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Williams
Manual of Hematology
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Williams
Manual of Hematology
Tenth Edition
Marshall A. Lichtman, MD
Professor Emeritus of Medicine (Hematology-Oncology)
and of Biochemistry and Biophysics
Dean Emeritus, School of Medicine and Dentistry; James P. 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 Hematology and Malignant Hematology
Adjunct in Genetics and Pathology
University of Utah & Huntsman Cancer Institute
Salt Lake City, Utah
1. interní klinika VFN a Ústav patologické fyziologie 1. LF School of Medicine
Universita Karlova, Prague, Czech Republic
Marcel M. Levi, MD, PhD
Professor of Medicine
Amsterdam University Medical Centers
University of Amsterdam
Amsterdam, The Netherlands
Professor of Medicine
University College London
London, United Kingdom
Linda J. Burns, MD
Consultant and Sr. Scientific Director
Center for International Blood and Marrow Transplant Research
Milwaukee, Wisconsin
David C. Linch, FRCP, FRCPath, FMed Sci
Professor of Haematology
Cancer Program Director
UCL/UCLH Biomedical Research Centre
University College London
London, United Kingdom
New York Chicago San Francisco Athens London Madrid Mexico City
Milan New Delhi Singapore Sydney Toronto
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A B C
D E F
G H I
J K
Plate A. Normal blood. The arrow points to a normochromic-normocytic discocyte. B. Stomatocytes. The double arrow points
to the two morphologic types o stomatocyte: upper cell with a slit-shaped pale area and lower cell with a small central circular
pale area. C. Echinocytes. The feld has several such cells. The arrow points to one example with evenly distributed, blunt, short,
circumerentially positioned projections. D. Acanthocytes. The arrow points to one example with a ew spike-shaped projections,
unevenly distributed and o varying lengths. E. Spherocytes. Small, circular, densely staining (hyperchromic) cells that, when ully
developed, show no central pallor. F. Schizocytes (schistocytes, helmet cells, ragmented red cells). These microcytic cell ragments
may assume varied shapes. The arrow points to a triangular shape, but two others o dierent shape are also present in the feld.
Despite being damaged and very small, they requently maintain a biconcave appearance, as seen by their central pallor. G. Sickle
cells (drepanocytes). Numerous sickle cells are shown. Two are in the classic shape o the blade on the agricultural sickle (arrow).
Many red cells that have undergone the transormation to a “sickle” cell take the slightly less extreme orm o elliptical cells with
a very narrow diameter with condensed hemoglobin in the center (para-crystallization). About eight such cells are in the feld.
H. Elliptocytes and ovalocytes. The lower arrow points to an elliptocyte (cigar-shaped). The upper arrow points to an ovalocyte
(ootball-shaped). Because both orms may be seen together in a case o inherited disease (same gene mutation resulting in both
shapes), as shown here, it has been proposed that all such shapes be called elliptocytes with a Roman numeral to designate the sever-
ity o the shape change toward the elliptical, that is, elliptocytes I, II, and III. I. Target cells (codocytes). The arrow points to one
characteristic example among several in the feld. The hemoglobin concentration corralled by membrane recurvature in the center o
the cell gives it the appearance o an archery target. J. Teardrop-shaped cells (dacryocytes). Three dacryocytes are in this feld. One
example is indicated by the arrow. K. Horn cell (keratocyte). Several examples are in the feld. The arrow points to a typical such
cell with two sharp projections. (Reproduced with permission rom Lichtman MA, Shaer MS, Felgar RE, et al: Lichtman’s Atlas
of Hematology 2016. New York, NY: McGraw Hill; 2017. www.accessmedicine.com)
PREFACE
The 10th edition o Williams Manual of Hematology ollows soon ater the publication o the new 10th edition
o the Williams Hematology textbook, as has been the custom or the last seven editions. The Manual provides
a condensation o the essential elements o 95 o the 140 chapters o the textbook, chapters that are ocused
on describing hematologic diseases or broadly applicable therapeutic approaches, such as hematopoietic stem
cell transplantation, the pharmacology and toxicity o antineoplastic drugs, and the application o genetically
engineered chimeric antigen receptor T lymphocytes. The Manual provides the clinician with a comprehen-
sive precis o the critical elements o diagnosis and management that is easily accessible and important to the
care o patients. It is keyed to the Williams Hematology textbook, allowing the physician to move to its more
comprehensive coverage as time and interest permit. We urge all readers to avail themselves o the richness o
the ull coverage provided in the Williams Hematology 10th edition textbook.
Hematology is a discipline or which the impact o advances in genetics, immunology, molecular biology,
biotechnology, biomedical inormatics, diagnostic imaging, and cytometry and the application o these dis-
ciplines to experimental therapeutics have led to an astounding array o pharmaceutical agents, including
monoclonal antibodies, advancing our ability to treat successully and, with increasing requency, to cure
hematologic diseases. Perhaps the most dramatic o these accomplishments is the advance in the treatment
o chronic myelogenous leukemia (CML). At the time o the publication o the 1st edition o Hematology in
1972 (to become Williams Hematology with the 5th edition), the 5-year survival o patients with CML was
approximately 20%. Today, study o patients consistently taking a tyrosine kinase inhibitor has ound that
they have a 90% 5-year survival. Analysis has shown that the lie expectancy o patients with CML is within
3 years o the general population in all age categories. Moreover, some patients may be cured, allowing them
to stop the drug. This dramatic and proound achievement and other parallel advances in the treatment o the
leukemias, lymphomas, myeloma, and the many nonmalignant, but consequential and oten lie-impairing or
lie-threatening, diseases o blood cells and coagulation proteins is a testament to the advances lowing rom
the investment in biomedical research.
This increase in knowledge is relected in the 10th edition o Williams Hematology being 1024 pages
longer than the 1st edition (despite artul editing!); hence, the raison d’être or the Manual as an essential
guide or the clinician. The editors o the Manual have endeavored to bring to the reader inormation,
ocused on pathogenesis, diagnosis, and management, in an organized and easy-to-use way, to assist the
clinician in the examining room, at the bedside, or when using telemedicine. The Manual has been an
important resource or clinicians preparing or certiication examinations in hematology or other disci-
plines requiring a knowledge o hematology because the inormation or patient diagnosis and manage-
ment is provided in a comprehensive document o manageable size and ormat and packed with essential
inormation.
We acknowledge the authors o the chapters in the 10th edition o Williams Hematology, who provided the
basis or the exposition o pathogenesis, diagnosis, and management in each chapter. We have translated and
condensed their current and state-o-the-art inormation or the users o the Manual.
We welcome David Linch, University College London, to the editorial board o the Williams Manual (and
textbook), thereby broadening its international perspective and reach. Its international import is attested to by
its having been translated into Chinese, Greek, Japanese, Portuguese, Russian, Spanish, and Turkish in one
recent edition or another.
xi
xii PREFACE
We grateully acknowledge Harriet Lebowitz or editorial development o the manuscript, the administra-
tive support o Jason Malley, and our production manager Richard Ruzycka, each at McGraw-Hill Education;
the valuable assistance o Susan M. Daley in Rochester who provided administrative assistance in the prepara-
tion o the manuscript and the management o chapter low; and Warishree Pant o KnowledgeWorks Global
Ltd. or the inal composition o the book.
Marshall A. Lichtman, Rochester, New York
Kenneth Kaushansky, Stony Brook, New York
Jose T. Prchal, Salt Lake City, Utah
Marcel M. Levi, Amsterdam, The Netherlands
Linda J. Burns, Milwaukee, Wisconsin
David C. Linch, London, United Kingdom
PART I
INITIAL CLINICAL EVALUATION
CHAPTER 1
Approach to the Patient
• 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 involve-
ment in the basic disease process, such as spinal cord compression from a plasmacytoma, ureteral or intes-
tinal obstruction from abdominal lymphoma, or stupor from exaggerated hyperleukocytosis in chronic
myelogenous leukemia.
FAMILY HISTORY
• Hematologic disorders may be inherited as autosomal dominant, autosomal recessive, or X chromosome–
linked traits (see Williams Hematology, 10th ed, Chap. 10). The family history is crucial to provide initial
clues to inherited disorders and should include information relevant to the disease in question in grandpar-
ents, 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 forgot-
ten years later.
• Consanguinity should be considered in a patient who belongs to a population group prone to marrying
family members.
• Absence of a family history in a dominantly inherited disease may indicate a de novo mutation or
nonpaternity.
• Deviations from Mendelian inheritance may result from uniparental disomy (patient receives two copies
of a chromosome, or part of a chromosome, containing a mutation from one parent and no copies from the
other parent) or genetic imprinting (same abnormal gene inherited from mother has a different phenotype
than that inherited from father as a result of silencing or imprinting of one parent’s portion of DNA) (see
Williams Hematology, 10th ed, Chap. 10).
SEXUAL HISTORY
• One should obtain the history of the sexual preferences and practices of the patient.
PHYSICAL EXAMINATION
Special attention should be paid to the following aspects of the physical examination:
• Skin: cyanosis, ecchymoses, excoriation, flushing, jaundice, leg ulcers, nail changes, pallor, petechiae,
telangiectases, rashes (eg, lupus erythematosus, leukemia cutis, cutaneous T-cell lymphoma)
• Eyes: jaundice, pallor, plethora, retinal hemorrhages, exudates, or engorgement and segmentation of retinal veins
• Mouth: bleeding, jaundice, mucosal ulceration, pallor, smooth tongue
• Lymph nodes: slight enlargement may occur in the inguinal region in healthy adults and in the cervical
region in children. Enlargement elsewhere, or moderate to marked enlargement in these regions, should be
considered abnormal
• Chest: sternal and/or rib tenderness
• Liver: enlargement
• Spleen: enlargement, splenic rub
• Joints: swelling, deformities
• Neurologic: abnormal mental state, cranial nerve abnormalities, peripheral nerve abnormalities, spinal cord signs
LABORATORY EVALUATION
The blood should be evaluated, both quantitatively and qualitatively. This is usually achieved using automated
equipment.
• Normal blood cell values are presented in Table 1–4. Normal total leukocyte and differential leukocyte
counts are presented in Table 1–5.
• 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 be higher than if the patient
were normovolemic; if the patient is fluid overloaded, those values will be lower than their actual level
when normovolemic. In both cases, the values return to normal when normal hydration is restored.
• 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:
hematocrit (mL/dL or %)
MCV = × 10
erythrocyte count (×1012 /L)
4 PART I Initial Clinical Evaluation
• 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 percentage.
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.
TABLE 1–5 REFERENCE RANGES FOR LEUKOCYTE COUNT, DIFFERENTIAL COUNT, AND HEMOGLOBIN CONCENTRATION IN CHILDRENa
Neutrophils
Leukocytes Total Hemoglobin
Age (× 109/L) Total Band Segmented Eosinophils Basophils Lymphocytes Monocytes (g/dL blood)
12 mo 11.4 (6.0–17.5) 3.5 (1.5–8.5) 0.35 (0–1.0) 3.2 (1.0–8.5) 0.30 (0.05–0.70) 0.05 (0–0.20) 7.0 (4.0–10.5) 0.55 (0.05–1.1) 12.6 (11.1–14.1)
31 3.1 28 2.6 0.4 61 4.8
4y 9.1 (5.5–15.5) 3.8 (1.5–8.5) 0.27 (0–1.0) 3.5 (1.5–7.5) 0.25 (0.02–0.65) 0.05 (0–0.2) 4.5 (2.0–8.0) 0.45 (0–0.8) 12.7 (11.2–14.3)
42 3.0 39 2.8 0.6 50 5.0
6y 8.5 (5.0–14.5) 4.3 (1.5–8.0) 0.25 (0–1.0) 4.0 (1.5–7.0) 0.23 (0–0.65) 0.05 (0–0.2) 3.5 (1.5–7.0) 0.40 (0–0.8) 13.0 (11.4–14.5)
CHAPTER 1
5
6 PART I Initial Clinical Evaluation
— This calculation assumes (1) the red cell life span is ~100 days; (2) a normal reticulocyte is identifi-
able 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 mar-
row 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 percentage of reticulocytes for the decreased red cells in an anemic person. This calculation pro-
vides 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 percentage must be adjusted for premature release of reticulocytes. This is
done by dividing the corrected reticulocyte percentage 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 percentage of 6 ÷ 2 results in a reticulocyte index of three times the
basal value, indicating red cell production is increased and the anemia is likely hemolytic.
• Enumeration of erythrocytes, leukocytes, and platelets can be performed using 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, 10th ed, Chap. 2; Chap. 61 (neutrophils); Chap. 65 (eosinophils);
Chap. 66 (basophils); Chap. 67 (monocytes and macrophages); and Chap. 73 (lymphocytes).
• 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, 10th 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.
Effects of Aging
• See Williams Hematology, 10th ed, Chap. 8.
• 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. The decrease in red cell mass is related in part to lower testosterone levels.
Anemia in an older person warrants careful evaluation as to its cause before concluding it is the anemia of
aging.
Approach to the Patient CHAPTER 1 7
A B C
D E F
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 morphol-
ogy. 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.
• 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.
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.
8 PART I Initial Clinical Evaluation
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 Target cells, sickle cells
Thalassemia minor (alpha or beta) Microcytosis, target cells, teardrop cells, basophilic stippling, other
misshapen cells
Thalassemia major (alpha or beta) Microcytosis, target cells, basophilic stippling, teardrop cells, other
misshapen cells (often more exaggerated than minor form)
Iron deficiency Microcytosis, hypochromia, absence of basophilic stippling
Lead poisoning Basophilic stippling
Vitamin B12 or folic acid deficiency Macrocytosis, with oval macrocytes, hypersegmented neutrophils
Myeloma, macroglobulinemia Pathologic rouleaux formation
Malaria, babesiosis, others Parasites in the erythrocytes
Consumptive coagulopathy Fragmented red cells (schistocytes)
Mechanical hemolysis Fragmented red cells (schistocytes)
Severe infection Increase in neutrophils; increased band forms, Döhle bodies,
neutrophil vacuoles
Infectious mononucleosis Reactive lymphocytes
Agranulocytosis Decreased neutrophils
Allergic reactions Eosinophilia
Chronic lymphocytic leukemia Absolute small-cell lymphocytosis
Chronic myelogenous leukemia Promyelocytes, myelocytes, basophils, hypersegmented neutrophils
Oligoblastic myelogenous leukemia Blast forms, acquired Pelger-Huët neutrophil nuclear abnormality,
(myelodysplasia) hypogranular neutrophils, anisocytosis, poikilocytosis, abnormally
sized or granulated platelets
Clonal cytopenias (myelodysplasia) Anisocytosis, anisochromia, poikilocytosis, hypogranular neutrophils,
acquired Pelger-Huët neutrophil nuclear abnormality, neutropenia,
thrombocytopenia, giant platelets
Acute leukemia Blast cells
Thrombocytopenia Decreased platelets
Thrombocytosis or Increased platelets
thrombocythemia
• 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 are
completed.
• Marrow biopsies are examined after fixation, sectioning, and staining. “Touch” preparations are made by
holding the biopsy specimen with a forceps and touching the end to one or more clean slides in several
places. 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.
Approach to the Patient CHAPTER 1 9
• Interpretation of marrow films and biopsy sections is discussed in Williams Hematology, 10th ed, Chap. 2
and in chapters describing specific diseases for which a marrow examination is usually performed. Williams
Hematology, 10th ed, Table 2–3 contains the normal differential count of cells in the marrow.
For a more detailed discussion, see Vishnu Reddy and Diana Morlote: Examination of
Blood and Marrow Cells, Chap. 2; James Palis and George B. Segel: Hematology of the
Fetus and Newborn, Chap. 6; William B. Ershler, Emma Groarke, and Neal S. Young: Hema-
tology in Older Persons, Chap. 8; Taco Kuijpers: Structure, Composition, Distribution,
and Production of Neutrophils, Chap. 61; William Shomali and Jason Gotlib: Eosinophils
and Their Disorders, Chap. 65; Stephen J. Galli, Dean D. Metcalfe, and Daniel A. Arber:
Basophils and Mast Cells and Their Disorders, Chap. 66; Steven D. Douglas and Ann
G. Douglas: Structure, Biochemistry, and Function of Monocytes and Macrophages,
Chap. 67; Natarajan Muthusamy and Michael A. Caligiuri: Structure of Lymphocytes and
Plasma Cells, Chap. 73 in Williams Hematology, 10th ed.
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PART II
DISORDERS OF RED CELLS
CHAPTER 2
Classification of Anemias and Erythrocytoses
• 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 impact is best expressed in terms of hemoglobin concentration.
— Disorders in which the red cell mass is increased (erythrocytoses); often referred to as polycythemia.
Here we have chosen to refer to polycythemia vera as polycythemia and other increases in red cell mass
as erythrocytosis. 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).
O2 transport ( 1
x Hct)
14 viscosity
12
O2 transport
Viscosity relative to H2O
10
2 Viscosity
0
0 20 40 60 80 100
Hematocrit (%)
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 tissue oxygen delivery increases and the curve shifts to the right; when decreased, it shifts to
the left.
12 PART II Disorders of Red Cells
• 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 erythrocytoses can each be subclassified as:
— Relative, where the red cell mass is normal but the amount of plasma is increased (relative anemia) or
decreased (relative erythrocytosis).
— Absolute, where the red cell mass is decreased (true anemia) or increased (true erythrocytosis).
• 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 parameters 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, which include 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; this parameter is an average value.
— 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 event
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, presence of nonhematopoietic par-
ticles 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 makes 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, with more severe anemias, because of con-
founding effects of two causal factors (eg, iron deficiency and folate deficiency), or well-established
megaloblastic anemia may have a normocytic index in otherwise asymptomatic individuals such as
those who are silent carriers or have α-thalassemia trait (one or two α-globin deletions) (see Chap. 15).
• A classification of the major causes of erythrocytosis is shown in Table 2–2.
• It is important to search for the specific cause of erythrocytosis. The diagnosis of erythrocytoses is dis-
cussed in Chaps. 27 (polyclonal erythrocytoses) and 42 (polycythemia vera).
For a more detailed discussion, see Josef T. Prchal: Clinical Manifestations and Classi-
fication of Erythrocyte Disorders, Chap. 35; Josef T. Prchal: Erythropoiesis and Red Cell
Turnover, Chap. 34; Josef T. Prchal: Primary and Secondary Erythrocytosis, Chap. 60;
Mohandas Narla: Structure and Composition of the Erythrocyte, Chap. 33 in Williams
Hematology, 10th ed.
16 PART II Disorders of Red Cells
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 2 to 5 cases per million population per year and 5 to 12 cases per million popula-
tion per year in the United States (and in other industrialized countries). Incidence is approximately twice
as high in Asian countries.
• Peak incidences are 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 3–2 SOME DRUGS ASSOCIATED WITH MODERATE RISK OF APLASTIC ANEMIAa
Acetazolamide
Carbamazepine
Chloramphenicol
Gold salts
Hydantoins
Oxyphenbutazone
Penicillamine
Phenylbutazone
Quinacrine
a
Drugs with 30 or more reported cases.
• Viruses (eg, Epstein-Barr; non-A, -B, -C, -D, -E, or -G hepatitis; human immunodeficiency virus)
• 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)
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.
Aplastic Anemia: Acquired and Inherited CHAPTER 3 19
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 pancytopenia; ± monosomy 7; increased
disorder) risk of AML
Congenital amegakaryocytic Thrombocytopenia; absent or markedly AR (compound MPL
thrombocytopenia decreased marrow megakaryocytes; heterozygotes)
hemorrhagic 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; AR LIG4
dysmorphic facies; aplastic pancytopenia
Dubowitz syndrome Intrauterine and postpartum growth AR Unknown
failure; short stature; microcephaly;
mental retardation; distinct dysmorphic
facies; aplastic pancytopenia; increased
risk of AML and ALL
Nijmegen breakage Microcephaly; dystrophic facies; short AR NBS1
syndrome stature; immunodeficiency; radiation
sensitivity; aplastic pancytopenia;
predisposition to lymphoid malignancy
Reticular dysgenesis Lymphopenia; anemia and neutropenia; XLR Unknown
(type of severe corrected by hematopoietic stem cell
immunodeficiency transplantation
syndrome)
Seckel syndrome Intrauterine and postpartum growth AR ATR (and
failure; microcephaly; characteristic RAD3-
dysmorphic facies (bird-headed profile); related
aplastic pancytopenia; increased risk of gene);
AML PCNT
WT syndrome Radial/ulnar abnormalities; aplastic AD Unknown
pancytopenia; 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.
Immunosuppressive Therapy
• Immunosuppressive therapy is the most successful therapy in patients unsuitable for allogeneic hematopoi-
etic stem cell transplantation (Table 3–8).
• Antithymocyte globulin (ATG) or antilymphocyte globulin (ALG)
20 PART II Disorders of Red Cells
A B
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. (Reproduced with permission from Kaushansky K, Prchal JT, Burns LJ, et al: Williams Hematology, 10th ed. New York,
NY: McGraw Hill; 2021.)
TABLE 3–7 ALLOGENEIC MARROW TRANSPLANTATION FOR SEVERE APLASTIC ANEMIA (PERCENT SURVIVAL)
Years of Observation
1 2 3 4 5 6
HLA-matched related Pediatric <18 y, n = 1044 92 91 90 90 90 90
HLA-matched related Adult ≥18 y, n = 1427 81 79 78 78 78 77
HLA-matched unrelated Pediatric <18 y, n = 727 81 80 79 79 79 78
HLA-matched unrelated Adult ≥18 y, n = 1024 72 69 68 67 65 64
HLA, human leukocyte antigen.
FIGURE 3–2 Flow chart with general guidelines for treatment of severe aplastic anemia (SAA). Response to horse antithymocyte
globulin (ATG), cyclosporine, and eltrombopag 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 the
next suitable option. In general, transplantation options are reassessed at 6 months after immunotherapy plus eltrombopag 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, comorbidi-
ties, 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, 41–55 years) based on the clinical status
and other features of the patient. Epo, erythropoietin; G-CSF, granulocyte colony-stimulating factor. (Reproduced with permission
from Scheinberg P, Young NS: How I treat acquired aplastic anemia, Blood 2012 Aug 9;120(6):1185-1196.)
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sincerely the Genevese gentlemen, for thus rejecting the influence of
the softer sex.
On the following day we visited the cathedral, and walked over the
town; the former is an ancient building, standing upon very high
ground, but which by its commanding view, I am informed, fully
repays the trouble of ascent.
The road to Vevay throughout lies by the side of the lake, and is so
narrow, being bounded by a wall on each side, that it is impossible
that two carriages could pass each other. The sides of the mountains
that bound the road on the left, and which are so steep as to appear
inaccessible, are richly clothed with vineyards, artfully formed into
terraces, rising in tiers, one above the other. These terraces are
formed by strong and high stone walls, which preserve the soil from
shelving down, and are ascended by flights of steps. The vineyards
thus formed, are exposed to frequent injuries, and often to utter
destruction, by the rapid impulse of the mountain torrents
descending from above, and which occasionally sweep away wall,
terrace, and vines, in one indiscriminate ruin. These natural
visitations are, however, borne by the Swiss peasant with
resignation; and notwithstanding he may have lost the whole harvest
of his hopes, he immediately applies himself, to repair the injury,
burying the past in the anticipation of the future.
After spending a very happy day, we were obliged, but with the
greatest regret, to leave our kind friend at an early hour, as we had
to prepare for our intended departure from Lausanne early on the
following morning.
The country between Soleure and Basle is very hilly, and regarded
as beautiful beyond description. We slept at a village five leagues
from Basle, at which place we arrived about noon on the following
day.
In the evening, after securing our places, we walked into the public
gardens, from whence a balloon was sent off, and which was
constructed in the shape of a wine cask, with a Bacchus astride it.
This was succeeded by a display of fire-works, with music and
dancing.
CHAP. XXVIII.
STRASBURG TO COBLENTZ.
The whole of the next day was alternately fine and showery. When
we had travelled two leagues from Landau, the spring of the carriage
broke down, and detained us two hours. We noticed that the wife of
the blacksmith, who repaired it, assisted her husband throughout the
process, and appeared even the more dexterous of the two. On
entering Gemmingen, however, their work gave way, and we were in
consequence detained two hours longer; even this afterwards broke
out again, but fortunately just as we reached the end of our journey.
These delays were mortifying enough, as we did not reach Spire
until three in the afternoon, instead of nine o’clock in the morning, as
we had expected.
About two leagues beyond this place, there is a bridge over the
Rhine, leading to the beautiful town of Manheim, situated on the
opposite bank of the river. After this we passed through Oppenheim,
Worms and Inheim, dining at the latter, and then proceeding to
Mayence, where we arrived about five o’clock, and took up our
quarters at the Three Crowns, an excellent inn, to which we had
been recommended by our French friend, who had left us at Spire,
under a promise of rejoining us here. He shortly afterwards came in
and informed us, that besides arranging his own business, he had
ascertained that a large boat sets out for Coblentz every morning at
six o’clock, the fare in which was six francs, with an additional trifle
for the luggage; this vessel, after stopping to dine at Bingen, arrives
at Coblentz, a distance of eighteen leagues, between six and nine
o’clock in the evening, according to the state of the wind; for sails are
made use of whenever the latter is favourable. In consequence of
this report, we determined to secure our passage for the morrow.
While dining at Bingen, twenty miles below Mentz, the grand duke
Nicholas of Russia passed through, on his way from the baths of
Emms, to visit the duke of Nassau, whose castle is situated on the
right banks of the Rhine, about four miles below Mentz.
The professor’s wife, and their son, were also of the party; the
latter was a handsome lad of fifteen, who sat in the cabriolet, and
occupied himself in smoking a pipe nearly half as long as himself.
We expressed our surprise at his being allowed to indulge himself in
this manner, but his mother stated that he had entered the college,
and therefore was of the age when it was customary to commence
inhaling the fumes of this deleterious herb.
But the ladies of Holland are too much used to this custom, to find
it disagreeable; not only habit, but an opinion of its utility, tends to
reconcile them to it. If it possesses any quality in destroying
contagion, I am disposed to imagine that this must depend upon the
stronger poison subduing the weaker, like Aaron’s serpent
swallowing up the rest.
This city is celebrated for having been the first to shake off the
galling yoke of Spain in the year 1579. It was here that the seven
provinces formed their alliance, under the counsels of William, prince
of Orange, in a conference known as the treaty of Utrecht.
We heard them very merry in the fore cabin, but had the one we
occupied to ourselves until about noon, when two elderly Dutch
ladies, who were conversant in French, joined us, and proved
agreeable companions, although they were negative characters.
The Emperor Alexander visited this spot in the year 1813, and left
two Latin inscriptions on marble, commemorative of the event.
After this, we walked about the village, visited the church, and
returned to Amsterdam for a late dinner, highly gratified with our
day’s excursion.
We devoted the greater part of the next day to examining the city
of Amsterdam, which is so intersected with streets, canals, and
bridges, bearing a strong similarity to each other, that it is not an
easy matter to gain an accurate knowledge of it. It takes its name
from the river Amstel, and Dam, signifying a mound, raised to
prevent this river from overflowing the surrounding country. The city
is principally built upon piles, driven into the morass to form a solid
foundation, and of which it is said, that no less than thirteen
thousand are fixed under the Stadt-house alone. We visited the
Exchange, one of the finest buildings of the kind in Europe. After
this, we entered a Jew’s synagogue, the noisy and discordant
devotion of which, soon tired us, so that we were glad to take our
departure, particularly as we had no expectation of being permitted
to bid for the key of the sanctum sanctorum. We regretted this day,
parting from our new and agreeable acquaintance, Mr. W⸺ and
his family, who left us for Utrecht.
I shall not attempt to enter into any particular description of the city
of Amsterdam, but merely observe, that I was forcibly impressed with
an idea of its similarity to Venice; both are situated on marshy
grounds, in the immediate vicinity of the sea, and intersected by
canals, which divide them into innumerable small islands; but the
farther parallel is certainly in favour of the latter; for although Pope
tells us, that
yet I think the natural salubrity of its climate, as well as the general
superiority of its buildings, and more extensive display of specimens
of the fine arts, would prove greater attractions in the eyes of the
stranger. With respect to the point of salubrity, the canals of Venice
are more uniformly covered with water than those of Amsterdam,
which offer a surface of mud, and hence fewer noxious exhalations
are here generated; not that I am ignorant that Venice is far from
being a healthy summer residence, in consequence of injurious
miasmata, raised from its very foundations, by the intensity of the
solar ray.
It is true, that the above custom also suits the calculating notions
of the Dutch. I am on this point forcibly reminded of the observation
of a solitary and smoking Dutchman, when Dr. Moore had
expressed, through the medium of an interpreter, his regret at being
unable to converse with him, in consequence of his ignorance of the
Dutch language; and which was to this effect: “They ought to console
themselves for the accident of not understanding each other; for as
they had no connexions, or dealings in trade together, their
conversing could not possibly answer any useful purpose.”
The first book which Coster brought out, and his original types, are
preserved in the Stadt-house for the inspection of the curious; we
had not, however, time to examine them, nor even to hear the
celebrated organ of this city, for we did not arrive on the day before
until after evening service had concluded; and to hear it at any other
time, is a gratification which must be handsomely paid for.
Both this town and Haarlem are famous for the long sieges they
supported against the Spaniards, under Frederic, son of the duke of
Alva, in the year 1573.
I should have felt pleasure in staying longer at this place, but that I
was desirous of getting to Brussels without delay. I therefore, in
company with Mr. T—, one of the English gentlemen, the other
staying behind with his lady, set off by the barge to the Hague. In our
way, we passed the village of Leysendam, which we walked through
to another barge, on the right of which is Catwick, where the last
branch of the Rhine, which retains its original name, loses itself in
the sands. At eight o’clock in the evening we reached the Hague,
after a journey of three hours, and took up our quarters at the hotel
of Marshal Turenne.