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WILLIAMS HEMATOLOGY
THE
Red Cell and
Its Diseases

Hill Josef T. Prchal Marshall A. Lichtman

WilliamsHematology
The Red Cell
and Its Diseases
Plate 1. The alphabet made of poikilocytes from a single patient with sickle cell anemia and B-thalassemia trait. Note the electron dense areas in
the cells that are in the patient who is homozygous for hemoglobin S, as a reflection of the para-crystallization of that hemoglobin in a low oxygen
environment (venous blood). The patient with B-thalassemia trait from whom many of these cells were imaged was a physician whose family arrived
to the United States originally from the United Kingdom with no apparent recent Mediterranean heritage. As a result of Rome’s invasion of Britain on
several occasions between 55 B.C.E. and 43 A.D., troops from current Italy, Spain, Egypt, and Syria garrisoned their married local Britons. (Reproduced
with permission from Lichtman MA, Shafer MS, Felgar RE, et al: Lichtman’s Atlas of Hematology 2016. New York, NY: McGraw Hill; 2017.)
Plate 2. Paul Alfred Weiss (1898-1989) was an American cell and neurobiologist who had emigrated from Austria and specialized in morphogenesis,
cell development, and differentiation. He encouraged cross-disciplinary interactions among scientist and was elected to the National Academy of
Sciences. He was one of the earliest scientists to propose that the cell microenvironment (né stroma) had important influences on the parenchymal
cells it held in its grasp as highlighted in this aphorism he coined, here spelled out with misshapen red cells. (Reproduced with permission from
Lichtman MA, Shafer MS, Felgar RE, et al: Lichtman’s Atlas of Hematology 2016. New York, NY: McGraw Hill; 2017.)
COVER IMAGE DESCRIPTION
The nine abnormal red cells depicted on the cover show the amaz-
ing plasticity of the red cell. Consider the membrane reorganization
required to maintain these deviations from a biconcave disk.
In veins, the shear rate is low, and normal red cells remain close to
a biconcave disk shape. They, also, may overlap tightly at very low flow
rates into stacks (rouleaux). When subjected to increased shear rates in
the arterial circulation, rouleaux would be dispersed and the red cells
deform. At high flow velocities the red cell tends to elongate parallel to
the direction of flow. The cytoplasm moves in what has been consid-
ered eddy flow. This eddy flow results from the shear flow of the blood
being transmitted to the cytoplasm through a motion of the membrane
around the elongated red cell, called tank-tread motion or tank-treading.
In a blood capillary with diameters smaller than their own diameter, red
cells are folded.
The markedly deformed red cells shown on the cover image were
each found in the blood of a patient with a red cell disease (eg, hemo-
globin SS, beta-thalassemia, or another red cell disorder). After enu-
cleation, red cells leave the marrow through very narrow, temporary,
apertures in the marrow sinus wall that separates hematopoietic cords
from the marrow sinus network requiring marked deformation upon
egress. Red cells navigate the confinements of capillary dimensions,
squeeze through the inter-endothelial cell spaces of the splenic sinus
walls, and navigate other physical constraints. Abnormal red cells may
be shunted around those constricted dimensions.
The shapes of seven of the nine images approximate an animal
form, if one’s imagination is permitted to operate. In the upper-left
corner is a slightly deformed (thickened edge) discocyte and in its
biconcavity rests a triangular-shaped extremely small microcytic, but
the latter, strikingly, retains its biconcavity. The other images are that
of a simulated dinosaur (aka Erythrosurus Rochesteriensis), an octopus
(although with more than eight limbs), a severely deformed red cell
with a retained concavity and a large hole perforating its cytoplasm, a
flying goose, a snail, dancing penguins, a shark, and a duckling, each
with their own irregularities requiring extraordinary membrane adap-
tations. Several have para-crystallization of hemoglobin SS as a deform-
ing force (eg, shark shape).
The distortions that can be maintained by abnormal red cells are
extraordinary to consider and certain patterns, discerned on a careful
examination of the blood film can be, and frequently are, important
diagnostic clues to the nature of the underlying disease. In the absence
of a crystallizing hemoglobin or a mutant gene that results in a mem-
brane protein misconfiguration, it is possible that acquired alterations
in the spectrin-based membrane protein network is altered so as to
maintain abnormal bends and distortions of the red cell surface.
These images and those in Plates 1 and 2 were captured by
Patricia A. Santillo, Senior Technologist, Electron Microscopy Laboratory,
Hematology Unit at the University of Rochester Medical Center and
have been used with permission from Lichtman’s Atlas of Hematology.
www.accessmedicine.com
Williams Hematology
The Red Cell
and Its Diseases
Josef T. Prchal, MD Marshall A. Lichtman, MD, MACP
Professor of Hematology and Malignant Professor Emeritus of Medicine and of Biochemistry
Hematology and Biophysics
Adjunct in Genetics and Pathology Dean Emeritus, School of Medicine and Dentistry
University of Utah & Huntsman Cancer Institute James P. Wilmot Cancer Institute
Salt Lake City, Utah University of Rochester Medical Center
1. interní klinika VFN a Ústav patologické fyziologie Rochester, New York
1. LF School of Medicine
Universita Karlova, Prague, Czech Republic

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 ix

CONTRIBUTORS
Karl E. Anderson, MD Ralph Green, MD, PhD, FRCPath
Professor of Medicine Professor of Pathology and Medicine
Division of Gastroenterology Department of Pathology and Laboratory Medicine
The University of Texas Medical Branch at Galveston University of California, Davis
Galveston, Texas Sacramento, California

Kelty R. Baker, MD, FACP [52] Xylina T. Gregg, MD

President Utah Cancer Specialists
Kelty R. Baker, M.D. P.A. Salt Lake City, Utah
Houston, Texas
Michael R. Grever, MD
Marije Bartels, MD, PhD Professor Emeritus
Pediatric Hematologist Division of Hematology
Van Creveldkliniek Department of Internal Medicine
University Medical Center Utrecht The Ohio State University
Utrecht University Columbus, Ohio
Utrecht, The Netherlands
Amel Hamdi, PhD
Jaime Caro, MD Department of Physiology
Professor of Medicine, Emeritus Lady Davis Institute
Division of Hematology McGill University
Cardeza Foundation for Hematological Research Montreal, Quebec, Canada
Sidney Kimmel Medical College
Philadelphia, Pennsylvania Xiangrong He, MD
Clinical Fellow
Theresa L. Coetzer, PhD Laboratory Medicine and Pathology
Department of Molecular Medicine and Haematology Mayo Clinic
School of Pathology Rochester, Minnesota
Faculty of Health Sciences
University of the Witwatersrand Jeanne E. Hendrickson, MD
Johannesburg, South Africa Professor
Departments of Laboratory Medicine and Pediatrics
Claudia S. Cohn, MD Yale University School of Medicine
Associate Professor New Haven, Connecticut
Laboratory Medicine and Pathology
University of Minnesota Paul C. Herrmann, MD, PhD
Minneapolis, Minnesota Professor and Chair
Department of Pathology and Human Anatomy
Ross M. Fasano, MD Loma Linda University School of Medicine
Center for Transfusion and Cellular Therapies Loma Linda, California
Department of Pathology and Laboratory Medicine
Emory University School of Medicine Achille Iolascon, MD, PhD
Atlanta, Georgia Professor of Medical Genetics
Department of Molecular Medicine and Medical Biotechnology
Tomas Ganz, PhD, MD University of Naples Federico II
Departments of Medicine and Pathology Naples, Italy
David Geffen School of Medicine
University of California, Los Angeles Rami Khoriaty, MD
Los Angeles, California Assistant Professor, Department of Internal Medicine
Assistant Professor, Department of Cell and Developmental Biology
Victor R. Gordeuk, MD Section Head, Classical Hematology
Professor of Medicine Core Member, Rogel Cancer Center
University of Illinois University of Michigan
Chicago, Illinois Ann Arbor, Michigan
x Contributors

Abdullah Kutlar, MD Diana Morlote, MD

Professor of Medicine Assistant Professor
Augusta University Hematopathology and Molecular Genetics Pathology
Augusta, Georgia Division of Genomics and Bioinformatics
Department of Pathology
Marshall A. Lichtman, MD, MACP The University of Alabama at Birmingham
Professor Emeritus of Medicine and of Biochemistry and Biophysics Birmingham, Alabama
Dean Emeritus, School of Medicine and Dentistry
James P. Wilmot Cancer Institute Srikanth Nagalla, MBBS, MS
University of Rochester Medical Center Chief of Benign Hematology
Rochester, New York Miami Cancer Institute
Miami, Florida
Christine Lomas-Francis, MSc, FIBMS
Immunohematology and Genomics Charles H. Packman, MD
New York Blood Center Professor of Medicine
Long Island City, New York Department of Hematologic Oncology and Blood Disorders
Levine Cancer Institute
Gerard Lozanski, MD University of North Carolina School of Medicine
Professor of Pathology Clinical Charlotte, North Carolina
Department of Pathology
The Ohio State University Charles J. Parker, MD
Columbus, Ohio Professor of Medicine
Department of Medicine
Naomi L.C. Luban, MD Division of Hematology and Hematologic Malignancies
Professor of Pediatrics and Pathology University of Utah School of Medicine
School of Medicine and Health Sciences Salt Lake City, Utah
George Washington University;
Medical Director, Office of Human Subjects Protection John D. Phillips, PhD
Senior Hematologist Division of Hematology
Children’s National Hospital Department of Medicine
Washington, DC University of Utah School of Medicine
Salt Lake City, Utah
Jeffrey McCullough, MD
Global Blood Advisor Josef T. Prchal, MD
Edina, Minnesota; Professor of Hematology and Malignant Hematology
Emeritus Professor Adjunct in Genetics and Pathology
Laboratory Medicine and Pathology University of Utah & Huntsman Cancer Institute
University of Minnesota Salt Lake City, Utah
Minneapolis, Minnesota 1. interní klinika VFN a Ústav patologické fyziologie, 1. LF School of
Medicine
Ananya Datta Mitra, MD Universita Karlova, Prague, Czech Republic
Section of Hematopathology
Department of Pathology and Laboratory Medicine Vishnu V.B. Reddy, MD
University of California, Davis Health, School of Medicine Section Head, UAB Hospital Hematology Bone Marrow Lab
Sacramento, California Director, Hematopathology Fellowship Program
Division of Laboratory Medicine
Joel Moake, MD Professor, Department of Pathology
Professor of Medicine Emeritus The University of Alabama at Birmingham
Baylor College of Medicine Birmingham, Alabama
Senior Research Scientist
Department of Bioengineering Roberta Russo, PhD
Rice University Assistant Professor of Medical Genetics
Houston, Texas Department of Molecular Medicine and Medical Biotechnology
CEINGE
Mohandas Narla, DSc Biotecnologie Avanzate
Laboratory of Red Cell Physiology University of Naples Federico II
New York Blood Center Naples, Italy
New York, New York
 Contributors xi

George B. Segel, MD Eduard J. van Beers, MD, PhD

Emeritus Professor of Pediatric Hematologist
Professor of Medicine Van Creveldkliniek
James P. Wilmot Cancer Institute University Medical Center Utrecht
University of Rochester Medical Center Utrecht University
Rochester, New York Utrecht, The Netherlands

Vivien A. Sheehan, MD, PhD Richard van Wijk, PhD

Assistant Professor of Pediatrics Associate Professor
Baylor College of Medicine Central Diagnostic Laboratory
Houston, Texas University Medical Center Utrecht
Utrecht University
Sujit Sheth, MD Utrecht, The Netherlands
Department of Pediatrics
Weill Cornell Medicine Neal S. Young, MD
New York, New York Chief, Hematology Branch
National Heart, Lung, and Blood Institute
Swee Lay Thein, MD Mark Hatfield Clinical Research Center
National Heart, Lung, and Blood Institute National Institutes of Health
The National Institutes of Health Bethesda, Maryland
Bethesda, Maryland

Perumal Thiagarajan, MD
Professor of Medicine and Pathology
Baylor College of Medicine
Director of Transfusion Medicine and Hematology Laboratory
Michael E. DeBakey VA Medical Center
Houston, Texas

PREFACE
The discovery of the ruddy globules (red cells) is attributed to Jan
Swammerdam (1637-1680) in Amsterdam; but, it was Antonj van
Leeuwenhoek (1632-1723) of Delft, who as a result of his ability to grind
lenses with greater magnifying power (x 275), made a more detailed
description of red cells, delineating their gross structure.
The biochemistry, physiology, and biophysics of the red cell have
been studied intensively over three centuries and, although considered
a “simple” structure, since it is anucleate and after one day in the cir-
culation has no cytoplasmic organelles, its mysteries have been slow
to be unraveled. The process of enucleation of the erythroblast in the
hematopoietic space and the movement of the anucleate cell from the
hematopoietic space to the marrow sinus and from there to the sys-
temic circulation, accomplished by a cell without an intrinsic apparatus
to support amoeboid motility, and the determinants of its average life
span of approximately 120 days are still being elucidated. Its structural
and biophysical properties, biochemical pathways, and the relationship
among those features have been of continued interest to scientists. Its
absence of interfering granules, containing proteolytic enzymes, organ-
elles, and other complexities have allowed the isolation of highly puri-
fied red cell membranes and the early exploration of the biochemical
and biophysical features of cell membranes, applicable to other cells,
including the characteristics of membrane transport of various mole-
cules. The nature of the structure and function of hemoglobin and the
exploration of the glycolytic pathway, the hexose monophosphate shunt,
and the Luebering-Rapoport pathway were other rewards reaped from
the study of red cells.
Much is known, but as our mentor, friend, and colleague, Ernest
Beutler, cautioned Ph.D. graduates at a Scripps Institute doctoral gradu-
ation, one should not assume that our understanding of the biomedical
sciences is so profound that what is left for us is to fill in some gaps.
He argued that much fundamental biomedical knowledge was still
undiscovered and waiting to be illuminated. Among his many contri-
butions to the pathogenesis of disease and application of therapy, his
contributions to understanding the red cell and anemia were notable.
These observations included a classic series of papers describing the
effects of oxidant stress on individuals with red cell glucose-6-phosphate
dehydrogenase deficiency and a life-long interest in the enzyme’s vari-
ants and epidemiology. His monograph on methods for measuring red
cell enzymes was an early contribution to enhancing the specificity of
the diagnosis of hemolytic anemia. Published over five decades ago,
it remains an unsurpassed source of methods for the assay of red cell
enzymes. Beutler, also, used red cell enzyme measurement as a surrogate
for diagnosis of systemic, until then difficult to diagnose diseases, such
as galactosemia, glycogen storage disorders, and others. He found that
red cell glucose-6-phosphate dehydrogenase deficiency was inherited
as an X chromosome-linked disorder and described the mosaicism of
normal and deficient red cells in heterozygous females. This finding of
mosaicism provided the basis for an intellectual jump to the hypothesis
of X chromosome inactivation in humans, coincident with Mary Lyon’s
description of the phenomenon in mice. He, also, made seminal contri-
butions to understanding the effects of iron deficiency in non-anemic
women and the expression of iron overload in those homozygous for
the HFE mutation and the value of additives for prolonged storage of
red cells, still in current use.
With no DNA or RNA synthesis, no mitochondria and their
related enzymatic biochemical energy generating pathways, and with
a relatively short life span, this amitotic cell is sustained at a normal
xiii
concentration in the blood by a robust daily production of new cells in
the marrow, the process of erythropoiesis. This process delivers two to
three million new red cells to the blood per second. Although remark-
able, it is also a vulnerability should red cell production be dampened by
disease or substrate insufficiency: the latter, a principal cause of anemia.
In 1929, 3 years after obtaining his M.D. degree at the University of
Manitoba, his family having immigrated to Canada from Austria, Maxwell
Myer Wintrobe, obtained his Ph.D. at Tulane University, his doctoral
thesis entitled “The Erythrocyte in Man.” Wintrobe is considered the
father of clinical hematology having published the first comprehensive
text in the English language, Clinical Hematology, in 1942. He intro-
duced the technique of the hematocrit device to measure the packed
red cell volume at a time when hemoglobin and red cell count mea-
surements were neither accurate nor reproducible. The word “hema-
tocrit” was so appealing that it became a synonym for the packed red
cell volume rather than the instrument of measurement as intended by
Wintrobe. Initially, the “Wintrobe” tube, as it became known, was filled
by pipette with blood to the 1 mL mark etched on the tube and the gra-
dations on the tube allowed one to read the fraction of blood that was
composed of red cells after centrifugation. Later, the microhematocrit
centrifuge, which reached G-forces that removed plasma trapping as a
significant consideration in the measurement in capillary tubes filled
with blood, could be found on every ward and clinical laboratory as the
principal means to measure the packed red cell volume and, thereby,
identify anemia or erythrocytosis. A chart allowed the determination
of the packed cell volume when the capillary tube, regardless of the
volume of blood it contained, was placed against its scales. Wintrobe
institutionalized the red cell indices, mean cell volume (MCV), mean
cell hemoglobin (MCH), and mean cell hemoglobin concentration
(MCHC) and showed in two classic paper in 1930 and 1934 that one
could classify the anemias for diagnostic purposes by distinguishing
among macrocytic, normocytic, simple microcytic, and hypochromic
microcytic anemias, a method of differential diagnosis still used today.
After moving to the University of Utah from Johns Hopkins University,
Wintrobe established one of the most esteemed hematology clinical and
research training programs in the world. He also described along with
his colleague George Cartwright that the average hematocrit and hemo-
globin concentration was higher in residents of Salt Lake City (eleva-
tion 4300 feet) than the value observed at Johns Hopkins in Baltimore
(elevation 480 feet). He deduced from that prescient observation that
hypoxia, in that instance from higher altitude, is a principal regulator of
normal erythropoiesis.
In 1953, F. William Sunderman and colleagues enhanced the accu-
racy of blood hemoglobin measurement by introducing the cyanmethe-
moglobin method. In 1956, Wallace Coulter introduced his high-speed,
automatic blood cell counter making blood cell counting accurate,
reproducible, and capable of meeting the demands of a busy clinic and
hospital environment. The “Coulter Principle” held that cells are poor
conductors of electricity in a salt solution. Thus, when cells are diluted
in saline and are drawn through a tiny aperture carrying a current, each
cell produces a slight impedance to current flow as it passes through the
narrow aperture. The pulse created by this impedance can be ampli-
fied and counted. Moreover, the size of the pulse is proportional to cell
volume. Thus, the number and volume distribution of red cells in a
measured volume of solution can be converted to red cell count and
volume electronically. Their product, red cell count and red cell volume,
provided the hematocrit, now a derived value. Thousands of cells can
xiv Preface
be counted per second. Since the red cells, leukocytes, and platelets are
sufficiently different in size, they can be discriminated. The electronic
particle counter’s derivative technology of cell flow analysis, dependent
on laser light, provided one of the most powerful diagnostic technolo-
gies in medicine, capable of measuring cell DNA content or the surface
antigen array of a specific cell type. One could use the device to isolate
purified, specific cell populations for analysis. The Coulter Principle
and its derivative technologies revolutionized diagnostic medicine, bio-
medical, and industrial research and, more specifically, the diagnosis
and management of red cell diseases.
A giant of studies of the red cell, perhaps little known to younger
scientists, was Eric Ponder (d. 1970), an original member of the Red
Cell Club (see further), whose treatise Hemolysis and Related Phenom-
ena in 1948, reissued in 1971 by Grune and Stratton with a forward by
Robert I. Weed, is an extraordinary compilation of his research on this
cell. Many of his studies are still relevant. All scientist interested in the
red cell should be familiar with this work. Weed, another gifted con-
tributor to our understanding of the red cell, died prematurely in 1976,
at the age of 48 years, of a glioblastoma. He was largely responsible for
convincing the National Institutes of Health to expand the designation
of the Heart and Lung Institute to the Heart, Lung and Blood Institute
in 1976, facilitating research support for blood cells, especially red cell
research. In 1976, in recognition of his leadership in that initiative and
his contributions to research on the red cell, he was named the third
recipient of the William Dameshek Award of the American Society of
Hematology. At the time, the Society had two prizes, The Henry Stratton
Lecture and The William Dameshek Prize. Stratton and Dameshek were
very close friends. Dameshek was among the very top academic clini-
cal hematologists in the United States and Stratton was the co-owner
of Grune and Stratton Publishers. They were the prime movers of the
establishment of the American Society of Hematology and started Blood
in 1946. Dameshek was the founding editor and Grune and Stratton the
publisher. Under Dameshek’s editorship Blood became the most presti-
gious journal of clinical and research hematology in the world. In 1976,
the journal became the official publication of the American Society of
Hematology; however, the publisher still owned the title and, techni-
cally, editorial control, but some of it was ceded to the Society. In 1989,
the American Society of Hematology bought the title to Blood from its
then publisher Saunders, Inc. and it became Blood, The Journal of the
American Society of Hematology. The purchase of title was an initiative
led by H. Franklin Bunn, a distinguished hematologist at Harvard Uni-
versity and a world’s authority on the structure and function of hemo-
globin. The purchase of the Journal has provided the Society with an
enormously successful economic engine to support its educational and
research programs, full control of its editorial policies, and an outlet for
the most impactful research in the field, including that of the red cell
and its diseases.
Bob Weed’s close colleagues at the University of Rochester, Claude
Reed and Scott Swisher, were pioneers in forecasting the key role of
a membrane protein abnormality as the primary lesion in hereditary
spherocytosis, whereas others were distracted by epiphenomena, such
as substrate transport. They showed that the membrane lipid com-
position of red cells in hereditary spherocytosis was normal but after
24 hours of incubation, lipids (cholesterol and phospholipids) were lost
to the medium in their exact molar proportion as in the red cell mem-
brane and this phenomenon could be decreased by adding glucose to
the medium. This finding strongly suggested that the loss of surface area
of the red cells and the disc to sphere transformation decreasing their
surface area to volume ratio and moving toward their critical hemolytic
volume was related to loss of pieces of membrane. This work published
in 1966 was well before methods for membrane protein analysis were
available. Later, the ability to characterize the protein composition of
“pure” red cell membranes (ghosts) in cases of specific disorders of the
red cell (eg, hereditary spherocytosis versus hereditary elliptocytosis)
allowed the assignment of functional characteristics to the missing or
mutant proteins. Red cell ghosts are a preparation of red cell membranes
freed of their internal contents, notable hemoglobin and enzymes and
substrates and colorless (ghostly pale) rather than red and are basically
pure red cell membranes, a key specimen for study.
A longstanding focus on the red cell by basic and clinical investi-
gators has been highlighted by the interactions of a group of scientists,
referred to as “The Red Cell Club,” which started in 1958 through the
initiative of Joseph Hoffman and Daniel Tosteson, then young scientists
at the National Institutes of Health. The spent their careers at Yale and
Harvard, respectively. The meetings are small, informal, and an ideal
milieu to focus on new science and the exchange of ideas. The Club,
in its 63rd year in 2021, meets now once a year on the campus of a
member to discuss new insights into the red cell and to share their cur-
rent research. It is a collegial group with new “blood” being cycled in
from laboratories throughout the United States and Canada as mentors
introduce their acolytes to the red cell’s charms. Usually, a preceding
round of golf is held for those devotees of the game, weather permitting.
Members, who for reasons of age or a change of interests leave the fold,
are never dropped from the invitation list. Nonparticipants are tenderly
referred to as “red cell ghosts.” In the last several years, scientists from
Europe and, occasionally Japan, have participated in these meetings.
A European Red Cell Club has been established highlighting that the
mysteries of the cell have not all been uncovered, confirming Beutler’s
admonition.
In this volume, we bring to the reader the most up-to-date con-
sideration of the structure and function of the red cell. After two
introductory chapters on the structure and biology of the red cell and
erythropoiesis, the focus turns to the comprehensive set of diseases,
either acquired or inherited, in which a quantitative (deficiency or
excess) or qualitative (membrane, enzyme, hemoglobin) abnormality of
the red cell results in disease. These chapters, also, may include impor-
tant, relevant basic scientific aspects of the clinical problem under dis-
cussion. The role of certain plasma constituents, iron, folic acid, and
cobalamin, critical to normal red cell production and hemoglobin syn-
thesis, is described as well.
We believe the authors have brought to our reader an insightful
exposition of the red cell and its disorders to enlighten the clinicians
faced with their challenges and to the benefit of the care of their patients.
In addition, we hope this text provides scientists a clear delineation of
the remaining mysteries of the cell and provides them with new founda-
tions for development of therapy of red cell diseases. We hope that this
text will fill the vacuum that has existed since the monograph published
in 1970 devoted to the red cell by John W. Harris, and Robert W.
Kellermeyer: The Red Cell: Production, Metabolism, Destruction: Nor-
mal and Abnormal.
The authors acknowledge and thank Karen Edmonson, Senior
Editor, formerly at McGraw-Hill, Education, for supporting the pro-
duction of this text and convincing management of its merits, Susan
Daley at the University of Rochester Medical Center for her adminis-
trative assistance, Harriet Lebowitz, Senior Project Development Editor
at McGraw-Hill Education for stewarding the final preparation of the
manuscript and Jason Malley, editor and Richard Ruzycka, production
supervisor, each at McGraw-Hill Education, and Warishree Pant, the
Project Manager at Knowledge Works Global, Ltd.
Marshall A. Lichtman, Rochester, NY
Josef T. Prchal, Salt Lake City, UT
Part I Structure and Physiology
of the Red Cell
1. Structure and Composition of the 2. Erythropoiesis and Red Cell Turnover . . . . . 21
Erythrocyte . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

CHAPTER 1
STRUCTURE AND
COMPOSITION OF THE
ERYTHROCYTE*
Mohandas Narla
SUMMARY
Collectively, the erythroid progenitors, terminally differentiating erythroblasts
(precursors), and adult red cells are termed the erythron to reinforce the idea
that they function as an organ. The widely dispersed cells comprising this
organ arise from pluripotential hematopoietic stem cells. Following commit-
ment to the erythroid lineage (unipotential progenitor), further maturation
gives rise to the erythroid progenitors, burst-forming unit–erythroid (BFU-E)
and, subsequently, colony-forming unit–erythroid (CFU-E), that can be iden-
tified by their development into representative clonal colonies of red cells in
vitro. The CFU-E then undergoes terminal differentiation, progressing through
four to five morphologic stages, each having characteristic light microscopic
and ultrastructural features. During terminal erythroid differentiation, there
is an increasing amount of hemoglobin synthesis accompanied by nuclear
chromatin condensation, and at the final stage of differentiation, there is
nuclear extrusion to generate an anucleate polychromatophilic macrocyte
(reticulocyte with supravital staining). The human polychromatophilic mac-
rocyte (reticulocyte) matures over 2 to 3 days, first in the marrow and then
in circulation into the discoid erythrocyte. During reticulocyte maturation,
cytoplasmic inclusions, including residual mitochondria and ribosomes, are
degraded, and the reticulocyte loses surface area to achieve the mean cell
volume and surface area of a discoidal erythrocyte. Mature erythrocytes are
approximately 7 to 8 μm in diameter and undergo extensive deformation to
pass through 3-μm-diameter capillaries and the 1-μm-wide and 0.5-μm-thick
endothelial slits in the red pulp of the spleen. The ability of the red cell to
undergo extensive reversible deformation is essential for both its function and
its survival. Red cell deformability is a function of its geometry, the viscosity
Acronyms and Abbreviations: BFU-E, burst-forming unit–erythroid; CFU-E,
colony-forming unit–erythroid; cP, centipoise; DIC, disseminated intravascular
coagulation; EMP, erythroblast macrophage protein; ICAM-4, intercellular
adhesion molecule-4; IL, interleukin; MCH, mean cell hemoglobin content; MCHC,
mean corpuscular hemoglobin concentration; MCV, mean cell volume; MDS,
myelodysplastic syndrome; SA:V, surface area-to-volume ratio; TTP, thrombotic
thrombocytopenic purpura.
*
This chapter contains text written for previous editions of this book by Brian Bull,
Paul Herrmann, and Ernest Beutler.
3
of the cytoplasm, largely determined by the concentration of hemoglobin.
Decreased deformability is a feature of red cells in various pathologic states.
The erythrocyte is unique among eukaryotic cells in that its principal physi-
cal structure is its cell membrane, which encloses a concentrated hemoglobin
solution. Thus, all structural properties of this cell are in some way linked to the
cell membrane. In contrast to other cells, the erythrocyte has no cytoplasmic
structures or organelles. Among human cells, only red cells and platelets do
not have a nucleus.
ERYTHRON
The mass of circulating erythrocytes constitutes an organ responsible
for the transport of oxygen to tissues and the removal of carbon diox-
ide from tissues for exhalation. Collectively, the progenitors, precursors,
and adult red cells make up an organ termed the erythron, which arises
from pluripotential hematopoietic stem cells. Following commitment
to the erythroid lineage, unipotential progenitors mature into the ery-
throid progenitors, the burst-forming unit–erythroid (BFU-E) and,
subsequently, the colony-forming unit–erythroid (CFU-E), which then
undergoes further maturation to generate anucleate polychromatophilic
macrocytes (reticulocytes on supravital staining). The BFU-E and
CFU-E are identified by their development into morphologically iden-
tifiable clonal colonies of red cells in vitro. The reticulocyte further
matures, first in the marrow for 2 to 3 days and, subsequently, in the
circulation for approximately 1 day, to generate discoid erythrocytes.1-5
The proerythroblast, the first morphologically recognizable erythroid
precursor cell in the marrow, typically undergoes 5 mitoses (range 4-6)
before maturation to an orthochromatic erythroblast, which then under-
goes nuclear extrusion. A feature of erythropoiesis is that after each cell
division, the daughter cells advance in their state of maturation with
significant changes in gene and protein expression compared with the
parent cell and, ultimately, become functional as mature erythrocytes.4
In this process, they acquire the human blood group antigens, transport
proteins, and all components of the erythrocyte membrane.4,6
In the adult stage of development, the total number of circulat-
ing erythrocytes is in a steady state, unless perturbed by a pathologic
or environmental insult. This effect does not hold during growth of
the individual in utero, particularly in the early stages of embryonic
development and during neonatal development as the total blood vol-
ume increases markedly. Consequently, erythrocyte production in the
embryo and fetus differs markedly from that in the adult.
THE EARLIEST ERYTHRON
In the very early stages of human growth and development, there are
two forms of erythroid differentiation: primitive and definitive.7-10
Chapters 2 and 17 provide detailed information of embryonic and
fetal hematopoiesis. The primitive erythron supplies the embryo with
oxygen during the phase of rapid growth before the definitive form of
maturation has had a chance to develop and seed an appropriate niche.
The hallmark of this primitive erythron is the release of nucleated ery-
throid precursors containing embryonic hemoglobin. Although prim-
itive in the sense that the cells contain nuclei when released into the
circulation, this form of maturation differs from avian and reptilian
erythropoiesis in that the nucleus is eventually expelled from the mam-
malian cells as they circulate. The transient presence of a nucleus in the
cells of the circulating primitive erythron can decrease the efficiency
of gas exchange in the lungs and microvasculature because the nucleus
4 Part I: Structure and Physiology of the Red Cell
prevents the red ce from behaving as a fuid dropet. 11 The definitive
stage of maturation makes its appearance around week 5 of embryo-
genesis when mutipotentia stem ces deveop and seed the iver,
which maintains the erythron for most of feta ife. In ater feta ife,
skeeta deveopment provides marrow niches to which erythropoie-
sis reocates, being sustained in the form of erythrobastic isands, a
centra macrophage with circumferentia ayers of deveoping ery-
throid ces.12 The definitive stage of erythroid maturation predomi-
nates during the remainder of feta deveopment and is the ony type
of erythroid maturation present through chidhood and adut ife.
A norma human erythropoiesis occurs in the marrow in the form
of erythrobastic isands.13
ERYTHROID PROGENITORS
Burst-Forming Unit–Erythroid
The eariest identifiabe progenitor committed to the erythroid ineage
is the BFU-E (Chap. 2, Fig. 2-1). A BFU-E is defined in vitro by its abiity
to create a “burst” on semisoid medium, that is, a coony consisting of
severa hundred to thousands of ces by 10 to 14 days of growth, during
which time smaer sateite custers of ces form around a arger centra
group of erythroid ces, giving rise to the designation of a “burst.” The
generation of BFU-E from hematopoietic stem ces requires intereukin
(IL)-3, stem ce factor, and erythropoietin for differentiation, proifera-
tion, prevention of apoptosis, and maturation (Chap. 2).5,13
Colony-Forming Unit–Erythroid
As erythroid maturation progresses, a ater progenitor, the CFU-E,
derived from the BFU-E, can be defined in vitro. The CFU-E is depen-
dent on erythropoietin for its deveopment and can undergo ony a few
ce divisions.5,14,15 Thus, the CFU-E forms a smaer coony of morpho-
ogicay recognizabe erythroid ces in 5 to 7 days (see Chap. 2,
Fig. 2-1). Adhesion between erythroid ces and macrophages occurs at
the CFU-E stage of maturation.
Using ce-surface markers, IL-3 receptor, CD34, and CD36, highy
purified popuations of BFU-E and CFU-E can be isoated from human
marrow.5 Gene expression profiing shows distinctive changes in gene
expression profies in hematopoietic stem ces, BFU-E, and CFU-E.5
Some of the marrow faiure syndromes are the resut of defects in differ-
entiation of stem ces into erythroid progenitors.
A B
Figure 1–1. Erythroblastic island. A. Erythroblastic island as seen in Wright-Giemsa–stained marrow. Note central macrophage surrounded by a
cohort of attached erythroblasts. B. Erythroblastic island in the living state examined by phase-contrast microscopy. The macrophage shows dynamic
movement in relation to its surrounding erythroblasts. (A, reproduced with permission from Lichtman MA, Shafer MS, Felgar RE, et al: Lichtman’s Atlas of
Hematology 2016. New York, NY: McGraw Hill; 2017.)
ERYTHROBLASTIC ISLAND
The anatomica unit of erythropoiesis in the norma adut is the ery-
throbastic isand or iset.13,16,17 The erythrobastic isand consists of
a centray ocated macrophage surrounded by maturing terminay
differentiating erythroid ces (Fig. 1-1A). Severa binding proteins
are impicated in the ce–ce adhesions important to this process.
These incude α4 β1 integrin, erythrobast macrophage protein (EMP),
and interceuar adhesion moecue-4 (ICAM-4) on the erythrobasts
and vascuar ce adhesion moecue (VCAM-1) EMP, αV integrin on
macrophages. 16 Additiona macrophage receptors incude CD69 (sia-
oadhesin) and CD163, but the counterreceptors for these on erythrob-
asts remains to be defined.16 Phase-contrast microcinematography
reveas that the macrophage is far from passive or immobie. Evidence
suggests that either the erythrobastic isands migrate or that erythroid
precursors move from isand to isand, because isands near sinusoids
are composed of more mature erythrobasts, whereas isands more
distant from the sinusoids are composed of proerythrobasts. 18 The
macrophage’s pseudopodium-ike cytopasmic extensions move rap-
idy over ce surfaces of the surrounding wreath of erythrobasts. On
phase-contrast micrographs, the centra macrophage of the erythrob-
astic isand appears spongeike, with surface invaginations in which
the erythrobasts ie (Fig. 1-1B). As the erythrobast matures, it moves
aong a cytopasmic extension of the macrophage away from the main
body. When the erythrobast is sufficienty mature for nucear expu-
sion, the erythrobast makes contact with an endotheia ce, passes
through a pore in the cytopasm of the endotheia ce, and enters
the circuation as a poychromatophiic macrocyte (reticuocyte).19-21
The nuceus is ejected before egress from the marrow, phagocytized,
and degraded by marrow macrophages.22 In addition to the unique
cytoogic features just described, the macrophage of the erythrob-
astic isand is aso moecuary distinct as demonstrated by a unique
immunophenotypic signature.23 In addition, the macrophage of the
erythrobastic isand appears to pay a stimuatory roe in erythropoie-
sis; independent of erythropoietin. The anemia of chronic infamma-
tion and of the myeodyspastic syndrome (MDS) may resut party
from inadequate stimuation of erythropoiesis by these macrophages
(Chaps. 2 and 6).
Despite the centra roe of erythroid isands in erythropoiesis
in vivo, morphoogicay norma deveopment of erythroid ces can be
 Chapter 1: Structure and Composition of the Erythrocyte 5

recapituated in vitro without these structures, assuming deveoping
ces are provided with supraphysioogic concentrations of appropriate
cytokines and growth factors. Such growth in vitro, however, is much
ess optima than when erythrobasts form erythrobastic isands.24 The
erythrobastic isand is a fragie structure. It is usuay disrupted in the
process of obtaining a marrow specimen by neede aspiration but can be
seen in marrow biopsies.
Macrophages in erythrobastic isands not ony affect erythroid
differentiation and/or proiferation but aso perform other functions,
incuding rapid phagocytosis (<10 min) of extruded nucei as a resut
of exposure of phosphatidyserine on the surface of the membrane sur-
rounding the nuceus.22 This phagocytosis is the reason for the inabiity
to find extruded nucei in marrow aspirates despite the fact that 2 miion
nucei are extruded every second during steady-state erythropoiesis.
A protective macrophage function inked to efficient phagocytosis has
been described. In norma mice, DNase II in macrophages degrades the
ingested nucear DNA, but in DNase II-knockout mice, the inabiity to
degrade DNA resuts in macrophage toxicity, with a resutant decrease
in the number of marrow macrophages and in conjunction with severe
anemia.25 Macrophages can pay both positive and negative reguatory
roes in human erythropoiesis, but the mechanistic basis for these reg-
uatory processes are not competey understood.16,24 These processes
may pay a roe in the ineffective erythropoiesis in disorders such as
MDS, thaassemia, and maaria anemia.
Another potentiay important roe originay proposed for the
centra macrophage is direct transfer of iron to deveoping erythrobasts
mediated by ferritin exchange between macrophages and erythrobasts
(Chap. 10).13 This is an interesting evoving concept with identification
of various transport proteins invoved in this exchange.
ERYTHROID PROGENITORS AND PRECURSORS
Early Progenitors
A “progenitor” in the hematopoietic system is defined as a marrow ce
that is a derivative of the puripotent hematopoietic stem ce through the
process of differentiation, and is antecedent to a “precursor” ce, the atter
being identifiabe by ight microscopy by its morphoogic characteristics.
In erythropoiesis, the eariest precursor is the proerythrobast. Erythroid
progenitor ces are identified as marrow ces capabe of forming erythroid
coonies in semisoid medium in vitro under conditions in which the appro-
priate growth factors are present. Progenitor ces aso may be identified by
characteristic profies of surface CD antigens using fow cytometry. Numer-
icay, erythroid progenitors, BFU-E, and CFU-E represent ony a minute
proportion of human marrow ces. BFU-E range from 300 to 1700 ×
106 mononucear ces and CFU-E range from 1500 to 5000 × 106 mono-
nucear ces.5 In vitro cutures using CD34+ ces from bood, cord bood,
and marrow as the starting materia have identified the critica cytokines
required for erythroid differentiation and maturation and have enabed the
identification and isoation of pure cohorts of erythroid progenitors and
erythrobasts at a stages of termina erythroid maturation.4,5
Precursors
Figure 1-2 shows the sequence of precursors as seen in marrow fims.
Figure 1-3 shows the marrow precursors as isoated by fow cytometry.

A B C

D E

Figure 1–2. Human erythrocyte precursors. Light microscopic appearance. Marrow films stained with Wright stain. There are five stages of erythrob-
last development recognizable by light microscopy. A. Proerythroblasts. Two are present in this field. They are the largest red cell precursor, with a fine
nuclear chromatin pattern, nucleoli, basophilic cytoplasm, and often a clear area at the site of the Golgi apparatus. B. Basophilic erythroblast. The cell
is smaller than the proerythroblast, the nuclear chromatin is slightly more condensed, and cytoplasm is basophilic. C. Polychromatophilic erythrob-
lasts. The cell is smaller on average than its precursors. The nuclear chromatin is more condensed, with a checkerboard pattern that develops. Nucleoli
are usually not apparent. The cytoplasm is gray, reflecting the staining modulation induced by hemoglobin synthesis, which adds cytoplasmic con-
tent that takes an eosinophilic stain, admixed with the residual basophilia of the fading protein synthetic apparatus. D. Orthochromic normoblast.
Smaller on average than its precursor, increased condensation of nuclear chromatin, with homogeneous cytoplasmic coloration approaching that of
a red cell. E. Late orthochromatic erythroblasts (asterisks). The orthochromatic erythroblast to the right is undergoing apparent enucleation. The other
three mononuclear cells are lymphocytes. A degenerating four-lobed neutrophil is also present. (Reproduced with permission from Lichtman MA, Shafer MS,
Felgar RE, et al: Lichtman’s Atlas of Hematology 2016. New York, NY: McGraw Hill; 2017.)
6 Part I: Structure and Physiology of the Red Cell

A B C D
Figure 1–3. Human erythroblast precursors as isolated by cell flow cytometry. Images are of populations of human erythroblast precursors at
stages of erythroid maturation when sorted from human marrow by flow cytometry. A and B. Proerythroblasts and early basophilic erythrob-
lasts; (C) polychromatic erythroblasts; and (D) orthochromatic erythroblasts.

Proerythroblasts On stained fims, the proerythrobast appears different parts of the ce periphery and are just as quicky retracted.13
as a arge ce, irreguary rounded or sighty ova.13 The nuceus occu- The movements probaby are made in preparation for ejection of the
pies approximatey 80% of the ce area and contains fine chromatin de- nuceus. The ce utrastructure is characterized by irreguar borders,
icatey distributed in sma cumps. One or severa we-defined nuceoi refecting its motie state. The heterochromatin forms arge masses.
are present. The high concentration of poyribosomes gives the cyto- Mitochondria are reduced in number and size (see Figs. 1-2, 1-7, and 1-8).
pasm of these ces its characteristic intense basophiia. At very high
magnification, ferritin moecues are seen dispersed singy throughout
the cytopasm and ining the cathrin-coated pits on the ce membrane
(Figs. 1-2 and 1-4). Diffuse cytopasmic density on sections stained for
peroxidase indicates that hemogobin is aready present. Dispersed gy-
cogen partices are present in the cytopasm.
Basophilic Erythroblasts Basophiic erythrobasts are smaer
than proerythrobasts. The nuceus occupies three-fourths of the ce
area and is composed of characteristic dark vioet heterochroma-
tin interspersed with pink-staining cumps of euchromatin inked by n
irreguar strands.13 The whoe arrangement often resembes whee
spokes or a cock face. The cytopasm stains deep bue, eaving a per-
inucear hao that expands into a juxtanucear cear zone around the
Gogi apparatus. Cytopasmic basophiia at this stage resuts from the
continued presence of poyribosomes (Figs. 1-2 and 1-5).
Polychromatophilic Erythroblasts After the mitotic division
of the basophiic erythrobast, the cytopasm changes from deep bue
to gray as hemogobin diutes the poyribosome content. Ces at this g
stage are smaer than basophiic erythrobasts. The nuceus occupies
ess than haf of the ce area. The heterochromatin is ocated in
we-defined cumps spaced reguary about the nuceus, producing n
a checkerboard pattern. The nuceous is ost, but the perinucear
hao persists.13 It is at this point that erythrobasts ose their mitotic
potentia. Eectron microscopy of the poychromatophiic erythrob-
ast reveas increased aggregation of nucear heterochromatin.13 Active
ferritin transport across the ce membrane is aways evident, and
siderosomes aong with dispersed ferritin moecues can be identified
within the cytopasm (Figs. 1-2 and 1-6). Figure 1–4. Proerythroblast. Phase-contrast micrograph (inset) of a
Orthochromic (syn. Orthochromatic) Erythroblasts After the proerythroblast showing the immature nucleus with nucleoli and finely
fina mitotic division of the erythropoietic series, the concentration of dispersed nuclear chromatin. The centrosome (juxtanuclear clear zone)
is apparent with its dense accumulation of mitochondria. Electron micro-
hemogobin increases within the erythrobast. Under the ight micro-
scopic section of the proerythroblast shows nucleoli (n) in contact with
scope, the nuceus appears amost competey dense and featureess. the nuclear membrane. Chromatin is finely dispersed and forms small
It is measuraby decreased in size. This ce is the smaest of the ery- aggregates in the fixed nuclear membrane. The perinuclear canal is nar-
throbastic series.13 The nuceus occupies approximatey one-fourth of row but well defined. Polyribosome groups, many in helical configuration,
the ce area and is eccentric. Ce movement can be appreciated under are dispersed throughout the cytoplasm. The Golgi apparatus (g) is well
the phase-contrast microscope. Round projections appear suddeny in developed, and regions of endoplasmic reticulum (arrows) are seen.
 Chapter 1: Structure and Composition of the Erythrocyte
pr
pr
Figure 1–5. Basophilic erythroblast. Phase-contrast photomicrograph
(inset) shows increased clumping of the nuclear chromatin and further
rounding of the cell, with aggregation of the mitochondria and cen-
trosome into the regions of nuclear indentation. The electron micro-
scopic section shows clumping of the nuclear chromatin, nuclear pores
(p), organization of the nucleoli, increased density of polyribosomes (pr),
well-developed Golgi apparatus (g), and a decrease in smooth endo-
plasmic reticulum.
Normal Sideroblasts A norma erythrobasts are siderobasts
in that they contain iron in structures caed siderosomes, as evident by
transmission eectron microscopy. These structures are essentia for the
transfer of iron for heme (hemogobin) synthesis. By ight microscopy,
under the usua conditions of Prussian bue staining for iron, a minority
of norma erythrobasts (approximatey 15%-20%) can be identified as
containing siderosomes, and those that can be so identified have very
few (1-4) sma Prussian bue–positive granues.
Pathologic Sideroblasts A heterogeneous group of erythro-
cyte disorders is accompanied by ineffective erythropoiesis, abnorma
erythrobast morphoogy, and hyperferremia. These disorders incude
acquired megaobastic anemia (Chap. 9), congenita dyserythropoietic
anemias (Chap. 14), thaassemias (Chap. 17), the inherited and acquired
siderobastic anemias, pyridoxine-responsive anemia, acoho-induced
siderobastic anemia, and ead intoxication (Chaps. 20 and 23). Some
of these conditions are characterized by the presence of pathoogic
siderobasts. Pathoogic siderobasts are of two types. The first is an
erythrobast that has an increase in number and size of Prussian bue–
stained siderotic granues throughout the cytopasm. The second is the
erythrobast that shows iron-containing granues that are arranged in
an arc or a compete ring around the nuceus (Fig. 1-8). These patho-
ogic siderobasts are referred to as ring or ringed sideroblasts.26,27 Eec-
tron microscopic studies show that granues in ringed siderobasts are
iron-oaded mitochondria. In ces with iron-oaded mitochondria,
many ferritin moecues are deposited between adjacent erythrobast
membranes.
7
C
Figure 1–6. Polychromatophilic erythroblast. Phase-contrast micro-
graph (inset) demonstrates diminished size of this cell compared with
its precursor. Further clumping of nuclear chromatin gives the nucleus
a checkerboard appearance. The centrosome is condensed, and a peri-
nuclear halo has developed. The electron microscopic section demon-
strates relative reduction of the density of polyribosomes and dilution
by the moderately osmiophilic hemoglobin in the cytoplasm. Nuclear
chromatin shows a marked increase in clumping, and nuclear pores (P)
are enlarged.
RETICULOCYTE
Birth
Before enuceation at the ate orthochromatic erythrobasts stage, inter-
mediate fiaments and the margina band of microtubues disappear.
Enuceation is a highy dynamic process that invoves coordinated action
of mutipe mechanisms.28-30 Tubuin and actin become concentrated at
the point where the nuceus wi exit. These changes, accompanied by
microtubuar rearrangements and actin poymerization, pay a roe in
nucear expusion. Expusion of the nuceus in vitro is not an instanta-
neous phenomenon; it requires a period of 6 to 8 minutes. The process
begins with severa vigorous contractions around the midportion of the
ce, foowed by a division of the ce into unequa portions. The smaer
portion consists of the expeed nuceus surrounded by a thin ring of
hemogobin and pasma membrane (Fig. 1-9). In vivo, expusion of the
nuceus may occur whie the erythrobast is sti part of an erythrobas-
tic isand and the outer eafet of the biaminar membrane surrounding
the expeed nuceus is high in phosphatidyserine, a signa for macro-
phage ingestion (Fig. 1-10).22 Two hypotheses have been proposed to
expain how the reticuocyte exits the marrow.19-21 The reticuocyte may
activey traverse the sinus epitheium to enter the umen. More ikey,
however, the reticuocyte may be driven across by a pressure differen-
tia because it appears incapabe of directed amoeboid motion. In vitro
experimenta evidence favors the hypothesis that pressure differentia is
ikey the driver for reticuocyte reease.21
8 Part I: Structure and Physiology of the Red Cell

pnc

Figure 1–7. Orthochromic erythroblast. Phase-contrast appearance

of this cell in the living state (inset) shows the irregular borders indica-
tive of its characteristic motility, the eccentric nucleus making contact
with the plasmalemma, further pyknosis of the nuclear chromatin, and
condensation of the centrosome. The electron microscopic section
shows further dilution of polyribosomes, some of which appear to be
Figure 1–8. Pathologic sideroblast is an erythroblast characterized by
disintegrating into monoribosomes, by the increasing hemoglobin.
the presence of mitochondrial deposits of iron-containing ferruginous
The number of mitochondria is decreased, and some mitochondria are
micelles (arrows) between the cristae.
degenerating. Nuclear chromatin is clumped into large masses, and a
perinuclear canal (pnc) is seen.

A B C D

Figure 1–9. Morphology of cells during reticulocyte maturation. A. Orthochromatic erythroblast extruding its nucleus. B. Multilobular, motile
reticulocyte generated after nuclear extrusion. C. The cup-shaped, nonmotile reticulocyte at a later stage of maturation. D. Mature discoid red cell.
 Chapter 1: Structure and Composition of the Erythrocyte
Figure 1–10. Orthochromic erythroblast ejecting its nucleus. A thin
rim of cytoplasm surrounds the nucleus. In the cytoplasm, a single cen-
triole (c) is partially encircled by some Golgi saccules.
Maturation
After nucear extrusion, the reticuocyte retains mitochondria, sma
numbers of ribosomes, the centrioe, and remnants of the Gogi appa-
ratus. It contains no endopasmic reticuum. Supravita staining with
briiant cresy bue or new methyene bue produces aggregates of
ribosomes, mitochondria, and other cytopasmic organees. These
aggregates stain deep bue and, arranged in reticuar strands, give
the reticuocyte its name. Maturation of the reticuocyte requires
48 to 72 hours. During this period, approximatey 20% of the membrane
surface area is ost and ce voume decreases by 10% to 15%, and the
fina assemby of the membrane skeeton is competed.31-33 Living retic-
uocytes observed by phase-contrast microscopy are irreguary shaped
ces with a characteristicay puckered exterior and a motie membrane.
Examined by eectron microscopy, reticuocytes are irreguary shaped
and contain many remnant organees.13 The organees, sma smooth
vesices, and an occasiona centrioe are grouped in the region of the
ce where the nuceus is expeed. In “young” reticuocytes, the majority
of ribosomes dispersed throughout the cytopasm are in the form of
poyribosomes. As protein synthesis diminishes during maturation, the
poyribosomes graduay transform into monoribosomes. During retic-
uocyte maturation, there is significant remodeing of the membrane,
incuding oss of membrane proteins that incude transferrin receptors,
Na-K adenosine triphosphatase, and adhesion moecues, as we as oss
of tubuin and cytopasmic actin.33 During the remodeing process, the
membrane becomes more eastic and acquires increased membrane
mechanica stabiity.32
Macroreticulocytes
“Stress” reticuocytes are reeased into the circuation during an intense
erythropoietin response to acute anemia or experimentay in response to
arge doses of exogenousy administered erythropoietin.34 These ces
may be twice the norma voume, with a corresponding increase in
mean ce hemogobin (MCH) content. Whether the increase resuts
from one ess mitotic division during maturation or from some other
process such as changes in ce cyce is not cear. Mice do not have the
abiity to produce stress reticuocytes with increased mean ce voume
9
(MCV) and MCH. In contrast, even under moderate erythropoietic
stress, some reticuocytes in the marrow poo shift to the circuating
poo. These “shift” reticuocytes with norma MCH contain a higher-than-
norma RNA content and can be quantified. Quantification is commony
performed by appying a fuorescent stain to tag RNA and then divid-
ing reticuocytes into high-, medium-, and ow-fuorescence categories
using a fuorescence-sensitive fow cytometer. The “stress” reticuocytes
of the oder iterature ikey fa in the high- and medium-fuorescence
categories. Currenty, itte attention is being paid to discriminate stress
and shift reticuocytes.
Pathology of the Reticulocyte
The reticuocyte may show pathoogic aterations in size or staining
properties. The reticuocyte may contain incusions visibe by ight
microscopy or identifiabe ony from utrastructura anaysis. Most
pathoogic incusions usuay attributed to erythrocytes are found
within reticuocytes and are nucear or cytopasmic remnants derived
from ate-stage erythrobasts. In patients who have undergone spenec-
tomy, they may aso be found in mature erythrocytes.
RED CELL INCLUSIONS
See Fig. 1-11 for images of red ce incusions.
Howell-Jolly Bodies
Howe-Joy bodies are sma nucear remnants that have the coor of a
pyknotic nuceus on Wright-stained fims and show a positive Feugen
reaction for DNA.35,36 They are sphericay shaped, randomy distrib-
uted in the red ce, and usuay no arger than 0.5 μm in diameter.
Howe-Joy bodies may be numerous, athough ony one is usuay
present. In pathoogic situations, they appear to represent chromo-
somes that have separated from the mitotic spinde during abnorma
mitosis, and they contain a high proportion of centromeric materia
aong with heterochromatin. More commony, during norma matura-
tion they arise from nucear fragmentation or incompete expusion of
the nuceus. Howe-Joy bodies are pitted from the reticuocytes dur-
ing their transit through the interendotheia sits of the spenic sinus.
They are characteristicay present in the bood of persons who have
undergone spenectomy and in patients with megaobastic anemia, and
hypospenic states.
Pocked (or Pitted) Red Cells
When viewed by interference-phase microscopy, pocked red ces
appear to have surface membrane “pits” or craters.37-39 The vesices or
indentations characterizing these ces represent autophagic vacuoes
adjacent to the ce membrane. The vacuoes appear to be instrumen-
ta in disposa of ceuar debris as the erythrocyte passes through the
microcircuation of the speen. Within 1 week after spenectomy, a
patient’s pocked red ce counts begin to rise, reaching a pateau at
2 to 3 months. Pocked red bood ce counts are sometimes used as a
surrogate test for spenic function.
Cabot Rings
The ring-ike or figure-of-eight structures sometimes seen in meg-
aobastic anemia within reticuocytes and in an occasiona, heaviy
stipped, ate-intermediate megaobast are designated Cabot rings.40,41
Their composition is nucear. Some investigators have suggested that
Cabot rings originate from spinde materia that was mishanded dur-
ing abnorma mitosis. Others have found no indication of DNA or
spinde fiaments but have shown the rings are associated with adher-
ent granuar materia containing arginine-rich histone and nonhemo-
gobin iron.
Another random document with
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The Project Gutenberg eBook of Divots
 This ebook is for the use of anyone anywhere in the United
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Title: Divots

Author: P. G. Wodehouse

Release date: November 25, 2023 [eBook #72227]

Language: English

Original publication: United States: George H. Doran Company,

1927

Credits: Aaron Adrignola, Tim Lindell and the Online Distributed

Proofreading Team at https://www.pgdp.net (This book
was produced from images made available by the
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*** START OF THE PROJECT GUTENBERG EBOOK DIVOTS ***

 DIVOTS
P. G. WODEHOUSE
 By P. G. WODEHOUSE

CARRY ON, JEEVES!

HE RATHER ENJOYED IT
BILL THE CONQUEROR
GOLF WITHOUT TEARS
JEEVES
LEAVE IT TO PSMITH
MOSTLY SALLY
THREE MEN AND A MAID
INDISCRETIONS OF ARCHIE
THE LITTLE WARRIOR
A DAMSEL IN DISTRESS
 DIVOTS
BY
P. G. WODEHOUSE

NEW YORK
GEORGE H. DORAN
COMPANY
COPYRIGHT, 1923, 1924, 1925, 1926 AND 1927,
BY P. G. WODEHOUSE

DIVOTS
—B—
PRINTED IN THE UNITED STATES OF AMERICA
 TO
My Daughter
LEONORA
WITHOUT WHOSE NEVER-FAILING
SYMPATHY AND ENCOURAGEMENT
THIS BOOK
WOULD HAVE BEEN FINISHED
IN
HALF THE TIME
 PREFACE
Before leading the reader out on to this little nine-hole course, I
should like to say a few words on the club-house steps with regard to
the criticisms of my earlier book of Golf stories, The Clicking of
Cuthbert. In the first place, I noticed with regret a disposition on the
part of certain writers to speak of Golf as a trivial theme, unworthy of
the pen of a thinker. In connection with this, I can only say that right
through the ages the mightiest brains have occupied themselves
with this noble sport, and that I err, therefore, if I do err, in excellent
company.
Apart from the works of such men as James Braid, John Henry
Taylor and Horace Hutchinson, we find Publius Syrius not disdaining
to give advice on the back-swing (“He gets through too late who
goes too fast”); Diogenes describing the emotions of a cheery player
at the water-hole (“Be of good cheer. I see land”); and Doctor Watts,
who, watching one of his drives from the tee, jotted down the
following couplet on the back of his score-card:

Fly, like a youthful hart or roe,

Over the hills where spices grow.

And, when we consider that Chaucer, the father of English poetry,

inserted in his Squiere’s Tale the line

Therefore behoveth him a ful long spoone

(though, of course, with the modern rubber-cored ball an iron would

have got the same distance) and that Shakespeare himself,
speaking querulously in the character of a weak player who held up
an impatient foursome, said:

Four rogues in buckram let drive at me

we may, I think, consider these objections answered.

A far more serious grievance which I have against my critics is that
many of them confessed to the possession of but the slightest
knowledge of the game, and one actually stated in cold print that he
did not know what a niblick was. A writer on golf is certainly entitled
to be judged by his peers—which, in my own case, means men who
do one good drive in six, four reasonable approaches in an eighteen-
hole round, and average three putts per green: and I think I am
justified in asking of editors that they instruct critics of this book to
append their handicaps in brackets at the end of their remarks. By
this means the public will be enabled to form a fair estimate of the
worth of the volume, and the sting in such critiques as “We laughed
heartily while reading these stories—once—at a misprint” will be
sensibly diminished by the figures (36) at the bottom of the
paragraph. While my elation will be all the greater should the words
“A genuine masterpiece” be followed by a simple (scr.).

One final word. The thoughtful reader, comparing this book with
The Clicking of Cuthbert, will, no doubt, be struck by the poignant
depth of feeling which pervades the present volume like the scent of
muddy shoes in a locker-room: and it may be that he will conclude
that, like so many English writers, I have fallen under the spell of the
great Russians.
This is not the case. While it is, of course, true that my style owes
much to Dostoievsky, the heart-wringing qualities of such stories as
“The Awakening of Rollo Podmarsh” and “Keeping in with Vosper” is
due entirely to the fact that I have spent much time recently playing
on the National Links at Southampton, Long Island, U.S.A. These
links were constructed by an exiled Scot who conceived the dreadful
idea of assembling on one course all the really foul holes in Great
Britain. It cannot but leave its mark on a man when, after struggling
through the Sahara at Sandwich and the Alps at Prestwick, he finds
himself faced by the Station-Master’s Garden hole at St. Andrew’s
and knows that the Redan and the Eden are just round the corner.
When you turn in a medal score of a hundred and eight on two
successive days, you get to know something about Life.

And yet it may be that there are a few gleams of sunshine in the
book. If so, it is attributable to the fact that some of it was written
before I went to Southampton and immediately after I had won my
first and only trophy—an umbrella in a hotel tournament at Aiken,
South Carolina, where, playing to a handicap of sixteen, I went
through a field consisting of some of the fattest retired businessmen
in America like a devouring flame. If we lose the Walker Cup this
year, let England remember that.
P. G. WODEHOUSE
The Sixth Bunker
Addington
 CONTENTS
CHAPTER PAGE
I THE HEART OF A GOOF 15
II HIGH STAKES 51
III KEEPING IN WITH VOSPER 85
IV CHESTER FORGETS HIMSELF 116
V THE MAGIC PLUS FOURS 153
VI THE AWAKENING OF ROLLO PODMARSH 183
VII RODNEY FAILS TO QUALIFY 210
VIII JANE GETS OFF THE FAIRWAY 246
IX THE PURIFICATION OF RODNEY SPELVIN 283
DIVOTS
 CHAPTER I
THE HEART OF A GOOF

It was a morning when all nature shouted “Fore!” The breeze, as it

blew gently up from the valley, seemed to bring a message of hope
and cheer, whispering of chip-shots holed and brassies landing
squarely on the meat. The fairway, as yet unscarred by the irons of a
hundred dubs, smiled greenly up at the azure sky; and the sun,
peeping above the trees, looked like a giant golf-ball perfectly lofted
by the mashie of some unseen god and about to drop dead by the
pin of the eighteenth. It was the day of the opening of the course
after the long winter, and a crowd of considerable dimensions had
collected at the first tee. Plus fours gleamed in the sunshine, and the
air was charged with happy anticipation.
In all that gay throng there was but one sad face. It belonged to
the man who was waggling his driver over the new ball perched on
its little hill of sand. This man seemed careworn, hopeless. He gazed
down the fairway, shifted his feet, waggled, gazed down the fairway
again, shifted the dogs once more, and waggled afresh. He waggled
as Hamlet might have waggled, moodily, irresolutely. Then, at last,
he swung, and, taking from his caddie the niblick which the intelligent
lad had been holding in readiness from the moment when he had
walked on to the tee, trudged wearily off to play his second.
The Oldest Member, who had been observing the scene with a
benevolent eye from his favourite chair on the terrace, sighed.
“Poor Jenkinson,” he said, “does not improve.”
“No,” agreed his companion, a young man with open features and
a handicap of six. “And yet I happen to know that he has been taking
lessons all the winter at one of those indoor places.”
“Futile, quite futile,” said the Sage with a shake of his snowy head.
“There is no wizard living who could make that man go round in an
average of sevens. I keep advising him to give up the game.”
“You!” cried the young man, raising a shocked and startled face
from the driver with which he was toying. “You told him to give up
golf! Why I thought—”
“I understand and approve of your horror,” said the Oldest
Member, gently. “But you must bear in mind that Jenkinson’s is not
an ordinary case. You know and I know scores of men who have
never broken a hundred and twenty in their lives, and yet contrive to
be happy, useful members of society. However badly they may play,
they are able to forget. But with Jenkinson it is different. He is not
one of those who can take it or leave it alone. His only chance of
happiness lies in complete abstinence. Jenkinson is a goof.”
“A what?”
“A goof,” repeated the Sage. “One of those unfortunate beings
who have allowed this noblest of sports to get too great a grip upon
them, who have permitted it to eat into their souls, like some
malignant growth. The goof, you must understand, is not like you
and me. He broods. He becomes morbid. His goofery unfits him for
the battles of life. Jenkinson, for example, was once a man with a
glowing future in the hay, corn, and feed business, but a constant
stream of hooks, tops, and slices gradually made him so diffident
and mistrustful of himself, that he let opportunity after opportunity
slip, with the result that other, sterner, hay, corn, and feed merchants
passed him in the race. Every time he had the chance to carry
through some big deal in hay, or to execute some flashing coup in
corn and feed, the fatal diffidence generated by a hundred rotten
rounds would undo him. I understand his bankruptcy may be
expected at any moment.”
“My golly!” said the young man, deeply impressed. “I hope I never
become a goof. Do you mean to say there is really no cure except
giving up the game?”
The Oldest Member was silent for a while.
“It is curious that you should have asked that question,” he said at
last, “for only this morning I was thinking of the one case in my
experience where a goof was enabled to overcome his deplorable
malady. It was owing to a girl, of course. The longer I live, the more I
come to see that most things are. But you will, no doubt, wish to hear
the story from the beginning.”
The young man rose with the startled haste of some wild creature,
which, wandering through the undergrowth, perceives the trap in his
path.
“I should love to,” he mumbled, “only I shall be losing my place at
the tee.”
“The goof in question,” said the Sage, attaching himself with quiet
firmness to the youth’s coat-button, “was a man of about your age,
by name Ferdinand Dibble. I knew him well. In fact, it was to me—”
“Some other time, eh?”
“It was to me,” proceeded the Sage, placidly, “that he came for
sympathy in the great crisis of his life, and I am not ashamed to say
that when he had finished laying bare his soul to me there were tears
in my eyes. My heart bled for the boy.”
“I bet it did. But—”
The Oldest Member pushed him gently back into his seat.
“Golf,” he said, “is the Great Mystery. Like some capricious
goddess—”
The young man, who had been exhibiting symptoms of
feverishness, appeared to become resigned. He sighed softly.
“Did you ever read ‘The Ancient Mariner’?” he said.
“Many years ago,” said the Oldest Member. “Why do you ask?”
“Oh, I don’t know,” said the young man. “It just occurred to me.”

Golf (resumed the Oldest Member) is the Great Mystery. Like

some capricious goddess, it bestows its favours with what would
appear an almost fat-headed lack of method and discrimination. On
every side we see big two-fisted he-men floundering round in three
figures, stopping every few minutes to let through little shrimps with
knock knees and hollow cheeks, who are tearing off snappy seventy-
fours. Giants of finance have to accept a stroke per from their junior
clerks. Men capable of governing empires fail to control a small,
white ball, which presents no difficulties whatever to others with one
ounce more brain than a cuckoo-clock. Mysterious, but there it is.
There was no apparent reason why Ferdinand Dibble should not
have been a competent golfer. He had strong wrists and a good eye.
Nevertheless, the fact remains that he was a dub. And on a certain
evening in June I realised that he was also a goof. I found it out quite
suddenly as the result of a conversation which we had on this very
terrace.
I was sitting here that evening thinking of this and that, when by
the corner of the clubhouse I observed young Dibble in conversation
with a girl in white. I could not see who she was, for her back was
turned. Presently they parted and Ferdinand came slowly across to
where I sat. His air was dejected. He had had the boots licked off
him earlier in the afternoon by Jimmy Fothergill, and it was to this
that I attributed his gloom. I was to find out in a few moments that I
was partly but not entirely correct in this surmise. He took the next
chair to mine, and for several minutes sat staring moodily down into
the valley.
“I’ve just been talking to Barbara Medway,” he said, suddenly
breaking the silence.
“Indeed?” I said. “A delightful girl.”
“She’s going away for the summer to Marvis Bay.”
“She will take the sunshine with her.”
“You bet she will!” said Ferdinand Dibble, with extraordinary
warmth, and there was another long silence.
Presently Ferdinand uttered a hollow groan.
“I love her, dammit!” he muttered brokenly. “Oh, golly, how I love
her!”
 I was not surprised at his making me the recipient of his
confidences like this. Most of the young folk in the place brought
their troubles to me sooner or later.
“And does she return your love?”
“I don’t know. I haven’t asked her.”
“Why not? I should have thought the point not without its interest
for you.”
Ferdinand gnawed the handle of his putter distractedly.
“I haven’t the nerve,” he burst out at length. “I simply can’t
summon up the cold gall to ask a girl, least of all an angel like her, to
marry me. You see, it’s like this. Every time I work myself up to the
point of having a dash at it, I go out and get trimmed by some one
giving me a stroke a hole. Every time I feel I’ve mustered up enough
pep to propose, I take ten on a bogey three. Every time I think I’m in
good mid-season form for putting my fate to the test, to win or lose it
all, something goes all blooey with my swing, and I slice into the
rough at every tee. And then my self-confidence leaves me. I
become nervous, tongue-tied, diffident. I wish to goodness I knew
the man who invented this infernal game. I’d strangle him. But I
suppose he’s been dead for ages. Still, I could go and jump on his
grave.”
It was at this point that I understood all, and the heart within me
sank like lead. The truth was out. Ferdinand Dibble was a goof.
“Come, come, my boy,” I said, though feeling the uselessness of
any words. “Master this weakness.”
“I can’t.”
“Try!”
“I have tried.”
He gnawed his putter again.
“She was asking me just now if I couldn’t manage to come to
Marvis Bay, too,” he said.
 “That surely is encouraging? It suggests that she is not entirely
indifferent to your society.”
“Yes, but what’s the use? Do you know,” a gleam coming into his
eyes for a moment, “I have a feeling that if I could ever beat some
really fairly good player—just once—I could bring the thing off.” The
gleam faded. “But what chance is there of that?”
It was a question which I did not care to answer. I merely patted
his shoulder sympathetically, and after a little while he left me and
walked away. I was still sitting there, thinking over his hard case,
when Barbara Medway came out of the club-house.
She, too, seemed grave and pre-occupied, as if there was
something on her mind. She took the chair which Ferdinand had
vacated, and sighed wearily.
“Have you ever felt,” she asked, “that you would like to bang a
man on the head with something hard and heavy? With knobs on?”
I said I had sometimes experienced such a desire, and asked if
she had any particular man in mind. She seemed to hesitate for a
moment before replying, then, apparently, made up her mind to
confide in me. My advanced years carry with them certain pleasant
compensations, one of which is that nice girls often confide in me. I
frequently find myself enrolled as a father-confessor on the most
intimate matters by beautiful creatures from whom many a younger
man would give his eye-teeth to get a friendly word. Besides, I had
known Barbara since she was a child. Frequently—though not
recently—I had given her her evening bath. These things form a
bond.
“Why are men such chumps?” she exclaimed.
“You still have not told me who it is that has caused these harsh
words. Do I know him?”
“Of course you do. You’ve just been talking to him.”
“Ferdinand Dibble? But why should you wish to bang Ferdinand
Dibble on the head with something hard and heavy with knobs on?”
“Because he’s such a goop.”