schistocytes)
Fragmented red cells (schistocytes)
Increase in neutrophils; increased band forms, Döhle bodies, neutrophil vacuoles
Reactive lymphocytes
Decreased neutrophils
Eosinophilia
Absolute small-cell lymphocytosis
Promyelocytes, myelocytes, basophils, hypersegmented neutrophils
Blast forms, acquired Pelger-Huët neutrophil nuclear abnormality, anisocytosis,
poikilocytosis, abnormal platelets
Anisocytosis, anisochromia, poikilocytosis, hypogranular neutrophils, acquired
Pelger-Huët neutrophil nuclear abnormality, neutropenia, thrombocytopenia, giant
platelets
Blast cells
Decreased platelets
Increased platelets

Infancy and Childhood

Some components of the blood count in infancy and childhood differ significantly from those in
adults.
Hemoglobin levels are high at birth (19.3 ± 2.2 [s.d.] g/dL) but fall over the first 12 weeks of
life to reach levels that persist throughout childhood (11.3 ± 0.9 [s.d.] g/dL). Adult levels in
males are achieved after puberty. Red cell values for infants during the first 12 weeks of life
are given in Williams Hematology, 9th ed, Chap. 7, Table 7–2.
The mean leukocyte count is high at birth (mean of 18 × 109/L); neutrophils comprise about
60% of the cells. The leukocyte count falls over the next 2 weeks or so, to reach levels that
persist throughout childhood. Lymphocytes are the predominant cell type for the remainder of
the first 4 years of life (45%–55%). Further details can be found in Williams Hematology, 9th
ed, Chap. 7, Table 7–3.
Platelet counts are at adult levels throughout childhood.
Leukocyte function may be depressed in normal infants in the newborn period.
Reference values for coagulation factors in neonates and infants may be found in Williams
Hematology, 9th ed, Chap. 7, Table 7–6, and for coagulation factor inhibitors in neonates and
 infants in Table 7–7.

Effects of Aging
See Williams Hematology, 9th ed, Chap. 9.
Blood count and cell function may also vary with advanced age.
The hemoglobin level of men older than 65 years of age is statistically lower than that of
younger men, even in the absence of a demonstrable cause for anemia, but is not sufficiently
lower to warrant use of specific normal values for older men. Anemia in an older person
warrants careful evaluation as to its cause before concluding it is the anemia of aging.
The hemoglobin level in women does not change significantly with advancing age.
Total and differential leukocyte counts also do not change significantly with advancing age.
Leukocytosis in response to infection (eg, appendicitis or pneumonia) is the same in older
individuals as in people younger than age 60, but special studies indicate that the marrow
granulocyte reserve may be reduced in older persons.
Both cellular and humoral immune responses are reduced in older patients.
The erythrocyte sedimentation rate increases significantly with age.
Aging is associated with a net procoagulant propensity and an increased risk of venous
thrombosis.

Utility of the Blood Film in Diagnosis

The blood film is invaluable in developing the differential diagnosis or the specific diagnosis
of a blood cell disorder. Table 1–6 lists several situations in which the blood film can be
important or decisive.

The Marrow
Examination of the marrow is important in the diagnosis and management of a variety of
hematologic disorders.
All bones contain hematopoietic marrow at birth.
Fat cells begin to replace hematopoietic marrow in the extremities in the fifth to sixth year of
life.
In adults, hematopoietic marrow is principally located in the axial skeleton (ribs, spine,
sternum, pelvis, scapula, clavicle, and base of the skull) and the proximal quarter of the
humeri and femora.
Hematopoietic marrow cellularity is reduced in the elderly, falling after age 60 from about
50% to 30%, roughly in inverse proportion to age.
Marrow is obtained by aspiration and/or needle biopsy. The most frequently utilized site is the
iliac crest at the posterior superior iliac spine. Modern biopsy instruments provide excellent
material for diagnostic study.
Aspirated marrow may be evaluated after preparation of films on glass slides and appropriate
staining.
Marrow biopsies are examined after fixation, sectioning, and staining. “Touch” preparations
made by holding the biopsy specimen with a forceps and touching the end to one or more clean
slides in several places. Imprints of the marrow remain on the slide. The slides are quickly air
dried, fixed with methanol, and stained. Morphologic details of the cells are preserved with
this type of preparation and thus provide additional information.
Interpretation of marrow films and biopsy sections is discussed in Williams Hematology, 9th
ed, Chap. 3 and in chapters describing specific diseases for which a marrow is usually
performed. Williams Hematology, 9th ed, Table 3–1 contains the normal differential count of
cells in the marrow.

For a more detailed discussion, see Marshall A. Lichtman and Linda J. Burns: Approach to the Patient, Chap.
1; Daniel H. Ryan: Examination of Blood Cells, Chap. 2; Daniel H. Ryan: Examination of the Marrow, Chap.
3; James Palis and George B. Segel: Hematology of the Fetus and Newborn, Chap. 7; William B. Ershler,
Andrew S. Artz, and Bindu Kanapuru: Hematology in Older Persons, Chap. 9; C. Wayne Smith: Morphology
of Neutrophils, Eosinophils, and Basophils, Chap. 60; Steven D. Douglas, Ann G. Douglas: Morphology of
Monocytes and Macrophages, Chap. 67; Natarajan Muthusamy and Michael A. Caligiuri: Structure of
Lymphocytes and Plasma Cells, Chap. 73 in Williams Hematology, 9th ed.
PART II
DISORDERS OF RED CELLS
CHAPTER 2
Classification of Anemias and Polycythemias

Clinically significant red cell disorders can be classified into:

— Disorders in which the red cell mass is decreased (anemias). The principal effect is
decreased oxygen-carrying capacity of the blood. Their severity is best expressed in terms
of hemoglobin concentration.
— Disorders in which the red cell mass is increased (polycythemias also known as
erythrocytoses). The principal effect is related to an increased viscosity of the blood (see
Figure 2–1). In addition to their specific effects, they are best expressed in terms of packed
red cell volume (hematocrit).
The red cell mass is the volume of the mass of red cells in the circulation.
— The normal red cell mass among women is 23 to 29 mL/kg.
— The normal red cell mass among men is 26 to 32 mL/kg.
— More accurate formulas based on body surface have been recommended.
Because the red cells are measured either as a concentration in the blood as the red cell count,
the hemoglobin content of the blood, or the hematocrit (packed red cell volume per 100 mL of
blood), rather than the volume of the red cell mass in the total circulation, the anemias and
polycythemias can each be subclassified as:
— Relative, where the red cell mass is normal but the amount of plasma is increased (relative
anemia) or decreased (polycythemia)
— Absolute, where the red cell mass is decreased (true anemia) or increased (true
polycythemia)
The various types of anemia are classified in Table 2–1.
It is essential that the specific cause of anemia be determined. The initial laboratory approach
to the diagnosis of anemia follows, and these four studies should be the prelude to guide
further specific testing.
— Hematocrit, hemoglobin, or red cell count to determine degree of anemia. In most cases,
these three variables are closely correlated. Hemoglobin concentration is the most direct
measure of oxygen-carrying capacity.
— Red cell indices, such as mean cell volume (MCV), mean cell hemoglobin (MCH), and
mean cell hemoglobin concentration (MCHC) to determine whether normocytic,
macrocytic, or microcytic and normochromic or hypochromic red cells are present on
average
— Measurement of red cell distribution width (RDW) to obtain a measure of anisocytosis
— Reticulocyte count or index to estimate whether marrow response suggests inadequacy of
red cell production or an appropriate erythropoietic response to hemolysis (or acute
bleeding). The latter is usually readily apparent clinically.
— Examination of the blood film to determine red cell size and shape, hemoglobin content,
 presence of red cell inclusions, presence of agglutination or rouleaux formation,
nonhematopoietic particles such as parasites (ie, Babesia and Plasmodium species) and
helminths (ie, Wuchereria bancrofti, nematodes), and accompanying abnormalities of white
cells and platelets
Important caveats:
— Red cell size and hemoglobin content are best determined from their indices because the
blood film will usually make evident only gross deviations (eg, the need to estimate red
cell volume from a two-dimensional area). Moreover, the blood in macrocytic anemia
usually contains many microcytic cells and in microcytic anemias, many normocytic cells,
which make determination of the average red cell volume from a blood film difficult.
— In general, the abnormalities in size, hemoglobin content, and shape are approximately
correlated with severity of anemia. If the anemia is slight, the other changes are often
subtle.
— Anemia classically categorized as macrocytic or microcytic may be present in the face of
red cell volumes that are in the normal range. This may be the case because the anemia is
so mild that red cell volumes have not yet deviated beyond the normal range, or may be the
case with more severe anemias because of confounding effects of two causal factors (eg,
iron deficiency and folate deficiency), or well-established megaloblastic anemia may have
normocytic index in otherwise asymptomatic individuals such as those being silent carriers
or having alpha thalassemia trait (one or two alpha globin deletions) (see Chap. 15).
A classification of the major causes of polycythemia is shown in Table 2–2.
It is important to search for the specific cause of polycythemia. The diagnosis of
polycythemias is discussed in Chaps. 27 (polyclonal polycythemias) and 41 (polycythemia
vera).
FIGURE 2–1 Viscosity of heparinized normal human blood related to hematocrit (Hct). Viscosity is measured with an Ostwald
viscosimeter at 37°C and expressed in relation to viscosity of saline solution. Oxygen transport is computed from Hct and oxygen
flow (1/viscosity) and is recorded in arbitrary units. Please note this curve of oxygen transport applies when red cell mass is normal.
When red cell mass is increased the curve shifts to the right, when decreased it shifts to the left.

TABLE 2–1 CLASSIFICATION OF ANEMIA

I. Absolute anemia (decreased red cell volume)
A. Decreased red cell production
1. Acquired
a. Pluripotential stem cell failure
(1) Autoimmune (aplastic anemia) (see Chap. 3)
(a) Radiation induced
(b) Drugs and chemicals (chloramphenicol, benzene, etc.)
(c) Viruses (non-A-G, H hepatitis, Epstein-Barr virus, etc.)
(d) Idiopathic
(2) Anemia of leukemia and of myelodysplastic syndromes (see Chaps. 44 and 45)
(3) Anemia associated with marrow infiltration (see Chap. 12)
(4) Postchemotherapy (see Chap. 38)
b. Erythroid progenitor cell failure
(1) Pure red cell aplasia (parvovirus B19 infection, drugs, associated with thymoma, autoantibodies, etc. [see Chap.
4])
(2) Endocrine disorders (see Chap. 6)
(3) Acquired sideroblastic anemia (drugs, copper deficiency, etc. [see Chap. 11])
c. Functional impairment of erythroid and other progenitors due to nutritional and other causes
(1) Megaloblastic anemias (see Chap. 8)
(a) B12 deficiency
 (b) Folate deficiency
(c) Acute megaloblastic anemia because of nitrous oxide (N2O)
(d) Drug-induced megaloblastic anemia (pemetrexed, methotrexate, phenytoin toxicity, etc.)
(2) Iron-deficiency anemia (see Chap. 9)
(3) Anemia resulting from other nutritional deficiencies (see Chap. 10)
(4) Anemia of chronic disease and inflammation (see Chap. 5)
(5) Anemia of renal disease (see Chap. 5)
(6) Anemia caused by chemical agents (lead toxicity [see Chap. 20])
(7) Acquired thalassemias (seen in some clonal hematopoietic disorders [see Chaps. 15 and 40])
(8) Erythropoietin antibodies (see Chap. 4)
2. Hereditary
a. Pluripotential hematopoietic stem cell failure (see Chap. 3)
(1) Fanconi anemia
(2) Shwachman syndrome
(3) Dyskeratosis congenita
b. Erythroid progenitor cell failure
(1) Diamond-Blackfan syndrome (see Chap. 3)
(2) Congenital dyserythropoietic syndromes (see Chap. 7)
c. Functional impairment of erythroid and other progenitors from nutritional and other causes
(1) Megaloblastic anemias (see Chap. 8)
(a) Selective malabsorption of vitamin B12 (Imerslund-Gräsbeck disease)
(b) Congenital intrinsic factor deficiency
(c) Transcobalamin II deficiency
(d) Inborn errors of cobalamin metabolism (methylmalonic aciduria, homocystinuria, etc.)
(e) Inborn errors of folate metabolism (congenital folate malabsorption, dihydrofolate deficiency,
methyltransferase deficiency, etc.)
(2) Inborn purine and pyrimidine metabolism defects (Lesch-Nyhan syndrome, hereditary orotic aciduria, etc.)
(3) Disorders of iron metabolism (see Chap. 9)
(a) Hereditary atransferrinemia
(b) Hypochromic anemia caused by divalent metal transporter (DMT)-1 mutation
(4) Hereditary sideroblastic anemia (see Chap. 11)
(5) Thalassemias (see Chap. 15)
B. Increased red cell destruction
1. Acquired
a. Mechanical
(1) Macroangiopathic (march hemoglobinuria, artificial heart valves [see Chap. 19])
(2) Microangiopathic (disseminated intravascular coagulation [DIC]; thrombotic thrombocytopenic purpura [TTP];
vasculitis [see Chaps. 19, 85, and 90])
(3) Parasites and microorganisms (malaria, bartonellosis, babesiosis, Clostridium perfringens, etc. [see Chap. 21])
b. Antibody mediated
(1) Warm-type autoimmune hemolytic anemia (see Chap. 22)
(2) Cryopathic syndromes (cold agglutinin disease, paroxysmal cold hemoglobinuria, cryoglobulinemia [see Chap.
23])
(3) Transfusion reactions (immediate and delayed [see Chap. 91])
c. Hypersplenism (see Chap. 26)
d. Red cell membrane disorders (see Chap. 13)
(1) Spur cell hemolysis
(2) Acquired acanthocytosis and acquired stomatocytosis, etc.
e. Chemical injury and complex chemicals (arsenic, copper, chlorate, spider, scorpion, and snake venoms, etc. [see
Chap. 20])
f. Physical injury (heat, oxygen, radiation [see Chap. 20])
2. Hereditary
a. Hemoglobinopathies (see Chap. 16)
(1) Sickle cell disease
(2) Unstable hemoglobins
b. Red cell membrane disorders (see Chap. 13)
(1) Cytoskeletal membrane disorders (hereditary spherocytosis, elliptocytosis, pyropoikilocytosis)
 (2) Lipid membrane disorders (hereditary abetalipoproteinemia, hereditary stomatocytosis, etc.)
(3) Membrane disorders associated with abnormalities of erythrocyte antigens (McLeod syndrome, Rh deficiency
syndromes, etc.)
(4) Membrane disorders associated with abnormal transport (hereditary xerocytosis)
c. Red cell enzyme defects (pyruvate kinase, 5’ nucleotidase, glucose-6-phosphate dehydrogenase deficiencies, other
red cell membrane disorders [see Chap. 14])
d. Porphyrias (congenital erythropoietic and hepatoerythropoietic porphyrias, rarely congenital erythropoietic
protoporphyria [see Chap. 28])
C. Blood loss and blood redistribution
1. Acute blood loss
2. Splenic sequestration crisis (see Chap. 26)
II. Relative (increased plasma volume)
A. Macroglobulinemia (see Chap. 69)
B. Pregnancy
C. Athletes (see Chap. 19)
D. Postflight astronauts
Source: Williams Hematology, 9th ed, Chap. 34, Table 34–1.

TABLE 2–2 CLASSIFICATION OF POLYCYTHEMIA

I. Absolute (true) polycythemia (increased red cell volume) (see Chap. 27)
A. Primary polycythemia
1. Acquired: polycythemia vera (see Chap. 41)
2. Hereditary (see Chap. 27): primary familial and congenital polycythemia (PFCP)
a. Erythropoietin receptor mutations
b. Unknown gene mutations
B. Secondary polycythemia
1. Acquired (see Chap. 27)
a. Hypoxemia
(1) Chronic lung disease
(2) Sleep apnea
(3) Right-to-left cardiac shunts
(4) High altitude
(5) Smoking
b. Carboxyhemoglobinemia (see Chap. 18)
(1) Smoking
(2) Carbon monoxide poisoning
c. Autonomous erythropoietin production (see Chap. 27)
(1) Hepatocellular carcinoma
(2) Renal cell carcinoma
(3) Cerebellar hemangioblastoma
(4) Pheochromocytoma
(5) Parathyroid carcinoma
(6) Meningioma
(7) Uterine leiomyoma
(8) Polycystic kidney disease
d. Exogenous erythropoietin administration (“EPO doping”) (see Chap. 27)
e. Complex or uncertain etiology
(1) Postrenal transplant (probable abnormal angiotensin II signaling) (see Chap. 27)
(2) Androgen/anabolic steroids (see Chap. 27)
2. Hereditary
a. High-oxygen affinity hemoglobins (see Chap. 17)
b. 2,3-Bisphosphoglycerate deficiency (see Chap. 14)
c. Congenital methemoglobinemias (recessive, ie, cytochrome b5 reductase deficiency, dominant globin mutations [see
Chaps. 17 and 27])
C. Disorders of Hypoxia sensing (see Chap. 27)
1. Proven or suspected congenital disorders of hypoxia sensing
a. Chuvash polycythemia
 b. High erythropoietin polycythemias due to mutations of von Hippel-Lindau gene other than Chuvash mutation
c. HIF-2 α (EPASI) mutations
d. PHD2 (EGLN1) mutations
II. Relative (spurious) polycythemia (normal red cell volume) (see Chap. 27)
A. Dehydration
B. Diuretics
C. Smoking
D. Gaisböck syndrome
Source: Williams Hematology, 9th ed, Chap. 34, Table 34–2.

For a more detailed discussion, see Josef T. Prchal: Clinical Manifestations and Classification of Erythrocyte
Disorders, Chap. 34; Josef T. Prchal: Erythropoiesis, Chap. 32; Josef T. Prchal: Primary and Secondary
Polycythemia (Erythrocytosis), Chap. 57; Mohandas Narla: Structure and Composition of the Erythrocyte,
Chap. 31 in Williams Hematology, 9th ed.
CHAPTER 3
Aplastic Anemia: Acquired and Inherited

DEFINITION
Aplastic anemia is marked by pancytopenia with markedly hypocellular marrow and normal
marrow cell cytogenetics.
Incidence worldwide is two to five cases/million population per year and five to twelve
cases/million population per year in the United States (and in other industrialized countries).
Incidence is approximately twice as high in Asian countries.
Peak incidence is between ages 15 and 25 and 65 and 69 years.
The definitions for spectrum of severity of aplastic anemia are shown in Table 3–1.

TABLE 3–1 DEGREE OF SEVERITY OF ACQUIRED APLASTIC ANEMIA*

Diagnostic Reticulocyte Neutrophil Platelet
Categories Hemoglobin Concentration Count Count Marrow Biopsy Comments
Moderately < 100 g/L < 40 × 109/L < 1.5 × < 50 × Marked decrease of At the time of diagnosis at
severe 109/L 109/L hematopoietic cells least two of three blood
counts should meet these
criteria.
Severe < 90 g/L < 30.0 × 109/L < 0.5 × < 30.0 × Marked decrease or Search for a histocompatible
109/L 109/L absence of sibling should be made if
hematopoietic cells age permits.
Very severe < 80 g/L < 20.0 × 109/L < 0.2 × < 20.0 × Marked decrease or Search for a histocompatible
109/L 109/L absence of sibling should be made if
hematopoietic cells age permits.
*These values are approximations and must be considered in the context of an individual patient’s situation. (In some clinical trials,
the blood count thresholds for moderately severe aplastic anemia are higher [eg, platelet count < 100 × 109/L and absolute
reticulocyte count < 60,000 × 109/L].) The marrow biopsy may contain the usual number of lymphocytes and plasma cells; “hot
spots,” focal areas of erythroid cells, may be seen. No fibrosis, abnormal cells, or malignant cells should be evident in the marrow.
Dysmorphic features of blood or marrow cells are not features of acquired aplastic anemia. Ethnic differences in the lower limit of
the absolute neutrophil count should be considered. (See Williams Hematology, 9th ed, Chaps. 64 and 65.)
Source: Williams Hematology, 9th ed, Chap. 35, Table 35–1.

ETIOLOGY AND PATHOGENESIS

Pathogenesis
Immune suppression of marrow by autoreactive T lymphocytes
Toxic injury to stem and/or progenitor cells (eg, certain chemotherapy or drugs) (see Table 3–
2)
Inherited intrinsic stem cell defect (eg, Fanconi anemia)
 TABLE 3–2 SOME DRUGS ASSOCIATED WITH MODERATE RISK OF APLASTIC ANEMIA*
Acetazolamide

Carbamazepine
Chloramphenicol
Gold salts
Hydantoins
Oxyphenbutazone
Penicillamine
Phenylbutazone
Quinacrine
*Drugs with 30 or more reported cases.
Source: Williams Hematology, 9th ed, Chap. 35, Table 35–3.

Acquired (see Table 3–3)

TABLE 3–3 ETIOLOGIC CLASSIFICATION OF APLASTIC ANEMIA

ACQUIRED
Autoimmune
Drugs (see Table 3–2)
Toxins
Benzene
Chlorinated hydrocarbons
Organophosphates
Viruses
Epstein-Barr virus
Non-A, -B, -C, -D, -E, or -G hepatitis virus
Human immunodeficiency virus (HIV)
Paroxysmal nocturnal hemoglobinuria
Autoimmune/connective tissue disorders
Eosinophilic fasciitis
Immune thyroid disease (Graves disease, Hashimoto thyroiditis)
Rheumatoid arthritis
Systemic lupus erythematosus
Thymoma
Pregnancy
Iatrogenic
Radiation
Cytotoxic drug therapy
INHERITED
Fanconi anemia
Dyskeratosis congenita
Shwachman-Diamond syndrome
Other rare syndromes (see Table 3–4)
Source: Williams Hematology, 9th ed, Chap. 35, Table 35–2.

Acquired T lymphocyte–mediated autoimmune suppression of hematopoietic stem cells and/or

progenitor cells in most cases (~70%)
Paroxysmal nocturnal hemoglobinuria (PNH) (may be manifest by cytopenias and hypoplastic
marrow)
 Chemicals (eg, high-dose benzene exposure); rare today in countries with workplace and
product regulations limiting exposure
Drugs (eg, chloramphenicol; see Table 3–2 for most frequent offenders; see also Williams
Hematology, 9th ed, Chap. 35, Table 35–3 for a more complete list)
Viruses (eg, Epstein-Barr; non-A, -B, -C, -D, -E, or -G hepatitis; HIV)
Immune and connective tissue diseases (eg, eosinophilic fasciitis, Hashimoto thyroiditis,
Graves disease, systemic lupus erythematosus)
Pregnancy
Iatrogenic or accidental (eg, intensive radiation to marrow-bearing bones, intensive marrow-
suppressive chemotherapy)

Inherited (see Table 3–3)

Fanconi anemia
— Inheritance is autosomal recessive.
— Any of 16 gene mutations, FANCA through FANCQ, account for about 95% of cases.
— Macrocytosis and poikilocytosis may precede cytopenias.
— Cytopenias, sometimes starting with thrombocytopenia, develop after age 5 to 10 years.
— Marrow hypocellularity explains cytopenias.
— Short stature; abnormal skin pigmentation (café-au-lait spots); skeletal abnormalities (eg,
dysplastic radii and thumbs); heart, kidney, and eye anomalies; microcephaly; and
hypogonadism in different combinations are often noted.
— Chromosome fragility may be present, especially after exposure to DNA cross-linking
agents such as diepoxybutane (used as a diagnostic test).
— Androgens occasionally may improve hematopoiesis.
— Allogeneic hematopoietic stem cell transplantation can be curative.
— There is risk of acute myelogenous leukemia and other cancers.
Dyskeratosis congenita
— Inheritance patterns: autosomal dominant, autosomal recessive, and X-linked (see Williams
Hematology, 9th ed, Chap. 35, Table 35–10)
— Gene mutations identified in majority of cases
— Mutations involving genes encoding proteins in the telomerase complex
— Resulting abnormalities in telomere length
— Mucocutaneous (eg, skin hyperpigmentation or hypopigmentation, alopecia leukoplakia)
and finger and toenail abnormalities (ridging and longitudinal splitting, atrophy) in
childhood
— Pulmonary (eg, fibrosis), gastrointestinal (eg, esophageal webs), urogenital (eg,
hypospadias), neurologic (eg, learning impairment), skeletal (eg, hypoplasia of mandible)
findings
— Aplastic anemia in early adulthood: principal cause of death
— Increased incidence of various mucosal cancers (eg, squamous cell carcinoma of mouth,
nasopharynx, esophagus, rectum, vagina, others)
Shwachman-Diamond syndrome
— The cause is mutation in the SBDS (Shwachman-Bodian-Diamond syndrome) gene on
chromosome 7.
 — Exocrine pancreatic insufficiency and neutropenia occur. Pancreatic endocrine function
(insulin secretion) generally remains intact.
— Neutropenia with functionally abnormal neutrophils (defective chemotaxis) is present in
virtually all patients.
— Anemia and thrombocytopenia are less common.
— Elevated hemoglobin F occurs in most patients.
— Pancytopenia occurs in about 20% of patients.
— Patients usually present in early infancy with malabsorption; steatorrhea; failure to thrive;
and deficiencies of fat-soluble vitamins A, D, E, and K.
— Approximately 50% of patients regain exocrine pancreatic function during later childhood.
— Skeletal anomalies (eg, short stature, osteochondrodysplasia [cartilage and bone
anomalies], osteoporosis) are present in about 75% of patients.
— Recurrent bacterial infections (eg, upper respiratory tract infections, otitis media, sinusitis,
pneumonia, paronychia, osteomyelitis, bacteremia) occur.
— Enzyme replacement therapy is given for exocrine pancreatic insufficiency.
— Progression to multicytopenia, hypoplastic marrow, myelodysplasia, or acute myelogenous
leukemia can occur.
— Allogeneic hematopoietic stem cell transplantation can be curative.
Other rare causes of aplastic anemia are shown in Table 3–4

TABLE 3–4 OTHER RARE INHERITED SYNDROMES ASSOCIATED WITH APLASTIC ANEMIA
Disorder Findings Inheritance Mutated Gene
Ataxia-pancytopenia Cerebellar atrophy and ataxia; aplastic AD Unknown
(myelocerebellar disorder) pancytopenia; ± monosomy 7; increased risk of
AML
Congenital amegakaryocytic Thrombocytopenia; absent or markedly decreased AR (compound MPL
thrombocytopenia marrow megakaryocytes; hemorrhagic heterozygotes)
propensity; elevated thrombopoietin; propensity
to progress to aplastic pancytopenia; propensity
to evolve to clonal myeloid disease
DNA ligase IV deficiency Pre- and postnatal growth delay; dysmorphic AR LIG4
facies; aplastic pancytopenia
Dubowitz syndrome Intrauterine and postpartum growth failure; short AR Unknown
stature; microcephaly; mental retardation;
distinct dysmorphic facies; aplastic
pancytopenia; increased risk of AML and ALL
Nijmegen breakage syndrome Microcephaly; dystrophic facies; short stature; AR NBS1
immunodeficiency; radiation sensitivity; aplastic
pancytopenia; predisposition to lymphoid
malignancy
Reticular dysgenesis (type of Lymphopenia; anemia and neutropenia; corrected XLR Unknown
severe immunodeficiency by hematopoietic stem cell transplantation
syndrome)
Seckel syndrome Intrauterine and postpartum growth failure; AR ATR (and RAD3-
microcephaly; characteristic dysmorphic facies related gene);
(bird-headed profile); aplastic pancytopenia; PCNT
increased risk of AML
WT syndrome Radial/ulnar abnormalities; aplastic pancytopenia; AD Unknown
 increased risk of AML
AD, autosomal dominant; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; AR, autosomal recessive; XLR,
X-linked recessive.
The listed clinical findings in each syndrome are not comprehensive. The designated clinical findings may not be present in all
cases of the syndrome. Isolated cases of familial aplastic anemia with or without associated anomalies that are not consistent with
Fanconi anemia or other defined syndromes have been reported.
Source: Williams Hematology, 9th ed, Chap. 35, Table 35–9.

CLINICAL FEATURES
Fatigue, pallor, dyspnea on exertion, bleeding, or infections occur as a consequence of the
cytopenias.
Physical examination generally is unrevealing except for signs of anemia, bleeding, or
infection.

LABORATORY FEATURES
Pancytopenia is present.
Red cells may be macrocytic.
Marrow is markedly hypocellular (Figure 3–1).
Abnormal clonal cytogenetic findings suggest hypoplastic myelodysplastic syndrome (clonal
myeloid disease) rather than aplastic anemia.
Blast cells in marrow suggest hypoplastic acute myelogenous leukemia.
Presence of CD55,CD59 on blood cells by flow cytometry rules out PNH.

FIGURE 3–1 Marrow biopsy in aplastic anemia. A. Normal marrow biopsy section of a young adult. B. Marrow biopsy section of
a young adult with very severe aplastic anemia. The specimen is devoid of hematopoietic cells and contains only scattered
lymphocytes and stromal cells. The hematopoietic space is replaced by reticular cells (preadipocytic fibroblasts) converted to
adipocytes. (Source: Williams Hematology, 9th ed, Fig. 35–2.)

Table 3–5 lists important diagnostic procedures.

TABLE 3–5 APPROACH TO DIAGNOSIS

• History and physical examination
• Complete blood counts, reticulocyte count, and examination of the blood film
• Marrow aspiration and biopsy
• Marrow cell cytogenetics to evaluate presence of a clonal myeloid disease
• DNA stability test as markers of Fanconi anemia
• Immunophenotyping of red and white cells, especially for CD55, CD59 to exclude paroxysmal nocturnal hemoglobinuria
• Direct and indirect antiglobulin (Coombs) test to rule out immune cytopenia
• Serum lactate dehydrogenase and uric acid, which if increased may reflect neoplastic cell turnover
• Liver function tests to assess evidence of any recent hepatitis virus exposure
• Screening tests for hepatitis viruses A, B, and C
• Screening tests for Epstein-Barr virus, cytomegalovirus, and HIV
• Serum B12 and red cell folic acid levels to rule out cryptic megaloblastic pancytopenia
• Serum iron, iron-binding capacity, and ferritin as a baseline prior to chronic transfusion therapy
Source: Williams Hematology, 9th ed, Chap. 35, Table 35–4.

TREATMENT
Table 3–6 lists important initial steps in management.

TABLE 3–6 INITIAL MANAGEMENT OF APLASTIC ANEMIA

• Discontinue any potential offending drug and use an alternative class of agents if essential.
• Anemia: transfuse leukocyte-depleted, irradiated red cells as required for very severe anemia.
• Very severe thrombocytopenia or thrombocytopenic bleeding: consider ∈-aminocaproic acid; transfusion of platelets as required;
thrombopoietin receptor agonists under study.
• Severe neutropenia: use infection precautions.
• Fever (suspected infection): microbial cultures; broad-spectrum antibiotics if specific organism not identified, granulocyte colony-
stimulating factor (G-CSF) in dire cases. If child or small adult with profound and prolonged infection (eg, gram-negative
bacteria, fungus, persistent positive blood cultures) can consider neutrophil transfusion from a G-CSF pretreated donor.
• If transplant candidate, immediate assessment for allogeneic stem cell transplantation: histocompatibility testing of patient,
parents, and siblings. Search databases for unrelated donor, if appropriate.
Source: Williams Hematology, 9th ed, Chap. 35, Table 35–5.

Allogeneic hematopoietic stem cell transplantation is often curative.

— It is indicated in patients < 55 years with a suitable donor and without serious comorbid
conditions. Age for transplantation may increase with advances in transplantation.
— Less than one third of patients in the United States have a matched sibling donor.
— Success of transplantation is a function of age and whether related donor is used (Figure 3–
2). Best results are in patients younger than 20 years of age with a related donor.
FIGURE 3–2 Probability of survival after hematopoietic stem cell transplantation for severe aplastic anemia by donor type and
age, 1998–2008. Patients receiving marrow from a matched sibling had better outcomes if they were 20 years of age or younger,
compared to those older than 20 years of age. Patients receiving marrow from a matched sibling fared better than those who
received marrow from a matched unrelated donor, at any age. Patients younger than 20 or older than 20 years of age did not have a
significant difference in outcome if they received marrow from an unrelated matched donor. (Reproduced with permission from
Pasquini MC, Wang Z. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2013.)

Immunosuppressive Therapy
Is the most successful therapy in patients unsuitable for allogeneic hematopoietic stem cell
transplantation (see Table 3–7)
Antithymocyte globulin (ATG) or antilymphocyte globulin (ALG)
— ATG prepared in horses or rabbits from human thymocytes and ALG prepared in horses or
rabbits from human thoracic duct lymphocytes
— Fifty percent response rate when used as single agent
— Dose: 15 to 40 mg/kg daily intravenously for 4 to 10 days
— Fever and chills common on first day of treatment
— Accelerated platelet destruction with thrombocytopenia frequent during infusion
— Serum sickness possible with fever, rash, and arthralgias 7 to 10 days after beginning
treatment
— Moderate dose of methylprednisolone usually used to decrease allergic reactions
Cyclosporine
— Treatment in patients if refractory to ATG
— Dose: 3 to 7 mg/kg daily orally for at least 4 to 6 months
— Dose adjusted to maintain appropriate blood levels (trough blood levels of 300–500
ng/mL)
— Renal impairment: common side effect
— Response in 25% of patients overall
Combination therapy: ATG and cyclosporine, which yield an significantly improved response
rate over either agent alone
High-dose glucocorticoids
— For example, 5 to 10 mg/kg methylprednisolone for 3 to 14 days
 — Very severe side effects: glycosuria, gastric distress, insomnia, psychosis, infection,
aseptic necrosis of the femoral head
— Little evidence for efficacy of glucocorticoids used alone
— Usually used in lower doses (2 mg/kg and then taper) as adjunct to ATG
High-dose cyclophosphamide (eg, 45 mg/kg per day for 4 doses)
Androgen therapy
— Danazol, 5 mg/kg per day for 6 months, as primary therapy not efficacious in severe or
moderate aplastic anemia
— Androgen therapy combined with ALG and cyclosporine being assessed
— Can induce severe masculinization and liver damage
G-CSF as primary therapy not efficacious
— Transient improvement in neutrophil counts observed with GM-CSF or G-CSF treatment in
some patients but not sustained
— G-CSF used in combined therapy with ATG and cyclosporine: no improved remission or
survival rates in most studies
Interleukin (IL)-3 or IL-1 as primary treatment not effective
Results of combined immunosuppressive (ATG and cyclosporine therapy)
— Marked hematologic improvement in 60% to 80% of patients
— Possible long-term problems after immunosuppressive therapy, such as continued moderate
anemia and thrombocytopenia, recurrent aplasia, PNH, acute myelogenous leukemia, or
myelodysplastic syndrome
Eltrombopag. This thrombopoietin receptor agonist has been used in patients who were not
successfully treated with combined immunotherapy. A significant portion (~45%) had
moderate to marked improvement in one or more blood cell counts or loss of red cell and
platelet transfusion requirements. A few returned to normal blood cell counts. In some so
treated, these effects have persisted for more than a year of observation. The initial studies
started with a dose of 50 mg, increasing to 150 mg/day over a 12-week period. Longer
treatment periods and higher doses may induce remissions in some patients. These variations
in treatment are currently under study.

TABLE 3–7 RESPONSE TO IMMUNOTHERAPY IN PATIENTS WITH SEVERE APLASTIC

ANEMIA
No. Pts
(Age Significant Survival at Relapse at
Year of range Response 5/10 Years 5 Years
Publication Principal Drugs Used [Years]) No. (%) (%) (Cum%) Comments
2011 ATG + CYA 95 (7–80) 63 (66) 76*/NR 33* Fewer early infections with G-CSF;
ATG + CYA + G-CSF 97 (2–81) 71 (73) 78*/NR 32* no difference in response or
survival
2008 ATG + CYA 77 (< 18) 57 (74) 83/80 25 8.5% evolved to clonal myeloid
disease
2007 ATG + CYA 44 (NR) 31 (70) NR/88 NR All cases were associated with
hepatitis
2007 ATG + CYA 47 (19–75) 31 (66) 80/NR 45 No late clonal diseases at 5 years
2007 ATG + CYA + G-CSF 48 (19–74) 37 (77) 90/NR 15 No late clonal diseases at 5 years
2006 ATG + CYA 47 (8–71) 37 (79) 80/75 NR No late clonal diseases at 10 years
2006 ATG + CYA + G-CSF + 30 (5–68) 22 (73) 80/75 NR One patient developed clonal myeloid
rhuEPO disease
ATG, antithymocyte globulin; Cum%, cumulative percent; CYA, cyclosporine; G-CSF, granulocyte colony-stimulating factor; No.
Pts, number of patients; NR, not reported; rhuEPO, recombinant human erythropoietin.
*At 6 years post-treatment.
Source: Williams Hematology, 9th ed, Chap. 35, Table 35–7.

Supportive Care
Immediate human leukocyte antigen (HLA) typing of patient and siblings as possible stem cell
donors
Minimal or no transfusions in potential transplant recipients, if possible
If transfusions are needed, no use of family donors in a potential transplant recipient
Transfusion of platelets based on assessment of risk of bleeding and not solely on platelet
count
Use of leukocyte-depleted, ABO blood group-compatible single-donor platelets, if possible,
to minimize HLA sensitization, subsequent refractoriness, and other problems
Aminocaproic acid, 4 to 12 g/d. This may decrease thrombocytopenic bleeding
Transfusion of packed red blood cells (irradiated, leukocyte-depleted) when hemoglobin level
is less than 8 g/dL. Use a higher threshold if comorbid conditions require
Cytomegalovirus (CMV) serology for prospective transplant recipients. Transfuse only CMV-
negative blood products until these results are known. If the patient is CMV-positive, these
precautions can be discontinued. Use of leukocyte depletion filters also decreases risk of
CMV acquisition
Neutropenic precautions for hospitalized patients with absolute neutrophil counts of less than
500/mL
Prompt institution of broad-spectrum intravenous antibiotics for fever after appropriate
cultures have been obtained

Clinical Course
Median survival of untreated severe aplastic anemia is 3 to 6 months (20% survive longer than
1 year). Allogeneic hematopoietic transplantation can cure a very large proportion of patients
depending on their age at transplantation and the immunologic similarity of the donor (see
Figure 3–3). Combined immunotherapy with ATG and cyclosporine can result in 10-year
survival rate of 70% to 80%.
FIGURE 3–3 Flow chart with general guidelines for treatment of severe aplastic anemia (SAA) as of 2012.* Response to horse
antithymocyte globulin (ATG) plus cyclosporine is followed for 6 months before deciding the patient has not responded adequately
unless the patient is doing poorly and the neutrophil count remains less than 200 × 109/L. In that case, one can proceed to next
suitable option. In general, transplantation options are reassessed at 6 months after immunotherapy and are dependent on donor
availability and quality of match, patient age, comorbid conditions that would increase transplantation risk, and the severity of the
depression in neutrophil count. In younger patients, a matched unrelated donor may be appropriate. In older patients, retreating with
immunotherapy would be favored unless the neutrophil count persists in the very severe risk category. After two unsuccessful
attempts at immunotherapy, therapy is individualized and a high-risk transplantation procedure (slight mismatched-related,
haploidentical, umbilical cord blood) may be considered, using the relevant variables (eg, age, comorbidities, performance status,
neutrophil count). The age of 40 years is an approximate guideline for considering an initial allogeneic hematopoietic stem cell
transplant (HSCT) and may be modified upward somewhat (eg, 41–50 years) based on the clinical status and other features of the
patient. *Based on observations reported in 2014, it would be appropriate to consider eltrombopag therapy, 3 to 6 months after the
failure of combined immunotherapy with ATG and cyclosporine, before going to next options outlined in algorithm in this figure. At
this writing, the Food and Drug Administration has not approved eltrombopag for use in patients with aplastic anemia, but such
approval is anticipated. (Reproduced with permission from Scheinberg P, Young NS: How I treat acquired aplastic anemia, Blood
2012 Aug 9;120(6):1185-1196.)

For a more detailed discussion, see George B. Segel and Marshall A. Lichtman: Aplastic Anemia: Acquired
and Inherited, Chap. 35 in Williams Hematology, 9th ed.
CHAPTER 4
Pure Red Cell Aplasia

DEFINITION
Pure red cell aplasia describes isolated anemia secondary to failure of erythropoiesis.
Cardinal findings are a low hemoglobin level combined with reticulocytopenia and absent or
extremely infrequent marrow erythroid precursors.

CLASSIFICATION
See Table 4–1.

TABLE 4–1 CLASSIFICATION OF PURE RED CELL APLASIA

Fetal red cell aplasia (nonimmune hydrops fetalis)
Parvovirus B19 in utero
Inherited (Diamond-Blackfan anemia): RPS19 and other RPS mutations
Acquired
Transient pure red cell aplasia
Acute B19 parvovirus infection in hemolytic disease (transient aplastic crisis; ~100% of cases)
Transient erythroblastopenia of childhood
Chronic pure red cell aplasia
Idiopathic
Large granular lymphocytic leukemia
Chronic lymphocytic leukemia
Clonal myeloid diseases (especially 5q-syndrome)
Persistent B19 parvovirus infection in immunodeficient host (~15% of cases)
Thymoma
Collagen vascular diseases
Post–stem cell transplantation
Anti-ABO antibodies
Drug induced
Antierythropoietin antibodies
Pregnancy
Source: Williams Hematology, 9th ed, Chap. 36, Table 36–1.

INHERITED PURE RED CELL APLASIA (DIAMOND-BLACKFAN

ANEMIA)
This form of pure red cell aplasia, which occurs early in childhood, is also known as either
Diamond-Blackfan or Blackfan-Diamond anemia.
It has an estimated annual incidence of five cases per 1 million live births.
Inheritance is usually autosomal dominant or occasionally autosomal recessive if a familial
 pattern. Sporadic cases are most frequent.
In this disease of abnormal ribosomal biogenesis, mutations involve the RPS19 gene in about
25% of cases; several other genes that regulate ribosome assembly have been implicated.
Pathophysiology is unclear.

Clinical Features
Presenting symptoms include pallor, listlessness, poor appetite, and failure to thrive.
One third of patients are diagnosed at birth or in the early neonatal period, but the disease may
appear at any time into adulthood.
Physical abnormalities occur in one third of patients (eg, craniofacial dysmorphism, short
stature, abnormalities of the thumb, web neck, and urogenital and cardiac abnormalities).
Disease may progress to severe anemia, with cardiac failure, dyspnea, and
hepatosplenomegaly.

Laboratory Features
Absolute severe reticulocytopenia occurs in all cases.
Normocytic, occasionally macrocytic, normochromic anemia is found.
Leukocyte count is normal or slightly decreased. Neutropenia may develop over several years.
Platelet count is normal or mildly increased.
Marrow is cellular but with marked erythroid hypoplasia. The few erythroid cells present may
have megaloblastic changes. Other marrow cells are normal.
Serum iron levels are elevated, and transferrin saturation is increased.
Erythropoietin levels are elevated.
Erythrocyte adenosine deaminase activity is elevated in 75% of patients.

Differential Diagnosis
Characteristic triad includes anemia, reticulocytopenia, and paucity/absence of marrow
erythroid precursors. Findings are supplemented by increased erythrocyte adenosine
deaminase activity and RPS19 gene mutations.
Fanconi anemia can be excluded by cytogenetic and gene mutation analyses.
Transient erythroblastopenia of childhood is established by spontaneous recovery.

Therapy, Course, and Prognosis

Transfusions relieve symptoms of anemia but lead to iron overload. Iron chelation therapy
should be initiated promptly (Chap. 9). Transfusions should be leukocyte depleted to avoid
alloimmunization (Chap. 91).
Glucocorticoid therapy may be beneficial, although its mechanism of action is unclear.
Response is not predictable.
Glucocorticoid therapy should be initiated with prednisone at a daily dose of 2 mg/kg per day,
orally, in three or four divided doses. A reticulocyte response is usually seen within 1 to 4
weeks. Once the hemoglobin level reaches 9 to 10 g/dL (90–100 g/L), the initial dose is
reduced very slowly to a single daily dose, then to an alternate-day schedule. The goal is to
get to low (1–2 mg/day), alternate-day therapy. Continuous therapy is typically required,
 because withdrawal of glucocorticoids is often, but not always, accompanied by relapse.
Severe side effects from glucocorticoid therapy frequently develop (eg, Cushing syndrome).
Long-term transfusions with iron chelation may be preferable to long-term higher dose
glucocorticoids and resultant side effects.
Allogeneic hematopoietic cell transplantation from a histocompatible sibling, when
successful, is curative. Allogeneic transplantation from unrelated donor sources, including
umbilical cord blood, has been less successful. However, transplantation has usually been
utilized late in the disease course due to its accompanying risks of morbidity and mortality.
High-dose methylprednisolone, immunosuppressive agents, and interleukin-3 have been
reported to ameliorate the disease but are not standard therapies.
Most deaths are a result of therapeutic complications from chronic iron overload,
hypercorticism, or hematopoietic cell transplantation.
Patients have developed acute myelogenous leukemia at a higher rate than expected.

TRANSIENT APLASTIC CRISIS AND TRANSIENT

ERYTHROBLASTOPENIA OF CHILDHOOD
This condition is clinically identical to pure red cell aplasia except for spontaneous resolution
of symptoms and laboratory findings.

Etiology
Most patients with aplastic crises are infected with B19 parvovirus (Figure 4–1), typically in
the context of an underlying hemolytic disease such as hereditary spherocytosis or sickle cell
disease (transient aplastic crisis).
This occurs in normal children after an infection by an unknown childhood virus (transient
erythroblastopenia of childhood).
Drugs implicated in chronic pure red cell aplasia may also induce transient aplastic crises.

FIGURE 4–1 A and B. Giant early erythroblast precursors in the marrow aspirate of a patient with chronic pure red cell aplasia
secondary to persistent B19 parvovirus infection. Note the nuclear inclusions (darker nuclear shading) representing parvovirus
infection. C. Marrow biopsy section. The arrows point to binucleate erythroid precursor cell with nuclear inclusions representing
parvovirus infection. (Reproduced with permission from Lichtman’s Atlas of Hematology, www.accessmedicine.com.)

Clinical Features
Transient aplastic crisis in the context of an underlying hemolytic disease results in more
evident pallor, fatigue on exertion, and lassitude. Gastrointestinal complaints or headache may
be associated symptoms. Physical examination findings may include tachycardia and a flow
murmur.
Another random document with
no related content on Scribd:
together with all other facts in the possession of the Executive Department relating
to this matter.
The diplomatic correspondence is herewith transmitted, together with some
correspondence between the naval officers for the time in command in Chilean
waters and the Secretary of the Navy, and also the evidence taken at the Mare
Island navy yard since the arrival of the Baltimore at San Francisco. I do not deem
it necessary in this communication to attempt any full analysis of the
correspondence or of the evidence. A brief restatement of the international
questions involved, and of the reasons why the responses of the Chilean
government are unsatisfactory is all that I deem necessary.
It may be well, at the outset, to say that whatever may have been said in this
country or in Chile in criticism of Mr. Egan, our minister at Santiago, the true
history of the exciting period in Chilean affairs, from the outbreak of the revolution
until this time, discloses no act upon the part of Mr. Egan unworthy of his position,
or that could justly be the occasion of serious animadversion or criticism. He has, I
think, on the whole borne himself in very trying circumstances with dignity,
discretion and courage, and conducted the correspondence with ability, courtesy
and fairness.
It is worth while, also, at the beginning to say that the right of Mr. Egan to give
shelter in the legation to certain adherents of the Balmaceda government who
applied to him for asylum has not been denied by the Chilean authorities, nor has
any demand been made for the surrender of these refugees.
That there was urgent need of asylum is shown by Mr. Egan’s note of August 24,
1891, describing the disorders that prevailed in Santiago, and by the evidence of
Captain Schley as to the pillage and violence that prevailed at Valparaiso. The
correspondence discloses, however, that the request of Mr. Egan for a safe conduct
from the country, in behalf of these refugees, was denied.
The precedents cited by him in the correspondence, particularly the case of the
revolution in Peru in 1865, did not leave the Chilean government in a position to
deny the right of asylum to political refugees, and seemed very clearly to support
Mr. Egan’s contention that a safe conduct to neutral territory was a necessary and
acknowledged incident of the asylum. These refugees have very recently, without
formal safe conduct, but by the acquiescence of the Chilean authorities, been
placed on board the Yorktown, and are now being conveyed to Callao, Peru.
This incident might be considered wholly closed but for the disrespect
manifested towards this government by the close and offensive police surveillance
of the legation premises which was maintained during most of the period of the
stay of the refugees therein.
After the date of my annual message and up to the time of the transfer of the
refugees to the Yorktown, the legation premises seem to have been surrounded by
police, in uniform, and police agents or detectives, in citizens’ dress, who
offensively scrutinized persons entering or leaving the legation, and, on one or
more occasions, arrested members of the minister’s family.
 Commander Evans, who, by my direction, recently visited Mr. Egan at Santiago,
in his telegram to the Navy Department described the legation as “a veritable
prison,” and states that the police agents or detectives were, after his arrival,
withdrawn during his stay. It appears further, from the note of Mr. Egan, of
November 20, 1891, that, on one occasion at least, these police agents, whom he
declares to be known to him, invaded the legation premises, pounding upon its
windows and using insulting and threatening language towards persons therein.
This breach of the right of a minister to freedom from police espionage and
restraint seems to have been so flagrant that the Argentine minister, who was dean
of the diplomatic corps, having observed it, felt called upon to protest against it to
the Chilean Minister of Foreign Affairs. The Chilean authorities have, as will be
observed from the correspondence, charged the refugees and the inmates of the
legation with insulting the police; but it seems to me incredible that men whose
lives were in jeopardy and whose safety could only be secured by retirement and
quietness, should have sought to provoke a collision which could only end in their
destruction, or to aggravate their condition by intensifying a popular feeling that at
one time so threatened the legation as to require Minister Egan to appeal to the
Minister of Foreign Affairs.
But the most serious incident disclosed by the correspondence is that of the
attack upon the sailors of the Baltimore in the streets of Valparaiso on the 16th of
October last. In my annual message, speaking upon the information then in my
possession, I said: “So far as I have yet been able to learn, no other explanation of
this bloody work has been suggested than that it had its origin in hostility to those
men as sailors of the United States, wearing the uniform of their government, and
not in any individual act or personal animosity.”
We have now received from the Chilean government an abstract of the
conclusions of the Fiscal General upon the testimony taken by the Judge of Crimes
in an investigation which was made to extend over three months. I very much
regret to be compelled to say that this report does not enable me to modify the
conclusion announced in my annual message. I am still of the opinion that our
sailors were assaulted, beaten, stabbed and killed, not for anything they or any of
them had done, but for what the government of the United States had done, or was
charged with having done by its civil officer and naval commanders. If that be the
true aspect of the case, the injury was to the government of the United States, not
to these poor sailors who were assaulted in the manner so brutal and so cowardly.
Before attempting to give an outline of the facts upon which this conclusion
rests, I think it right to say a word or two upon the legal aspect of the case. The
Baltimore was in the harbor of Valparaiso by virtue of that general invitation which
nations are held to extend to the war vessels of other powers with which they have
friendly relations. This invitation I think must be held ordinarily to embrace the
privilege of such communication with the shore as is reasonable, necessary and
proper for the comfort and convenience of the officers and men of such vessels.
Captain Schley testifies that when his vessel returned to Valparaiso, on September
14th, the city officers, as is customary, extended the hospitalities of the city to his
officers and crew.
It is not claimed that every personal collision or injury in which a sailor or officer
of such naval vessel visiting the shore may be involved raises an international
question; but I am clearly of the opinion that where such sailors or officers are
assaulted by a resident population, animated by hostility to the government whose
uniform these sailors and officers wear, and in resentment of acts done by their
government, not by them, their nation must take notice of the event as one
involving an infraction of its rights and dignity, not in a secondary way as where a
citizen is injured and presents his claim through his own government, but in a
primary way, precisely as if its minister or consul of the flag itself had been the
object of the same character of assault.
The officers and sailors of the Baltimore were in the harbor of Valparaiso under
the orders of their government, not by their own choice. They were upon the shore
by the implied invitation of the government of Chile and with the approval of their
commanding officer, and it does not distinguish their case from that of a consul
that his stay is more permanent or that he holds the express invitation of the local
government to justify his longer residence. Nor does it affect the question that the
injury was the act of a mob. If there had been no participation by the police or
military in this cruel work, and no neglect on their part to extend protection, the
case would still be one, in my opinion, when its extent and character are
considered, involving international rights.
The incidents of the affair are, briefly, as follows: On the 16th of October last,
Captain Schley, commanding the United States steamer Baltimore, gave shore
leave to 117 petty officers and sailors of his ship. These men left the ship about 1.30
P.M. No incident of violence occurred; none of our men were arrested; no complaint
was lodged against them; nor did any collision or outbreak occur until about 6
o’clock P.M. Captain Schley says that he was himself on shore and about the streets
until 5.40 P.M.; that he met very many of his men who were upon leave; that they
were sober and were conducting themselves with propriety, saluting Chilean and
other officers as they met them. Other officers of the ship, and Captain Jenkins, of
the merchant ship Keweenaw, corroborate Captain Schley as to the general
sobriety and good behavior of our men.
The Sisters of Charity at the hospital to which our wounded men were taken,
when inquired of, stated that they were sober when received. If the situation had
been otherwise, we must believe that the Chilean police authorities would have
made arrests. About 6 P.M. the assault began, and it is remarkable that the
investigation by the Judge of Crimes, though so protracted, does not enable him to
give any more satisfactory account of its origin than is found in the statement that
it began between drunken sailors. Repeatedly in the correspondence it is asserted
that it was impossible to learn the precise cause of the riot. The Minister of Foreign
Affairs, Matta, in his telegram to Mr. Montt under date of December 31st, states
that the quarrel began between two sailors in a tavern, and was continued in the
street, persons who were passing joining in it.
 The testimony of Talbot, an apprentice, who was with Riggin, is that the
outbreak in which they were involved began by Chilean sailor spitting in the face of
Talbot, which was resented by a knock-down. It appears that Riggin and Talbot
were at that time unaccompanied by any others of their shipmates.
These two men were immediately beset by a crowd of Chilean citizens and
sailors, through which they broke their way to a street car and entered it for safety.
They were pursued, driven from the car, and Riggin was so seriously beaten that he
fell in the street apparently dead. There is nothing in the report of the Chilean
investigation made to us that seriously impeaches this testimony. It appears from
Chilean sources that almost instantly, with a suddenness that strongly implies
premeditation and preparation; a mob, stated by the police authorities at one time
to number 2000, and at another 1000, was engaged in the assault upon our sailors,
who are represented as resisting “with stones, clubs and bright arms.” The report
of the Intendente of October 30th states that the fight began at 6 P.M. in three
streets, which are named, that information was received at the intendencia at 6.15,
and that the police arrived on the scene at 6.30, a full half hour after the assault
began. At that time he says that a mob of 2000 men had collected, and that for
several squares there was the appearance of a “real battle-field.”
The scene at this point is very graphically set before us by the Chilean testimony.
The American sailors, who, after so long an examination, have not been found
guilty of any breach of the peace, so far as the Chilean authorities are able to
discover, unarmed and defenceless, are fleeing for their lives, pursued by
overwhelming numbers, and fighting only to aid their own escape from death or to
succor some mate whose life is in greater peril. Eighteen of them are brutally
stabbed and beaten, while one Chilean seems, from the report, to have suffered
some injury; but how serious or with what character of weapon, or whether by a
missile thrown by our men or by some of his fellow-rioters is unascertained.
The pretense that our men were fighting “with stones, clubs, and bright arms,”
is, in view of these facts, incredible. It is further refuted by the fact that our
prisoners, when searched, were absolutely without arms, only seven penknives
being found in the possession of the men arrested, while there were received by our
men more than thirty stab wounds, every one of which was inflicted in the back,
and almost every contused wound was in the back or back of the head. The
evidence of the ship’s officer of the day is that even the jack-knives of the men were
taken from them before leaving the ship.
As to the brutal nature of the treatment received by our men, the following
extract from the account given of the affair by the La Patria newspaper, of
Valparaiso, of October 17th, cannot be regarded as too friendly: “The Yankees, as
soon as their pursuers gave chase, went by way of the Calle del Arsenal towards the
city car station. In the presence of an ordinary number of citizens, among whom
were some sailors, the North Americans took seats in the street car to escape from
the stones which the Chileans threw at them. It was believed for an instant that the
North Americans had saved themselves from popular fury, but such was not the
case. Scarcely had the car begun to move, when a crowd gathered around and
stopped its progress.
“Under these circumstances, and without any cessation of the howling and
throwing of stones at the North Americans, the conductor entered the car, and
seeing the risk of the situation to the vehicle, ordered them to get out. At the
instant the sailors left the car, in the midst of a hail of stones, the said conductor
received a stone blow on the head. One of the Yankee sailors managed to escape in
the direction of the plaza Wheelright, but the other was felled to the ground by a
stone. Managing to raise himself from the ground where he lay he staggered in an
opposite direction from the station. In front of the house of Señor Mazzini he was
again wounded, falling then senseless and breathless.”
No amount of evasion or subterfuge is able to cloud our clear vision of this brutal
work. It should be noticed, in this connection that the American sailors arrested,
after an examination, were, during the four days following the arrest, every one
discharged, no charge of any breach of the peace or other criminal conduct having
been sustained against a single one of them.
The Judge of Crimes, Foster, in a note to the Intendente, under date of October
22d, before the dispatch from the government, of the following day, which aroused
the authorities of Chile to a better sense of the gravity of the affair, says: “Having
presided temporarily over this court in regard to the seamen of the United States
cruiser Baltimore, who have been tried on account of the deplorable conduct which
took place.” The noticeable point here is that our sailors had been tried before the
22d of October, and that the trial resulted in their acquittal and return to their
vessel.
It is quite remarkable and quite characteristic of the management of this affair
by the Chilean police authorities that we should now be advised that seaman
Davidson, of the Baltimore, has been included in the indictment, his offence being
so far as I have been able to ascertain, that he attempted to defend a shipmate
against an assailant who was striking at him with a knife. The perfect vindication of
our men is furnished by this report; one only is found to have been guilty of
criminal fault, and that for an act clearly justifiable.
As to the part taken by the police in the affair, the case made by Chile is also far
from satisfactory. The point where Riggin was killed is only three minutes walk
from the police station and not more than twice that distance from the
Intendencia; and yet, according to their official report, a full half hour elapsed after
the assault began before the police were upon the ground. It has been stated that
all but two of our men have said that the police did their duty. The evidence taken
at Mare Island shows that if such a statement was procured from our men it was
accomplished by requiring them to sign a writing in a language they did not
understand and by the representation that it was a mere declaration that they had
taken no part in the disturbance. Lieutenant McCrea, who acted as interpreter,
says in his evidence that when our sailors were examined before the Court the
subject of the conduct of the police was so carefully avoided that he reported the
fact to Captain Schley on his return to the vessel.
 The evidences of the existence of animosity toward our sailors in the minds of
the Chilean navy and of the populace of Valparaiso are so abundant and various as
to leave no doubt in the mind of any one who will examine the papers submitted. It
manifested itself in threatening and insulting gestures toward our men as they
passed the Chilean men-of-war in their boats, and in the derisive and abusive
epithets with which they greeted every appearance of an American sailor on the
evening of the riot.
Captain Schley reports that boats from the Chilean warships several times went
out of their course to cross the bows of his boats, compelling them to back water.
He complained of the discourtesy, and it was corrected. That this feeling was
shared by men of higher rank is shown by an incident related by Surgeon Stitt, of
the Baltimore. After the battle of Placilla he, with other medical officers of the war
vessels in the harbor, was giving voluntary assistance to the wounded in the
hospitals. The son of a Chilean army officer of high rank was under his care, and
when the father discovered it he flew into a passion and said he would rather have
his son die than have Americans touch him, and at once had him removed from the
ward.
This feeling is not well concealed in the dispatches of the Foreign Office, and had
quite open expression in the disrespectful treatment of the American Legation. The
Chilean boatmen in the bay refused, even for large offers of money, to return our
sailors who crowded the Mole, to their ship when they were endeavoring to escape
from the city on the night of the assault. The market boats of the Baltimore were
threatened, and even quite recently the gig of Commander Evans, of the Yorktown,
was stoned while waiting for him at the Mole.
The evidence of our sailors clearly shows that the attack was expected by the
Chilean people; that threats have been made against our men, and that in one case,
somewhat early in the afternoon, the keeper of one house into which some of our
men had gone, closed his establishment in anticipation of the attack, which he
advised them would be made upon them as darkness came on.
In a report of Captain Schley to the Navy Department he says: “In the only
interview that I had with Judge Foster, who is investigating the case relative to the
disturbance before he was aware of the entire gravity of the matter, he informed
me that the entire assault upon my men was the outcome of hatred for our people
among the lower classes because they thought we had sympathized with the
Balmaceda Government on account of the Itata matter, whether with reason or
without he could, of course, not admit; but such he thought was the explanation of
the assault at that time.”
Several of our men sought security from the mob by such complete or partial
changes in their dress as would conceal the fact of their being seamen of the
Baltimore, and found it then possible to walk the streets without molestation.
These incidents conclusively establish that the attack was upon the uniform—the
nationality—and not upon the men.
The origin of this feeling is probably found in the refusal of this government to
give recognition to the Congressional party before it had established itself, in the
seizure of the Itata for an alleged violation of the Neutrality law in the cable
incident, and in the charge that Admiral Brown conveyed information to
Valparaiso of the landing at Quinteros. It is not my purpose to enter here any
defense of the action of this government in these matters. It is enough for the
present purpose to say that if there was any breach of international comity or duty
on our part it should have been made the subject of official complaint through
diplomatic channels, or of reprisals for which a full responsibility was assumed.
We cannot consent that these incidents and these perversions of the truth shall
be used to excite a murderous attack upon our unoffending sailors and the
Government of Chile go acquit of responsibility. In fact the conduct of this
government during the war in Chile pursued those lines of international duty
which we had so strongly insisted upon on the part of other nations when this
country was in the throes of civil conflict. We continued the established diplomatic
relations with the government in power until it was overthrown, and promptly and
cordially recognized the new government when it was established.
The good offices of this government were offered to bring about a peaceful
adjustment, and the interposition of Mr. Egan to mitigate severities and to shelter
adherents of the Congressional party were effective and frequent. The charge
against Admiral Brown is too base to gain credence with any one who knows his
high personal and professional character.
Recurring to the evidence of our sailors, I think it is shown that there were
several distinct assaults, and so nearly simultaneous as to show that they did not
spread from one point. A press summary of the report of the Fiscal shows that the
evidence of the Chilean officials and others was in conflict as to the place of origin,
several places being named by different witnesses as to the locality where the first
outbreak occurred. This, if correctly reported, shows that there were several
distinct outbreaks, and so nearly at the same time as to cause this confusion.
La Patria, in the same issue from which I have already quoted, after describing
the killing of Riggin and the flight which from that point extended to the Mole,
says: “At the same time in other streets of the port the Yankee sailors fought
fiercely with the people of the town, who believed to see in them incarnate enemies
of the Chilean navy.”
The testimony of Captain Jenkins, of the American merchant ship Keweenaw,
which had gone to Valparaiso for repairs, and who was a witness of some part of
the assault upon the crew of the Baltimore, is strongly corroborative of the
testimony of our own sailors when he says that he saw Chilean sentries drive back
a seaman, seeking shelter, upon a mob that was pursuing him. The officers and
men of Captain Jenkins’ ship furnish the most conclusive testimony as to the
indignities which were practiced toward Americans in Valparaiso. When American
sailors even of merchant ships, can only secure their safety by denying their
nationality, it must be time to readjust our relations with a government that
permits such demonstrations.
As to the participation of the police, the evidence of our sailors shows that our
men were struck and beaten by police officers before and after arrest, and that one,
at least, was dragged with a lasso about his neck by a mounted policeman. That the
death of Riggin was the result of a rifle shot fired by a policeman or soldier on duty
is shown directly by the testimony of Johnson, in whose arms he was at the time,
and by the evidence of Charles Langen, an American sailor, not then a member of
the Baltimore’s crew, who stood close and saw the transaction. The Chilean
authorities do not pretend to fix the responsibility of this shot upon any particular
person, but avow their inability to ascertain who fired it, further than that it was
fired from a crowd.
The character of the wound, as described by one of the surgeons of the
Baltimore, clearly supports his opinion that it was made by a rifle ball, the orifice
of exit being as much as an inch or an inch and a quarter in width. When shot, the
poor fellow was unconscious, and in the arms of a comrade, who was endeavoring
to carry him to a neighboring drug store for treatment. The story of the police, that
in coming up the street they passed these men and left them behind them is
inconsistent with their own statement as to the direction of their approach and
with their duty to protect them, and is clearly disproved. In fact, Riggin was not
behind, but in front of the advancing force, and was not standing in the crowd, but
was unconscious and supported in the arms of Johnson when he was shot.
The communications of the Chilean government in relation to this cruel and
disastrous attack upon our men, as will appear from the correspondence, have not
in any degree taken the form of a manly and satisfactory expression of regret,
much less of apology. The event was of so serious a character that if the injuries
suffered by our men had been wholly the result of an accident in a Chilean port, the
incident was grave enough to have called for some public expression of sympathy
and regret from the local authorities. It is not enough to say that the affair was
lamentable, for humanity would require that expression even if the beating and
killing of our men had been justifiable.
It is not enough to say that the incident is regretted, coupled with the statement
that the affair was not of an unusual character in ports where foreign sailors are
accustomed to meet. It is not for a generous and sincere government to seek for
words of small or equivocal meaning in which to convey to a friendly power an
apology for an offence so atrocious as this. In the case of the assault by a mob in
New Orleans upon the Spanish consulate in 1851, Mr. Webster wrote to the
Spanish minister, Mr. Calderon, that the acts complained of were a “disgraceful
and flagrant breach of duty and propriety,” and that his government “regrets them
as deeply as Minister Calderon or his government could possibly do;” that “these
acts have caused the President great pain, and he thinks a proper acknowledgment
is due to her Majesty’s government.” He invited the Spanish consul to return to his
post, guaranteeing protection, and offering to salute the Spanish flag if the consul
should come in a Spanish vessel. Such a treatment by the government of Chile of
this assault would have been more creditable to the Chilean authorities; and much
less can hardly be satisfactory to a government that values its dignity and honor.
In our note of October 23d last, which appears in the correspondence, after
receiving the report of the board of officers appointed by Captain Schley to
investigate the affair, the Chilean government was advised of the aspect which it
then assumed, and called upon for any facts in its possession that might tend to
modify the unfavorable impression which our report had created. It is very clear
from the correspondence that before the receipt of this note the examination was
regarded by the police authorities as practically closed. It was, however, reopened
and protracted through a period of nearly three months. We might justly have
complained of this unreasonable delay, but in view of the fact that the government
of Chile was still provisional, and with a disposition to be forbearing and hopeful of
a friendly termination, I have awaited the report which has but recently been
made.
On the 21st instant I caused to be communicated to the government of Chile, by
the American minister at Santiago, the conclusions of this government after a full
consideration of all the evidence and of every suggestion affecting this matter, and
to these conclusions I adhere. They were stated as follows:
“First—That the assault is not relieved of the aspect which the early information
of the event gave to it, viz: That an attack was made upon the uniform of the
United States Navy, having its origin and motive in a feeling of hostility to this
government, and not on any account of the sailors or any of them.
“Second—That the public authorities of Valparaiso flagrantly failed in their duty
to protect our men, and that some of the police and of the Chilean soldiers and
sailors were themselves guilty of unprovoked assaults upon our sailors before and
after arrest. He (the President) thinks the preponderance of the evidence and of
the inherent probabilities lead to the conclusion that Riggin was killed by the
police or soldiers.
“Third—That he (the President) is therefore compelled to bring the case back to
the position taken by this government in the note of Mr. Wharton on October 23d
last, *** and to ask for a suitable apology and for some adequate reparation for the
injury done to this country.”
In the same note the attention of the Chilean government was called to the
offensive character of a note addressed by Mr. Matta, its Minister of Foreign
Affairs, to Mr. Montt, its minister at this capital, on the 11th ult. This dispatch was
not officially communicated to this government, but as Mr. Montt was directed to
translate it, and to give it to the press of this country, it seemed to me that it could
not pass without official notice. It was not only undiplomatic, but grossly insulting
to our naval officers and to the Executive Department, as it directly imputed
untruth and insincerity to the reports of the naval officers and to the official
communications made by the Executive Department to Congress. It will be
observed that I have notified the Chilean government that unless this note is at
once withdrawn and an apology as public as the offence made, I will terminate
diplomatic relations.
The request for the recall of Mr. Egan upon the ground that he was not persona
grata, was unaccompanied by any suggestion that could properly be used in
support of it, and I infer that the request is based upon official acts of Mr. Egan,
which have received the approval of this government. But however that may be, I
could not consent to consider such a question until it had first been settled whether
our correspondence with Chile could be conducted upon a basis of mutual respect.
In submitting these papers to Congress for that grave and patriotic consideration
which the questions involved demand, I desire to say that I am of the opinion that
the demands made of Chile by this government should be adhered to and enforced.
If the dignity as well as the prestige and influence of the United States are not to be
wholly sacrificed we must protect those who, in foreign ports, display the flag or
wear the colors of this government against insult, brutality, and death, inflicted in
resentment of the acts of their government, and not for any faults of their own. It
has been my desire in every way to cultivate friendly and intimate relations with all
the governments of this hemisphere.
We do not covet their territory; we desire their peace and prosperity. We look for
no advantage in our relations with them except the increased exchanges of
commerce upon a basis of mutual benefit. We regret every civil contest that
disturbs their peace and paralyzes their development, and are always ready to give
our good offices for the restoration of peace. It must, however, be understood that
this government, while exercising the utmost forbearance towards weaker powers,
will extend its strong and adequate protection to its citizens, to its officers, and to
its humblest sailor, when made the victims of wantonness and cruelty in
resentment, not of their personal misconduct, but of the official acts of their
government.
Upon information received that Patrick Shields, an Irishman and probably a
British subject, but at the time a fireman of the American steamer Keweenaw, in
the harbor of Valparaiso for repairs, had been subjected to personal injuries in that
city—largely by the police—I directed the Attorney-General to cause the evidence of
the officers and crew of that vessel to be taken upon its arrival in San Francisco,
and that testimony is also herewith transmitted.
The brutality and even savagery of the treatment of this poor man by the Chilean
police would be incredible if the evidence of Shields was not supported by other
direct testimony, and by the distressing condition of the man himself when he was
finally able to reach his vessel. The captain of the vessel says:
“He came back a wreck: black from his neck to his hips, from beating; weak and
stupid, and is still in a kind of paralyzed condition, and has never been able to do
duty since.”
A claim for reparation has been made in behalf of this man, for, while he was not
a citizen of the United States, the doctrine long held by us, as expressed in the
Consular Regulations, is:
“The principles which are maintained by this government in regard to the
protection as distinguished from the relief of seamen are well settled. It is held that
the circumstance that the vessel is American is evidence that the seamen on board
are such; and in every regularly documented merchant vessel the crew will find
their protection in the flag that covers them.”
 I have as yet received no reply to our note of the 21st inst., but, in my opinion, I
ought not to delay longer to bring these matters to the attention of Congress for
such action as may be deemed appropriate.
Benjamin Harrison.

Executive Mansion, Jan. 25, 1892.

 The National Conventions of 1892.

REPUBLICAN.

The National Republican Convention for 1892 was called to meet

at Minneapolis June 7th. The Convention was close at hand before
any candidates were named, other than President Harrison. In
February Mr. Blaine had written to Mr. Clarkson, Chairman of the
National Convention, saying that his name would not be presented as
a candidate, and declining in such positive terms that it was accepted
as meaning what it said at the time. Later on the opposition to the
President’s nomination, led by a syndicate of very strong names—
Platt, of New York; Quay, of Pennsylvania; Clarkson, of Iowa;
Conger, of Ohio; Kellogg, of Louisiana; Wolcott, of Colorado; Bourne,
of Oregon; Filley, of Missouri—agreed to present Mr. Blaine, upon
the statement that he would accept if his nomination was plainly for
the good of the party. Three days preceding the Convention Mr.
Blaine suddenly resigned as Secretary of State, and thus created the
impression that he would accept and that he was a candidate. The
first effect of the resignation was to enthuse his friends, many of
them already assembled at Minneapolis, but when the
correspondence was published, and its terseness was traceable
entirely to Mr. Blaine’s haste, a great reaction followed in all parts of
the country, and groups of businessmen from all prominent towns
and cities wired their delegates of the change in sentiment, and as a
rule they were asked to re-nominate President Harrison. A feeling
affected the Blaine delegates, and many of the leaders began to look
for a third man, in the person of Major McKinley, the father of the
tariff bill of 1890, since chosen Governor of Ohio. Major McKinley
himself voted for Harrison and resisted a proposed stampede in his
own behalf, which had been planned to plump Ohio, Oregon and
Pennsylvania solidly for McKinley. The plan failed, partly because
Harrison had gained largely over estimates after New York had
voted, and Pennsylvania cast 19 votes for him at the only moment
which could have been at all critical.
The Convention organized at noon on the 7th, with Major
McKinley as its President. The first contest was upon the question of
the majority and minority reports of the Committee on Contests, the
majority being adopted and generally regarded as a victory for the
friends of Harrison. The contests were important only in the case of
Alabama, where two full sets of delegates disputed for the seats.
Senator Wolcott, of Colorado, presented the name of Mr. Blaine,
and it was seconded by ex-Senator Warner Miller, of New York.
Ex-Secretary of the Navy Richard T. Thompson, of Indiana (on
that day eighty-three years of age, and a delegate to every previous
Republican National Convention), presented the name of President
Harrison. It was seconded by Chauncey M. Depew, of New York, in a
speech remarkable for its force and eloquence.
The first and only ballot was taken on the morning of June 10th,
with the following result:
 THE BALLOT IN DETAIL.
States. Harrison. Blaine. McKinley.
Alabama 15 0 7
Arkansas 15 0 1
California 8 9 1
Colorado 0 8 0
Connecticut 4 0 8
Delaware 4 1 1
Florida 8 0 0
Georgia 26 0 0
Idaho 0 6 0
Illinois 34 14 0
Indiana 30 0 0
Iowa 20 5 1
Kansas 11 0 9
Kentucky 22 2 1
Louisiana 8 8 0
Maine 0 12 0
Maryland 14 0 2
Massachusetts 18 1 11
Michigan 7 2 19
Minnesota 8 9 1
Mississippi 13½ 4½ 0
Missouri 28 4 2
Montana 5 1 0
Nebraska 15 0 1
Nevada 0 6 0
New Hampshire 4 2 0
New Jersey 18 2 0
New York 27 35 10
North Carolina 17⅔ 2⅔ 1
North Dakota 2 4 0
Ohio 1 0 45
Oregon 1 0 7
Pennsylvania 19 3 42
Rhode Island 5 1 1
South Carolina 13 3 2
South Dakota 8 0 0
Tennessee 17 4 3
Texas 22 6 0
Vermont 8 0 0
 Virginia 9 13 2
Washington 1 6 1
West Virginia 12 0 0
Wisconsin 19 2 3
Wyoming 4 2 0

Territories.
Alaska 2 0 0
Arizona 1 1 0
Dist. of Columbia 0 2 0
Indian Territory 1 1 0
New Mexico 6 0 0
Oklahoma 2 0 0
Utah 2 0 0
Total 535⅙ 182⅙ 182
Absent and not voting, 1⅔.
Reed, of Maine, received 3 votes, and Lincoln, of Illinois, 1.
Major McKinley moved to make the nomination unanimous, and it
was adopted with great enthusiasm.
In response to the unanimous request of the New York delegation,
Hon. Whitelaw Reid was nominated for Vice-President by
acclamation.
[See Book II. for Platform and Comparison of Platforms; Book III.
for speech of Hon. Chauncey M. Depew.]

DEMOCRATIC.

The Democratic National Convention assembled at Chicago, June

21st, and its deliberations excited great interest because of the
opposition of the New York delegation to the nomination of
Cleveland. Under the leadership of Governor Hill, the New York
Democracy, in the canvass of 1891, carried the State, electing Flower
as Governor, and Hill as U. S. Senator, the latter only after a severe
contest and depriving three Republican State Senators of their seats
by contests settled before partisan courts. The New York opposition
to Cleveland, with the active aid of Tammany, united upon Hill as a
Presidential candidate. A “snap” or mid-winter State Convention was
called to elect delegates to the National Convention, and 72 Hill men
were chosen and instructed. This system of forestalling public
sentiment angered the Cleveland Democrats, who signed a protest to
the number of 200,000 and three months later elected a contesting
delegation, with instructions for Cleveland. Mr. Croker, Tammany’s
Chief, and State Chairman Murphy were the Hill leaders at Chicago,
and they gave early and public notice, in very bitter language, that if
nominated Cleveland could not carry New York. Ex-Secretary of the
Navy Whitney was the Cleveland leader, and he readily mustered
more than two-thirds of the Convention, and felt so assured of
victory that he advised the withdrawal of the contest against Hill’s
delegation. Singularly enough the minority desired the repeal of the
unit rule, for they had ascertained, after a careful canvass, that
Cleveland would lose enough votes to check and possibly prevent his
nomination if all of the delegates were permitted to vote separately.
The unit rule, however, was carefully re-enacted in the report of the
Committee on Rules.
Governor Wm. L. Wilson, of West Virginia, was elected President.
Governor Leon Abbett, of New Jersey, presented the name of Grover
Cleveland; William C. DeWitt, of New York, that of Senator David B.
Hill, and John M. Duncombe, of Iowa, that of Governor Boies. A
ballot was reached at 4 o’clock on the morning of the 23d, the
Cleveland leaders doing this to prevent combinations by the
opposition.
 THE BALLOT IN DETAIL.

States. Cleveland. Hill. Boies. Gorman. Scattering.

Alabama 14 2 1 1 4
Arkansas 16 0 0 0 0
California 18 0 0 0 0
Colorado 0 3 5 0 0
Connecticut 12 0 0 0 0
Delaware 6 0 0 0 0
Florida 5 0 0 0 3
Georgia 17 5 0 4 0
Idaho 0 0 6 0 0
Illinois 48 0 0 0 0
Indiana 30 0 0 0 0
Iowa 0 0 26 0 0
Kansas 20 0 0 0 0
Kentucky 18 0 2 0 6
Louisiana 3 1 11 1 0
Maine 9 1 0 1 1
Maryland 6 0 0 9½ 0
Massachusetts 24 4 1 0 1
Michigan 28 0 0 0 0
Minnesota 18 0 0 0 0
Mississippi 8 3 3 4 0
Missouri 34 0 0 0 0
Montana 0 0 6 0 0
Nebraska 15 0 0 1 0
Nevada 0 0 4 2 0
New Hampshire 8 0 0 0 0
New Jersey 20 0 0 0 0
New York 0 72 0 0 0
North Carolina 3⅓ 1 0 0 17⅔
North Dakota 6 0 0 0 0
Ohio 14 6 16 5 5
Oregon 8 0 0 0 0
Pennsylvania 64 0 0 0 0
Rhode Island 8 0 0 0 0
South Carolina 2 3 13 0 0
South Dakota 7 0 1 0 0
Tennessee 24 0 0 0 0
Texas 23 1 6 0 0
 Vermont 8 0 0 0 0
Virginia 12 11 0 1 0
Washington 8 0 0 0 0
West Virginia 7 1 0 3 1
Wisconsin 24 0 0 0 0
Wyoming 3 0 0 3 0

Territories
Alaska 2 0 0 0 0
Arizona 5 0 0 1 0
Dist. of Columbia 2 0 0 0 0
New Mexico 4 1 1 0 0
Oklahoma 2 0 0 0 0
Utah 2 0 0 0 0
Indian Territory 2 0 0 0 0
Total 617⅓ 115 103 36½ 38⅔
Number of votes cast, 909½. Necessary to a choice, 607.
Of the scattering votes Campbell got two from Alabama.
Carlisle got 3 from Florida, 6 from Kentucky, 5 from Ohio. Total
14.
Stephenson got 16⅔ from North Carolina.
Pattison got 1 from West Virginia.
Russell got 1 from Massachusetts.
Whitney got 1 from Maine.
Adlai E. Stevenson, of Illinois, former Assistant Postmaster-
General, was nominated Vice-President on the first ballot, his chief
competitor being Senator Gray, of Indiana.
[See Book II. for Democratic National Platform and Comparison;
Book III. for Governor Abbett’s speech nominating Cleveland.]
A notable scene in the Convention was created by Mr. Neal, of
Ohio, who moved to substitute a radical free trade plank as a
substitute for the somewhat moderate utterances reported by ex-
Secretary of the Interior Vilas, who read the report of the Committee
on Platform. The substitute denounced the protective tariff as a
fraud.
Mr. Neal made an earnest speech in support of his substitute and
was ably seconded by Mr. Watterson.
 Mr. Vilas replied defending the majority report in a vigorous
speech, which was as generously applauded as that which preceded.
The debate was animated and made specially interesting by the
suggestions and calls from the galleries. The substitute was finally
accepted by Chairman Jones on behalf of the committee, but this did
not satisfy the friends of the substitute, who persisted in having a roll
call upon its adoption.
A synopsis of the platform was submitted to and received the
approval of Mr. Cleveland, and it was reported that the Neal
substitute was prepared by the anti-Cleveland leaders, and the fact
that the roll call was persisted in by the anti-Cleveland men gave
color to this report.
There was a great deal of confusion and excitement preceding the
roll call, and its progress was watched with as much interest as
though its result was to decide the nomination. The States at the
head of the roll generally cast their votes according to what was
believed to be the feeling of their delegations on the Presidency, but
later on the order was more varied, States known to be for Cleveland
casting their solid vote for the substitute. New York was loudly
cheered when the 72 votes of the State were given for the substitute.
It was a most inconsistent vote, as Tammany is not regarded as a free
trade organization—rather as one favoring moderate tariffs. A ripple
of excitement was occasioned when Chairman Hensel cast the 64
votes of Pennsylvania against the substitute. Mr. Wallace protested
that 15 of the delegates favored the substitute, and he demanded that
the delegation be polled. A colloquy followed between Hensel and
Wallace on the rules of the Convention, and the point raised by the
former that Wallace’s motion was not in order under the unit rules
was sustained by the Chair.
The result of the vote was 564 for the substitute and 342 against it.