Immune hemolytic anemias

593 Pages·2004·20.49 MB·English

by  Lawrence D Petz

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Library of Congress Cataloging-in-Publication Data
Petz, Lawrence D.
Immune hemolytic anemias / Lawrence D. Petz, George Garratty.—2nd ed.
p. ; cm.
Rev. ed. of: Acquired immune hemolytic anemias. 1980.
Includes bibliographical references.
ISBN 0-443-08559-5
1. Hemolytic anemia, Autoimmune. I. Garratty, George. II. Petz, Lawrence D. Acquired
immune hemolytic anemias. III. Title.
[DNLM: 1. Anemia, Hemolytic, Autoimmune. WH 170 P513i 2004]
RC641.7.H4P47 2004
616.1′52—dc21
2003043767
Printed in United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Preface to the Second Edition
We thought we might have set a record for the longest time between editions of a
book, since the first edition of this book, entitled Acquired Immune Hemolytic Anemias,
was published 24 years ago. However, our mentor, Professor Sir John Dacie, published
the third edition of Autoimmune Haemolytic Anaemias (Volume 3 of The Haemolytic
Anemias) in 1992, just 30 years after the publication of the previous edition of that
volume!
We have been flattered during these long years by a number of physicians,
immunohematologists, and blood bankers who insist that they still use the first edition
and have continued to press us for the second. As with the first edition, this book is
intended primarily as a useful source of information for those who care for patients
who have immune hemolytic anemias, that is, clinicians with patient care responsibil-
ity and blood bank professionals, including physicians and technical staff. However,
this purpose cannot be properly served without an adequately detailed scientific back-
ground, and we have endeavored to supply this. We have attempted to be rather com-
prehensive, but we do not intend this book to be only a reference volume and have
therefore included practical aspects of the evaluation and management of patients with
hemolysis.
Patients with immune hemolytic anemias are sufficiently common as to constitute
an important problem, but, on the other hand, they are sufficiently unusual that it is dif-
ficult for many individuals outside of referral centers to acquire adequate experience to
feel at ease in managing the multitude of problems such patients may present. We
earnestly hope that sharing our experiences through the medium of this book will be of
value to others who confront such problems less commonly.
During the years between editions of this text, medical disciplines that were rather
early in their developmental stages, such as hematopoietic cell and solid organ trans-
plantation, have emerged to be major components of health care and have contributed
to the emergence of entirely new causes of immune hemolysis. Also, new “generations”
of drugs have been developed, one of the consequences of which is an expansion of the
causes of drug-induced immune hemolytic anemias. Molecular biology and DNA
technology have evolved to become a part of our everyday scientific lives and are being
utilized in hematology as in all other disciplines. We have attempted to bring our first
edition up to date while not ignoring important earlier contributions. We have added
chapters on Historical Concepts of Immune Hemolytic Anemias, Hemolytic Disease of
the Fetus and Newborn, Immune Hemolysis Associated with Transplantation, and
Hemolytic Transfusion Reactions.
As we emphasized in the preface to the first edition, one of the important aspects
of diagnosis and management of patients with immune hemolytic anemias is that the
care of such patients depends on a knowledge of some aspects of both clinical and
laboratory medicine. Although this is true throughout clinical medicine, a problem of
particular magnitude is created by the need for clinicians to be able to interpret such
unusual laboratory tests as the direct antiglobulin test with monospecific antiglobulin
sera and the specificity and thermal range of allo- and autoantibodies. Similarly,
vi Preface to the Second Edition
laboratory personnel should be able to assist clinicians in the interpretation of import-
ant data, as when transfusion is indicated for a patient whose serum reacts with all
RBCs in compatibility tests. Accordingly, one of the primary purposes of this book is to
present both the clinical and laboratory aspects of immune hemolytic anemias in a
single volume. We strongly feel that neither laboratory personnel (including physi-
cians) nor clinicians can optimally contribute to the care of patients with immune
hemolytic anemias without a firm understanding of both aspects of the subject.
Lawrence D. Petz
George Garratty
Preface to the First Edition
This book is intended to be a useful source of information for those who care for
patients who have immune hemolytic anemias, i.e., clinicians with primary responsi-
bility for patient management, physicians concerned with laboratory medicine, includ-
ing blood bank directors, and the technical staff of such laboratories. It is not intended
as an encyclopedic review or as a “tour de force” exposition of facts that are of interest
primarily to those with extensive background and a highly specialized interest in the
field.
Patients with immune hemolytic anemias are sufficiently common as to constitute
an important problem but, on the other hand, are sufficiently unusual that it is difficult
for many individuals outside of referral centers to acquire adequate experience to feel
at ease in managing the multitude of problems such patients may present. We have had
a special interest in these disorders and we earnestly hope that sharing our experiences
through the medium of this book will be of value to others who confront such problems
less commonly. We include previously unpublished data concerning our experiences
with various phases of the diagnosis and management of more than 300 patients, as
well as a review of relevant information available in the medical literature.
Although the primary purpose of this book is, therefore, to be a source of informa-
tion that will be of value in management of patients, this purpose cannot be adequately
served merely by a superficial exposition of “practical” facts, and we do not intend this
book to be a manual of patient care. We trust that the interested reader would demand
an adequately detailed scientific background to make meaningful the recommended
laboratory procedures and their clinical interpretation. For example, the knowledge
that the direct antiglobulin (Coombs’) test performed on red cells from patients with
cold agglutinin syndrome is invariably positive using anit-C3d antiglobulin serum and
invariably negative using anti-IgG antiglobulin serum is of some clinical value (Ch. 6).
When such information is augmented by an understanding of pertinent aspects of the
serum complement system (Ch. 3) and the mechanisms of immune hemolysis (Ch. 4),
one then has a basis for understanding such facts and their clinical significance.
Writing this book presents a unique problem. That is, one of the important aspects
of diagnosis and management of patients with immune hemolytic anemias is that the
care of such patients depends upon a knowledge of some aspects of both clinical and
laboratory medicine. Although this is true throughout medicine, a problem of unusual
magnitude is created by the fact that most clinicians have very little exposure to
immunohematology. Results of direct antiglobulin tests with monospecific antiglobulin
sera and the characterization of serum antibody specificity and thermal range is
information that is difficult or impossible for most practicing physicians to utilize. This
problem is augmented by the fact that laboratory personnel are faced with difficult
technical tasks, and, in the very best of hands, uncertainties may remain. For example,
in regard to blood transfusion (Ch. 10), what is the probability of not detecting a red cell
alloantibody in the serum of a patient with autoimmune hemolytic anemia when the
serum reacts with all donor cells tested, and what is the risk of transfusion of blood that
is incompatible because of the presence of an autoantibody? One of the prime purposes
viii Preface to the First Edition
of this book, and one of the more difficult tasks we faced in writing it, is to present both
the laboratory and clinical aspects of immune hemolytic anemias in a single volume in
a manner that is understandable by those in both fields. Neither laboratory personnel
(including physicians) nor clinicians can optimally contribute to the care of patients
with immune hemolytic anemias without an understanding of both aspects of the
subject. Therefore, it is our firm opinion that, with few exceptions (e.g., some sections
concerning technical details which may justifiably be ignored by clinicians, and some
aspects of therapy which may not be essential knowledge for technologists), the infor-
mation herein is important to those in both clinical and laboratory medicine for proper
management of patients with immune hemolytic anemias.
Lawrence D. Petz
George Garratty
Acknowledgments
As indicated in the first edition, we are both indebted to Professor Sir John Dacie
for the privilege of working in his laboratory at the Royal Postgraduate Medical School
and Hammersmith Hospital in London. His teachings served as a foundation for our
work and, moreover, we have attempted to emulate his dedication and precision in
scientific investigation.
Grateful acknowledgment is also due to the numerous physicians and technolo-
gists who were kind enough to refer interesting and challenging clinical and laboratory
problems to us. Without this continued support it would have been impossible to
acquire the experience and data necessary to compile this volume. In addition, we
appreciate the collaboration of our colleagues at the City of Hope Medical Center,
Duarte, California, and the University of California Los Angeles Medical Center
(Dr. Petz) and American Red Cross Blood Services, Southern California Region
(Dr. Garratty).
We would especially like to thank some extraordinary medical technologists who
were not just a “pair of hands” in the laboratory but were innovative contributors to the
design and results of our studies: Donald Branch (now the proud possessor of a PhD);
Alana (Loni) Calhoun, Patricia Arndt, Regina Leger, Sandra Nance, and Nina Postoway.
Their relevant roles were obvious from our publications mentioned throughout the
book. Dr. Garratty would especially like to thank Ann Tunick, his administrative assist-
ant (since 1978), who typed multiple error-free drafts of material, found and formatted
references, and dealt imperturbably with all problems that arose. Without her help
Dr. Garratty’s contributions would never have appeared in this book!
Both of us would like to acknowledge the tremendous support of our wives
(Thelma Petz and Eileen Garratty), who put up with our working every weekend and
many evenings without too many grumbles!
C H A P T E R 1
Historical Concepts
of Immune Hemolytic
Anemias
Immune hemolysis is a short- process of agglutination, understanding the distinction
ening of red blood cell (RBC) between congenital and acquired disorders, under-
survival due, directly or indi- standing that premature destruction of RBCs can cause
rectly, to antibodies. These anti- anemia and jaundice, recognizing spherocytes and
bodies may be autoantibodies abnormal osmotic fragility of RBCs and determining
or alloantibodies. This chapter their significance in patients with hemolysis, recogniz-
will deal mainly with historical ing reticulocytes, determining that serum antibodies
aspects of autoimmune hemo- may cause destruction of foreign cells and also autolo-
lytic anemia (AIHA), followed gous cells, developing means to measure RBC survival,
by a brief discussion of histori- developing diagnostic assays for antibodies, refuting
cal aspects of hemolytic transfusion reactions. the concept of horror autotoxicus, and understanding the
AIHAis an acquired immunologic disease in which role of the spleen and splenectomy.
the patient’s RBCs are selectively attacked and The discoveries that led to the development of our
destroyed (hemolysed) by autoantibodies produced knowledge about these concepts are herein reviewed
by the patient’s own immune system. Shortened RBC in the approximate order in which the relevant obser-
survival is frequently associated with the presence of vations were made. Here, then, is how our knowledge
a reticulocytosis, spherocytes in the peripheral blood of AIHA came to be. The development of this short
film, autoantibodies in the patient’s serum, and occa- review was aided significantly by previous reviews on
sionally splenomegaly, hemoglobinemia, and hemo- various aspects of hemolysis and AIHA.1-9
globinuria. Although these facts are common
knowledge now, it was not always so. Reviewing how THE LESSONS OF HISTORY
these concepts developed over the centuries by obser-
vation and clinical and laboratory experimentation is
both fascinating and instructive. Everyone who studies the stories of discovery in what
It is evident that concepts that collectively led to our has come to be called the field of hematology will rec-
present understanding of AIHArequired knowledge of ognize the early gropings in the midst of profound
the existence of RBCs, understanding the possibility of ignorance and the difficulties that confronted the
anemia without blood loss, distinguishing hemoglo- investigators. We have gained an understanding of
binuria from hematuria, understanding the mechanism biology that could hardly have been dreamed of only
by which hemoglobinuria occurs, recognizing the a short time ago, let alone at the time of the first
1
2 Immune Hemolytic Anemias
tentative forays into the unknown. Moreover, under- did they fail to make mistakes. Indeed, incorrect
standing has been crowned by tangible benefits for theories have hampered the advance of knowledge,
humanity. It is worthwhile to consider how such great especially when these theories were widely dissemin-
progress comes about and why. How is knowledge ated and were pronounced by eminent authorities. A
achieved, and what can we learn from the process by number of such examples appear in the following
which important discoveries were made?10 pages.
The first lesson to be learned of history is that the It follows that authorities must be humble and
path of progress is anything but straight. The course novices skeptical.
of research has been likened to the flow of a stream
that ultimately becomes a rushing torrent whose
importance is obvious. This certainly has been the EARLIEST DESCRIPTIONS OF POSSIBLE
history of research in hematology. ACQUIRED HEMOLYTIC ANEMIA
It certainly does not follow that, because a concept
is plausible and is in accord with the understanding of
the time, it is necessarily correct. The following pages The first written description of what may have been
provide many examples of misinterpretations result- an acquired hemolytic anemia, albeit not of an
ing from such an assumption. Furthermore, because immune nature, was Galen’s description in 150 AD of
they have been plausible, such views often have a person bitten by a viper whose “skin turned the
endured and have stood in the way of acceptance of color of a ripe leek.”1,4,11 Galen’s understanding of
observations and interpretations that proved to be the physiology was such that he implicated the spleen as
correct ones. leading to the skin discoloration, an association of the
Discovery begins with an observation or the posing spleen and hemolysis that was not confirmed until the
of a question. But observation is not as simple as it late nineteenth century.1
sounds. Indeed, many look but few see. It is the excep- PCH may have been described as early as 1529 by
tional person who recognizes the unusual event or Johannes Actuarius, a court physician in Constan-
manifestation. Still fewer pursue it to new under- tinople. In his work, De Urinis, Acturarius described a
standing. Many may ask questions but few have the condition in which the urine is “azure & livid as well
imagination, the energy, and the overpowering drive as black” in patients being of melancholic humor and
to persist in the search for an answer, especially when complaining of loss of strength, after an exposure to
this must be done in the face of difficulties and fail- cold.4Further mention of PCH seems, however, to be
ures and even despite scorn from their peers. absent for nearly 300 years, until the latter half of the
Imagination and industry alone, however, have not nineteenth century.
sufficed. Means have had to be devised to explore the
questions that were posed. When these were provided,
it is impressive to see what the introduction of a new EARLY EXPERIMENTAL
technique made possible for an area of inquiry. A INVESTIGATION OF BLOOD
simple example, described later, is the introduction of
the antiglobulin test, which very rapidly led to a much
clearer distinction between immune and nonimmune Description of Red Blood Cells.The development of
hemolytic anemias. the scientific method led to the seminal discoveries of
Progress depends on the contributions of many. the circulation of blood by Harvey in the early sixteenth
Moreover, scientific discipline has benefited from century and the cardinal experiments with transfusion
developments in other fields, progress in one field of blood by Lower in England and Denis in Paris in the
spurring another, and vice versa. As knowledge has mid-seventeenth century. Despite this interest in blood,
grown, it has become impossible for a single human the discovery of the RBCs had to await the appearance
being to encompass the whole, and the discovery and of the microscope around 1650. The first observation of
growth of understanding have become more and more an RBC was likely made by Malpighi in 1661, when he
dependent on interchange among scientific disciplines. described the circulation of RBCs in the capillaries, and
Still another aspect of the progress of understand- this was followed in 1663 by Swammerdan’s descrip-
ing is worth noting. It is not generally appreciated tion of minute globules in the blood of a frog. Adecade
how often curiosity concerning an observation made later, human RBCs were described in detail by van
at the bedside by clinicians has led to far-reaching Leeuwenhoek (Fig. 1-1),12 who also established their
investigations. An example is the observation size at about 1⁄ of an inch by comparing an RBC with
3000
of hemoglobinuria, which led to the understanding of a grain of sand of known size.
destruction of RBCs and to the early delineation of John Huxham, in 1770, described the changing
certain clinical syndromes (e.g., paroxysmal cold shapes of degenerating RBCs and, importantly, recog-
hemoglobinuria [PCH], paroxysmal nocturnal hemo- nized that such cells were the origin of hemoglobin.4
globinuria [PNH], and march hemoglobinuria) char- Anemia without Blood Loss. In 1843, Andral
acterized by hemoglobin in the urine. (Fig. 1-2) described a spontaneous anemia, which
Investigators have not always been farseeing and arises without any prior blood loss.13 He quantified
logical, moving steadily and directly to their goal, nor red blood globules in healthy patients and reported
Historical Concepts of Immune Hemolytic Anemias 3
FIGURE 1-1. Antonj van Leeuwenhoek (1632–1723). (From
Wintrobe MM: Milestones on the path of progess. In: Wintrobe
MM (ed): Blood, Pure and Eloquent. New York: McGraw-Hill Book
Company, 1980:1–31.)
FIGURE 1-2. Gabriel Andral (1797–1876). (From Wintrobe MM:
Milestones on the path of progress. In: Wintrobe MM (ed): Blood,
Pure and Eloquent. New York: McGraw-Hill Book Company,
1980:1–31.)
4 Immune Hemolytic Anemias
16 early case of anemia. Although he provided no
other information concerning the patients’ condition,
what is important in relation to hemolytic anemia is
the observation of anemia without prior blood loss.
Hemoglobinuria. Vogel, in 1853,14 stated that the
matter in the urine is the same as that in the blood and
suggested that the matter in the urine consists of a
“decomposition of blood discs.” He suggested that
the degree of blood decomposition can readily be
ascertained by the degree of coloration in the urine,
and he indicated a connection between fevers, colored
urine, decomposition of blood discs, and anemia. This
represents one of the early examples of the association
between a decreased RBC count and the term anemia.
It also represents early evidence suggesting that
anemia may be secondary to infections.
RED BLOOD CELL AGGLUTINATION
The description of the phenomenon of RBC agglutina-
tion and its development as a tool in elucidating blood
groups took place in the last 30 years of the nineteenth
century in Germany and Austria, and were reviewed in
depth in 2002 by Hughes-Jones and Gardner.15The dis-
coveries were largely the work of three people: Adolf
Creite, a medical student in Göttingen, Germany;
Leonard Landois, Director of the Physiological Institute FIGURE 1-3. Adolf Creite, about 1920. (From Hughes-Jones NC,
Gardner B: Red cell agglutination: The first description by Creite (1869)
at the University of Greifswald, Germany; and Karl
and further observations made by Landois (1875) and Landsteiner
Landsteiner, working in the Pathological Anatomy
(1901). Br J Haematol 2002;119:889–893.)
Institute in Vienna, Austria.15
Adolph Creite. Creite’s (Fig. 1-3) almost unknown
contribution was published in 1869 under the title
“Investigations concerning the properties of serum
proteins following intravenous injection.”16 His work fresh rabbit blood, then you observe under the micro-
is quite remarkable in that it showed that serum pro- scope that in the regions where the foreign serum
teins had the property of both “dissolving” and bring- mixes with the rabbit red cells, the cells suddenly flow
ing about “clustering” of red cells, that is, lysis and together in a peculiar way forming different shaped
agglutination in present-day terms, anticipating the drop-like clusters with irregular branches. I believed
discovery of antibodies by a quarter of a century. that I had found an explanation for the appearance of
Creite injected sera from calf, pig, dog, sheep, cat, blood in the urine, as it was possible that some blood
chicken, duck, and goat into rabbits. The first three cells had dissolved completely.”
had little or no effect on the recipient, but the sera of Leonard Landois.RBC agglutination and lysis were
the latter five almost always resulted in the appear- put on an even firmer basis by Landois, who pub-
ance of “blood-stained urine,” general malaise, and lished an extensive monograph on the subject of
death of the animal. He noted that the urine was free transfusion,17which included a section describing his
of intact RBCs. He concluded that serum contains in vitro experiments. In his experiments, Landois was
agents that are able to dissolve red cells “directly.” He successful in demonstrating both lysis and agglutina-
performed additional experiments in which he tion. (It should be noted that the terms lysisand agglu-
removed protein from the serum before its injection tinationwere not in use until the end of the nineteenth
and observed that “all of the urine samples examined century. For lysis, both Creite and Landois used a
until the evening of the following day are normal.” German word meaning “dissolve”; for agglutination,
Accordingly, he concluded that the most likely words translatable as “accumulation,” “ball forma-
active ingredients were serum proteins, but added, tion,” or “sticky clumps” were used.) Landois also
“However, I cannot say how they function.” distinguished agglutination from rouleaux, for which
He also performed in vitro experiments and pro- he used the term, “like rolls of coins.”
vided a remarkably clear account of what is probably Landois added 4 to 5 mLof clear serum into a test
the first description of agglutination. He reported, “If tube and then added fresh defibrinated blood. He
you add blood serum from any of the animals with incubated the mixture at 37°C to 38°C or at room tem-
which I have carried out my experiments to a drop of perature and observed the initiation of the RBC lysis.