Hematology. Landmark Papers of the Twentieth Century

1020 Pages·2000·40.15 MB·English

by  M.D., Marshall A. Lichtman, Jerry L. Spivak, Laurence A. Boxer, Sanford J. Shattil, and Edward S. Henderson, M.D. (Eds.)

Preface
Numbers ending in zero motivate people. Thus, the year of the brain to the mind to unravel, and a full application of
2000 is an attraction that is irresistible, provoking activities genetic manipulation to agriculture and human health. The
of a broad sort. Digit preference has had a strong influence basic knowledge required to achieve these goals, however,
on the affairs of Americans. We exuberantly celebrate events will have been generated in this century. Medicine has been
on anniversary years ending in zero, but not two or seven. one of the principal beneficiaries of the progress in science
The United States Census Bureau had to calculate age from and technology. Perhaps this is another reason for hematolo-
birth dates because when asked one's age respondents gists to examine the observations that advanced hematology
rounded to the nearest even rather than odd number, giving during this period.
a sawtoothed appearance to the age curves, even peaks and A few words about the process that was undertaken to
odd valleys. arrive at the articles that were chosen for reproduction. One
The attraction of the number 2000, and the hoopla that of us (MAL) developed a list of about 450 articles that was
surrounds it, accounts for our taking stock of the last one divided among eight categories: anemias, white cell disor-
hundred years in hematology as we approach the end of the ders, platelet disorders, disorders of hemostasis, hematologi-
century and the millennium. The participants in this en- cal malignancies, lymphocyte and immune disorders, trans-
deavor considered which reports over the last hundred years fusion medicine, and laboratory methods. The participants
have made a difference to the practitioners of hematology were asked to add any others they felt merited inclusion,
and the patients they serve. Once again, digit preference especially in the areas of their special expertness. Thereafter,
accounts for our choice of the one hundred-year period in- two commentators were asked to review the articles in the
voked. The century began on January 1, 1901 and, thus, ends areas of their particular interest. A photocopy of every rele-
on December 31, 2000, but few care to wait until January vant article was provided to the participants. The participants
2001 to celebrate or commemorate. That year has an odd made a preliminary estimate of priority for selection within
terminal digit and, like the census respondents, the world is each of the eight categories, and these results were shared
rounding down to an even number. with all the reviewers. A consensus developed around one
The twentieth century will be remembered as unprece- hundred and seven articles. Each commentator was asked to
dented in human history. Events of extraordinary conse- vote on inclusion or exclusion of these one hundred and
quence have occurred. On the darker side, the use of poison seven. The votes were tallied and reviewed by the partici-
gas on the battlefield, the only truly worldwide war (the pants at a subsequent meeting in Phoenix at which all were
second), the carefully premeditated, government-sponsored present. The charm of the Arizona Biltmore Hotel, where the
attempt at genocide, the Holocaust, and the unleashing of group met with Kerry Willis of Academic Press, was not
atomic weaponry. Paradoxically, the century has seen the muted by the midday June desert temperatures. The group
demise of many tyrannies and colonialism, a remarkable arrived at a final list of eighty-five papers. One substitution
increase in nation states and democratic governments, a and one addition were made after that meeting. The former
nearly unrestricted movement of peoples throughout the reflected a shift in favor of one among two important early
world, the relative success of the United Nations, and the reports on the treatment of Hodgkin's disease with radiation.
disappearance of geographic boundaries for corporate enter- The latter was the result of an inability to select between two
prises. Despite these and others epic events, the century will seminal but different approaches to the same topic, the iden-
be marked principally by the accomplishments of science tification of an erythropoietic activity in the blood.
and technology. In no other one hundred year period has Before our meeting in Phoenix, the list of one hundred
there been, or is there likely to be, an equivalent growth in and seven articles was circulated and a provisional mail vote
knowledge of the physical, engineering, and life sciences on inclusion or exclusion was made. We had made an arbi-
and their application to improve the human condition. There trary decision to limit the number of reproduced pages to
is still much to learn and do. There are great discoveries to about eighty articles of average length of about ten pages, or
be made, space to explore, commercial rocket planes to about eight hundred pages total. Of the one hundred and
develop, the further expansion of electronic communica- seven articles, sixty-six received votes for inclusion from
tions, cancer and other diseases to conquer, the relationship four or five participants; fourteen articles received votes of
~o
xviii
inclusion from three of five commentators. Ultimately, dis- Cancer Institute, and (4) the inclusion of prophylactic central
cussion of the reasoning for the choices resulted in the inclu- nervous system therapy with more comprehensive systemic
sion of eighty-five articles, with one added later, as noted therapy by the physicians at St. Jude Children's Research
earlier. Following the choice of the reports to be included, Hospital. Each was a step toward the cure of most afflicted
the papers were grouped into four categories. Twenty-six fell children.
into the category of description of a new disease or syn- We have tried in our commentaries on selected papers to
drome; nineteen papers were concerned with the pathophysi- provide some perspective on the antecedent and subsequent
ology of hematologic disease; twenty-three articles were events that led to or grew out of the landmark report. Indeed,
descriptions of advances in treatment; eighteen reports had in most cases, one should view the choice less as landmark
to do with introduction of laboratory or diagnostic tests. papers than landmark topics, which form the basis for the
Reducing the landmark papers in hematology to eighty- commentary. Again, the breadth of the task required arbitrary
six for this compendium required a series of arbitrary deci- boundaries in the selection of citations. We are not providing
sions. First, we focused on articles that pioneered the clinical medical or scientific reviews, rather commentary. The bibli-
description, pathogenesis, diagnosis, or treatment of disease. ography near the end of the book contains many, alas not all,
We could not encompass the basic sciences, pathological of the important observations or reports that advanced
insights, or all the laboratory developments that contributed knowledge as a precedent or derivative of the landmark
to the extraordinary growth of knowledge during the last articles.
century. Hematology is a laboratory-based discipline. Meas- In some of the earlier papers, one can sense the limited
urement is its hallmark. The engineering advances that have knowledge with which the observer was operating and the
led to the flow cytometer and the high-speed cell sorter, the insight required to recognize the importance of the observa-
immunologically based techniques to perform many impor- tion. One wonders, too, what took so long in some cases.
tant diagnostic tests, the molecular diagnostic techniques, Leeuwenhoek reported his observation of red cells in the
including the polymerase chain reaction, to improve diagno- blood using his newly crafted optical magnifying device in
sis and prognostication are examples of such important de- two letters written during April 1674. It took 236 years for
velopments. Although mentioned and sometimes cited in the James Herrick to report the misshapen cells of sickle cell
commentaries, the seminal report of each of these and other anemia and link them to a clinical disorder, despite its preva-
important developments are not included. The editors chose lence throughout the world. The struggles of Fanconi, Glan-
to limit their choices, where possible, to clinically relevant zmann, and von Willebrand are evident as they each grap-
advances. In a few cases, we selected articles that might be pled with what they recognized as new and different clinical
construed as basic science at the time of their publication. syndromes and tried to place them in the existing framework
We did so because they provided the basis for an extraordi- of the diseases recognized at that time. Their exhaustive (and
nary growth in knowledge that had broad clinical applica- sometimes exhausting) case-study approach seems ungainly
tion. The development of "stem cell" and progenitor cell by today's standards.
assays is an example of such advances. These discoveries Several treatises have considered: Who deserves credit
have enabled biomedical scientists to isolate, characterize, for a discovery? What represents a discovery? Why is dis-
and study generative marrow cells, previously inaccessible covery held in such esteem? Bessis and Delpech, in their
to the scientist or physician, to identify cytokines that influ- thought provoking article in 1981 in Blood Cells, defined
ence those cells that now are used in therapy, to advance pioneers, observers, investigators, discoverers, inventors,
stem cell transplantation, and to await advances in gene and forerunners, and delved into the difficulties in assigning
therapy. The interests of the individual commentator, al- credit, particularly in the distant past. The Editors weighed
though ideally subjugated to the task at hand, inevitably several factors in making their decisions about inclusion. In
influenced his decisions. choosing a Nobel or Pulitzer Prize winner, there is usually
Few meritorious developments come crisply from one no unambiguous or incontestable best choice; the best one
observation. The cure of childhood acute lymphocytic leuke- can do is choose one who is worthy, if not unique. So argued
mia is an example in which a series of drugs and approaches Arne Tiselius, himself a Nobel laureate in chemistry, when
over several decades were required to reach that goal. This he served later as Chair of the Nobel Foundation. We believe
is reflected, however, in four papers on the topic that ended the selected topics are worthy. We hope the reader derives
up in the list of eighty-six. These papers highlight (1) the pleasure and enlightenment from visiting or revisiting some
introduction of folate antagonists at the Boston Children's of the classic observations that brought us to where we are
Hospital, (2) the introduction of glucocorticoid hormones as in clinical hematology as we enter the next century and
therapeutic agents for hematological diseases mediated by millennium.
lymphocytes, (3) the success of four complementary drugs
in the initial therapy of childhood leukemia at the National Marshall A. Lichtman, M.D
Acknowledgments
We acknowledge the support and encouragement of five the approximately five hundred photocopies of articles of
participants in this project at Academic Press. Kerry Willis, initial interest. Many libraries in the United States and other
Ph.D. former Editor-in-Chief, Emelyn Eldridge, former Ac- countries provided reprints of articles for review. Of the
quisitions Editor, and Robert Harington, Executive Editor eighty-six articles reproduced, two were photographed at
and Manager, Life Sciences, James Mowery, Publication Johns Hopkins University School of Medicine, one at Albert
Services Manager, and Aaron Johnson, the Editorial Coordi- Einstein College of Medicine of Yeshiva University, and one
nator. at the State University of New York at Buffalo School of
Kerry Willis saw the potential merit of the work and Medicine and Biomedical Sciences. We are grateful for the
supported its initiation. Emelyn Eldridge enthusiastically help provided by those institutions.
picked up the responsibilities after Kerry left Academic Anne Birien translated two of the three papers from
Press. Robert Harington later assumed the responsibility and French to English, and Sabine Meyer and Ulrike Hagemann
provided excellent advice in developing the plans for the translated six articles from German to English. Each was a
final production. graduate student in linguistics at the University of Rochester
Tim Oliver copy-edited and typeset the commentaries, at the time. They accomplished this task very well despite
the translations, the bibliography of cited articles, the list of their unfamiliarity with some of the medical terminology.
reference sources, and the appendix, and made helpful sug- The excellent assistance of Susan M. Daley is acknow-
gestions during preparation of the book. ledged with gratitude. She entered into a database the nearly
Christopher Hoolihan, the History of Medicine Librarian five hundred articles of interest and stratified them by eight
in the Edward J. Miner Library, University of Rochester areas of hematology from which we made our selection of
Medical Center, provided invaluable aid. He acquired cer- eighty-six papers. She managed the database and the com-
tain early-in-the-century journals, assisted in the search for munications among the commentators in Ann Arbor, Balti-
information on authors or source books, supervised the pho- more, Buffalo, La Jolla, and Rochester throughout the proc-
tographic reproduction of eighty-two of the eighty-six arti- ess of article selection and preparation of the commentaries.
cles and thirty figures, and brought his knowledge to bear She arrayed the alphabetical list of about one thousand arti-
on the use of reference source material. Sandra Charchalis cles cited in the Bibliography. She also assisted with various
arranged all the interlibrary loans required for compilation of aspects of the editing process.
~ x
Acknowledgment of Permissions
from Publishers and Organizations
The following generously provided permission for the repro- Johns Hopkins University Press, Joumal of Intemal Medi-
duction of full articles or figures: Academic Press, American cine, S. Karger AG, Lippincott Williams & Wilkins, Macmil-
Academy of Pediatrics, American Association for the Ad- lan Magazines Limited, Lancet Limited, Massachusetts
vancement of Science, American Association for Cancer Re- Medical Society, Mayo Foundation, Minnesota Medical As-
search, American College of Physicians, American Medical sociation, Mosby-Year Book Incorporated, National Acad-
Association, American Pediatric Society, American Physi- emy of Sciences of the United States, Rockefeller University
ological Society, American Society of Clinical Investigation, Press, Radiological Society of America, W. B. Saunders
Blackwell Science Limited, BMJ Publishing Group, Elsevier Company Incorporated, F. K. Schattauer, Socirt6 de Biolo-
Science Limited, Intemational Engineering Consortium, gie of France, John Wiley and Sons Incorporated.
mti
page 6 Osier W (1903): Chronic cyanosis, with polycythemia and en-
C o MMEN TARY larged spleen: A new clinical entity. American Journal of the
Medical Sciences 126:187-201.
illiam Osler was not the first to describe the While Osler's emphasis on chronic cyanosis may seem
disorder that we now recognize as poly- strange to us since we associate this description with an
~ cythemia vera. With a generosity of spirit increase in deoxygenated hemoglobin, Osler understood that
sometimes lacking among academicians to- his patients were not hypoxemic. Rather, he considered the
day, he tightly assigned the "priority of description" to chronic cyanosis to be a consequence of an expanded red cell
Vaquez in 1892. Osler's important contribution, in keeping mass, an increased blood viscosity, a reduction in blood flow
with his characteristic clinical genius, was to promote the and dilation, and loss of tone in the peripheral veins, a
concept that the rare patients exhibiting erythrocytosis, contention which was substantiated forty years later (Alt-
chronic cyanosis, and splenomegaly whom he encountered in schule et al., 1940). Osier was also the first to link poly-
his practice and those that had been described in isolated case cythemia vera to erythromelalgia.
reports by Vaquez, Cabot, McKeen, and Saundby and Russell The reader will also note that neither leukocytosis nor
at the turn of the century did represent "a definite clinical thrombocytosis was initially recognized by Osier as a signifi-
entity and one which is new to medical science." cant feature of polycythemia vera, nor were they emphasized
At the turn of the century, the differential diagnosis of initially by other observers, although Osier did mention the
chronic cyanosis included cardiac disease, pulmonary dis- presence of nucleated red cells and an increase in circulating
ease, and toxin-induced methemoglobinemia. The differen- neutrophils in his patients. He measured the hematocrit in
tial diagnosis of polycythemia or polyglobulism included one of his patients, and it was not long before other physi-
causes in which the plasma volume was diminished (relative cians provided careful descriptions of leukocyte abnormali-
polycythemia) and "true" causes, in which the increase in red ties and also measured the red cell mass in a polycythemia
cell mass was absolute and generally ascribed to high-alti- vera patient (Weber, 1905), substantiating Osler's emphasis
tude exposure or cardiac or pulmonary disease. As Osier on erythrocytosis as the cause of the chronic cyanosis. By
emphasized, the newly described illness that he called 1912, the disease had attracted such interest that Lucas could
erythremia or polycythemia rubra vera constituted an entity report on one hundred and seventy-nine published cases in
distinct from these other causes of erythrocytosis. Given the addition to several of his own. Finally, Osler's recommenda-
limited diagnostic tools of the time, his contention was re- tions for therapy m phlebotomy and splenic irradiation m
markably prescient and still valid today. Indeed, very little also seem remarkably modem.
has changed since Osler's time with respect to the clinical Considering the substantial advance in clinical insight
diagnosis of polycythemia vera. that Osler's observations provided, it would be interesting
Osier recognized that the ruddy complexion of his pa- to see his reaction to the current clinical understanding of
tients was not specific for polycythemia vera but even could polycythemia vera and how it should be treated. In contrast
be seen in anemic patients, a condition he called anemia to so many of the blood disorders first recognized at the
rubra. As a consequence, Osier required that three criteria beginning of the twentieth century, advances in under-
be satisfied to establish the diagnosis of polycythemia vera: standing of the pathophysiology of polycythemia vera and
(1) chronic cyanosis, (2) an absolute increase in red the development of an appropriate therapy for it, have been
cell number, and (3) splenomegaly. If measurement of arte- slow to accrue.
rial oxygen saturation is substituted for chronic cyanosis, The development of myelofibrosis in polycythemia vera
Osler's clinical diagnostic criteria are identical to those of was not described until 1935 (Hirsch), and the progression
the Polycythemia Vera Study Group established sixty years of the disease from an active to a spent phase as well as its
later to examine diagnostic criteria and treatment. Osier association with acute leukemia were described by Rosen-
(1908) succinctly stated in his lecture at the Radcliffe Infir- thai and Bassen in 1938. By placing polycythemia vera
mary that "nothing is more certain in the microcosm as patients in oxygen tents, Barach and McAlpine demonstrated
in the macrocosm; given a demand there is soon a supply. in 1933 what Osier had predicted: that erythropoiesis in this
But here is a condition in which, so far as we know, there disorder was autonomous. It was also demonstrated that the
is an oversupply without any corresponding demand," a life-span of polycythemia vera erythrocytes was not pro-
rather clear insight into the pathogenesis of polycythemia longed (London et al., 1949).
vera and, for that matter, any clonal proliferative disorder of Dameshek in 1951 provided order for a confusing situ-
the blood. ation by the assignment of polycythemia vera along with
several other progressive marrow disorders characterized by outstanding congruence of basic science and clinical re-
overproduction of cells to a disease cluster he called the search, the experimental observation that truncation of the
chronic myeloproliferative disorders. Adamson and his col- erythropoietin receptor cytoplasmic domain led to increased
leagues (1976) offered a biologic basis for Dameshek's pro- sensitivity of erythroid progenitor cells to erythropoietin
posal when they established that polycythemia was a clonal (D'Andrea et al., 1991) explained the erythrocytosis in sev-
disorder and one in which erythropoietin production was eral families (de la Chapelle et al., 1993; Sokol et al., 1995).
severely depressed (Adamson, 1968). Plethoric individuals in these families were found to express
With the development of a sensitive radioimmunoassay a truncated erythropoietin receptor lacking the terminal forty
for plasma erythropoietin (Egrie et al., 1987; see Commen- to seventy amino acids. Interestingly, inherited erythropoie-
tary, page 465), suppression of erythropoietin production was tin receptor truncations are associated with an increased
confirmed (Koeffler and Goldwasser, 1981). The demonstra- sensitivity of erythroid cells to insulin growth factor-1, sug-
tion by Prchal and Axelrod (1976) that erythroid progenitor gesting a possible universal mechanism for erythroid pro-
cells from patients with polycythemia vera could grow in genitor cell expansion (Damen et al., 1998). Third, with the
vitro in the absence of erythropoietin confirmed that autono- development of efficient methods for hemoglobin electro-
mous erythropoiesis occurred in this disease. Subsequently, phoresis, high-affinity hemoglobins were identified that
Means and coworkers (1989) and Dai and colleagues (1992, caused erythrocytosis (Charache et al., 1966) (see Appendix,
1994), all in Krantz's laboratory, demonstrated that poly- Fig. 9). Spodaro and Forkner published a comprehensive
cythemia vera erythroid progenitor cells were hypersensitive review of benign familial polycythemia as early as 1933.
to a variety of growth factors in vitro, including interleukin-3, The slow progress in defining the molecular basis of
stem cell factor, and granulocyte- and macrophage-colony- polycythemia vera has its parallel in the development of
stimulating factor, but that there was no abnormality of the appropriate therapy. Phlebotomy was adopted early as a form
erythropoietin receptor. Correa et al. (1994) subsequently of therapy. Arsenicals, phenylhydrazine, lead compounds,
demonstrated that erythroid progenitor cells from poly- benzol, and hookworm infestation have all had their advo-
cythemia vera patients required only insulin growth factor-1 cates but were not noteworthy successes. Arsenicals were
to grow in vitro. Furthermore, the survival of erythroid pro- widely used in medicine without a scientific basis at the
genitor cells from patients with the disease in the absence of beginning of the twentieth century, which makes their ree-
erythropoietin, in contrast to normals, appeared to be due to mergence in the treatment of acute promyelocytic leukemia
resistance to apoptosis associated with an increase in expres- interesting from a historical viewpoint (see Commentary,
sion of the Bcl-xl gene (Silva et al., 1998). Polycythemia vera page 753). Given the slow accrual of knowledge concerning
hematopoietic progenitor cells also exhibited clonal domi- the pathophysiology of the disease, it is not surprising that
nance and suppressed normal polyclonal hematopoiesis Frank Gardner could document that sixteen different
(Adamson et al., 1980). So-called "erythropoietin inde- chemotherapeutic agents were employed at one institution
pendence" did not define the limits of the abnormal clone, during the period from 1928 to 1965 in the treatment of
however, since erythropoietin-independent progeny could polycythemia vera in addition to irradiation and radioactive
still give rise to erythropoietin-dependent ones (Cashman et phosphorus.
al., 1983). It was therefore appropriate that the National Cancer In-
The observation by Wendling and colleagues (1986) stitute fostered the establishment of the Polycythemia Vera
that the myeloproliferative leukemia virus, or MPLV, caused Study Group in 1967. Louis Wasserman was the principal
polycythemia in mice and also immortalized hematopoietic investigator, and the Group had its headquarters at Mount
progenitor cells in vitro paved the way for the next major Sinai Hospital in Manhattan. The purpose of the group was
advance in understanding the pathogenesis of polycythemia, to conduct long-term studies of various treatments for poly-
since the transduced protooncogene in this virus is a trun- cythemia vera to measure efficacy and toxicity.
cated thrombopoietin receptor. Molitemo, Hankins, and Spi- Given the perceived difficulties in treating patients with
vak (1998) demonstrated that polycythemia vera platelets polycythemia vera, particularly the concern some had about
and megakaryocytes lacked a functional thrombopoietin re- phlebotomy, because they believed the resulting severe iron
ceptor, a defect that is specific for polycythemia vera among deficiency created "polycythemic cripples" and increased the
all the disorders causing erythrocytosis. platelet count, which might further predispose to thrombus
With respect to disorders causing erythrocytosis not formation, alternative forms of therapy were sought. Phlebot-
known to Osier, several are worth noting. First, the discovery omy also was considered a possible stimulant to the growth
of erythropoietin (see Commentary, page 465) led to the of the abnormal clone, which might favor the development of
recognition of ectopic or inappropriate erythropoietin pro- myelofibrosis. Thus, it is not surprising that radioactive phos-
duction as a cause of erythrocytosis. Second, cloning of the phorus and later any new alkylating agent was embraced as
erythropoietin receptor (D'Andrea et al., 1989) also provided possible therapies. Concerns about phlebotomy therapy were
new insights into causes of non-clonal erythrocytosis. In an unfounded. Studies of polycythemia vera patients suggest
that chronic iron deficiency in the absence of anemia is not in 1965 demonstrated that radioactive phosphorus caused
harmful in adults (Rector et al., 1982) and that phlebotomy acute leukemia in polycythemia vera patients at a much
does not provoke thrombosis but prevents it. Phlebotomy greater frequency (eleven percent) than occurred in untreated
should not stimulate proliferation of hematopoiesis in this patients (one percent) and that the effect was related to
setting since it is autonomous and the cell cycle time is not cumulative dose of administered isotope.
different from normal in the presence or absence of erythro- The Polycythemia Vera Study Group developed criteria
poietin. Failure to sufficiently reduce the red cell mass by for the diagnosis to ensure a valid study population and
phlebotomy in polycythemia vera patients is most likely the studied the effects of different types of therapy over long
principal underlying cause of thrombosis in so-called "phle- periods of observation. They established that phlebotomy
botomy failures." Thus, the therapist should consider that a was a more effective treatment than the alkylating agent
hematocrit of fifty percent in a polycythemia vera patient is chlorambucil. The latter drug was associated with an in-
not equivalent to the same hematocrit in a normal individual
creased risk of progression to acute leukemia (Berk et al.,
but is associated with an elevated red cell mass in many
1981). Although the high rate of thrombosis they observed
patients (Berlin, 1975). In women with polycythemia vera, a
was initially attributed to thrombocytosis, a subsequent study
hematocrit of fifty percent reflects an elevated red cell mass
by this group found that thrombotic events were unrelated to
in all such patients. Failure to consider these facts or to
the platelet count (Tartaglia et al., 1986).
distinguish women and men with respect to the application of
Thus, today Osier would observe that our therapy for
phlebotomy therapy may explain the high rate of thrombosis
polycythemia vera patients is no more advanced than in his
observed in polycythemia vera patients on phlebotomy ther-
day nor are our diagnostic criteria, although we now have a
apy in some reports.
molecular defect to enhance diagnosis in patients in whom
Hematologists frustrated by the difficulties associated
the syndrome is not fully developed. Hopefully, improved
with the use of phlebotomy began promoting the use of
understanding of the role of phlebotomy, an examination of
radioactive phosphorus. Although a practical agent to use for
the role of interferon (Silver, 1993), and the introduction of
controlling marrow hyperactivity in polycythemia vera, con-
new approaches to limit disease progression will improve the
cern about the development of acute leukemia became a
survival and quality of life of afflicted patients.
substantial issue. In a landmark study, Modan and Lilienfeld
T H E
AMERICAN JOURNAL
OF THE MEDIC AL SCIENCES.
AU G U S T , 1 9 0 3 .
CHRONIC GYANOSIS, WITH POLYCYTH/EMIA AND ENLARGED
SPLEEN- A NEW CLINICAL ENTITY.
B Y W I L L I A M O S L E R , M.D.,
PROFESSOR OF MEDICINE IN JOHNS I~OPKINS UNIVERSITY.
THE group of cases here reported, with those collected from the
literature, are worthy of careful study, as we have here in all prob-
ability " a definite clinical entity and one which is new to medical
science," to use the words of Saundby and Russell in describing their
case. The condition is characterized by chronic cyanosis, polycy-
th~emia, and moderate enlargement of the spleen. The chief symptoms
have been weakness, prostration, constipation, headache, and vertigo.
A further analysis will be reserved until after the consideration of the
c a s e s �9
CASE I. Cyanosis for years, of unknown origin; albuminuria ; rapid
pulse ; polyc~th~'mia ; high vascular te~sion.--Dr. K., aged forty-four
years, consulted me October 28, 1901, complaining of a rapid pulse
and diffuse cyanosis. He has been a very healthy man, active and
vigorous, of good habits; has had no serious illnesses. He has been
uneasy about himself, as he had detected a trace of albumin in the
urine. For several years his wife has noticed that he has had a very
congested appearance, and the eyes would often be deeply suffused.
I have seen him at intervals for the past five years and have known
him to be a very blue-faced man. He has been of a constipated habit.
His eyes are somewhat prominent, but his wife says this is natural to
him. He has constantly a feeling of fulness in the head, sometimes
a sensation of vertigo, and for these symptoms he consulted me.
He was a well-built, well-nourished man; the face much suffused;
the ears looked a little b lue ; t he con~unctiv~ were iniected, and the
lips distinctly cyanotic. The tongue also looked cyanotic. The gen-
eral surface of the skin looked suffused and the anaemia left after
pressure of the hand on the skin was very marked and very slowly
VOL. 126, ~0. 2,--AUG~yr, 1908.
188 O S L E R " C H R O N I C C Y A N O S I S .
obliterated. The feet and hands were quite cyanosed. The radials
and temporals were moderately sclerotic. Pulse 120, regular. Apex
beat in fifth, just inside the nipple line; sounds clear; aortic second a
little accentuated. There was no enlargement of the thyroid. No
enlargement of the liver; moderate enlargement of the spleen, the
edge of which was palpable. The chest was well formed, not barrel-
shaped; the cervical muscles not prominent. Expansion of the chest
good. No sign of emphysema. Expiration not prolonged. Once or
twice he called on cold days to show the extreme cyanosis, and twice
he came in with cough, which troubled him chiefly at night.
Several careful analyses of the urine were made by Dr. Futcher.
The specific gravity ranged from 1012 to 1017 ; albumin was constantly
present, as a rule only a trace; no sugar. On centrifugalizing there
were a few hyaline and finely granular casts.
I was very much puzzled as to the nature of this case, and thought
that he had some chronic degeneration of the kidneys, with slight
arterio-sclerosis, but I did not think it could be advanced, as there was
no marked hypertrophy of the heart, and the aortic second was not
specially ringing. I could not account for the cyanosis.
Blood. The examinations were made by Dr. Futcher. Drop from
ear almost black in color; flows sluggishly. A striking feature is
the slowness with which the drop spreads under the cover. With the
usual-sized drop the field is found almost filled with red cells; they
look natural. Another striking feature is the relative scarcity of
leucocytes. Red blood corpuscles, 9,952,000; leucocytes, 4000; h~mo-
globin, 120 per cent. (Fleischl). No measurements of the red cells
were made. Several counts were made, as it was thought that there
might have been a mistake.
Two observations of the blood pressure, taken on the right arm when
he had been in the sitting posture for about ten minutes, gave maxi-
mum pressure, 203 ram. Hg.; minimum pressure, 175 mm. Hg. Five
minutes later the maximum pressure, 200 rain. Hg.; minimum pressure,
172 ram. Hg.
I saw this patient repeatedly during 1902. There was very little
change in the condition, The cyanosis was always marked. He was
able to attend to his practice. There was no shortness of breath; the
heart's action became slower. I once counted it at 72, but he said
that it was often at 120 per minute. The last examination of the
urine, November 14th, showed only a trace of albumin and a few
hyaline casts. The spleen never became much enlarged, but it was
always easily palpable. He went to California and has since been
under the observation of Dr'. McBride.
CAssII . Recurring attac~ of nausea and vomiting; remarkable
cyanos~, of some years' duration; pain in side; polycytha~mia ; albumin-
uria.--M. C. (General Hospital Nos. 31202, 34970, 38753, 40820,
42041), aged thirty-five years, a Russian Jew; tailor by occupation;
admitted for the first time on July 11, 1900, complaining of constipation.
The family history was unimportant.
Personal History. The patient has always been well. Since coming
to this country, six years ago, he has been pressing in a tailor-shop,
and has had to work standing. He denies gonorrhcea and s philis. He
uses alcohol moderately. Ever since coming to the Unite~ States the
patient has been troubled with constipation, the bowels never moving
O S L E R : C H R O N I C C Y A N O S I S . 189
more frequently thim every second day. This is worse in the summer.
Three years ago, during the summer, the bowels on one occasion were
constipated for fourteen days. There is no pain during these attacks.
For a long time he has been dark in color; he does not know for
how long, but his friends have noticed it.
The patient's bowels moved eight days before admission after taking
licorice powder. He had been constipated for four days previous to
that. Seven days ago the patient began to vomit after each meal.
He has vomited daily since. Castor oil, Epsom salts, and licorice
powder have been ineffectual. There have been no other symptoms
save that of drowsiness. The patient has voided very little urine
during these eight days.
On examination the patient was a well-nourished man, with marked
cyanosis of the face, hands, and mucous membrane; the tongue was
heavily coated.
The physical examination proved entirely negative, except for the
cyanosis already noted. The temperature reached 102 ~ shortly after
admission, and fell to normal by midnight and remained so. On this
day the blood count was:red blood corpuscles, 7,172,000; hucocytes,
21,800; h~moglobin, 120 per cent.; no malarial parasites found;
Widal reaction negative.
On July 16th the blood count was" red blood corpuscles, 6,520,000;
leucocytes, 14,400 ; h~moglobin, 102 per cent. The patient is feeling
very much better and the bowels are moving regularly.
The patient was admitted for the second time on May 27, 1901, com-
plaining of vomiting, which came on five days before admission. The
patient admitted excessive indulgence in soda-water .on the day of the
illness. He states that he has vomited " every moment" since the
onset, and that there has been some blood in the vomitus, which is
very foul-smelling. The bowels have been constipated since the onset.
He has eaten nothing for several days. There is no abdominal pain.
May 29th. Dr. Further noted that the cyanosis was still very
marked, especially in the buccal mucosa, and that there was a marked
pyorrhea alveolaris. Slight tenderness in the right iliac fossa. The
spleen and liver were not enlarged.
27th. The blood count gave red blood corpuscles, 8,900,000; leuco-
cytes, 23,000; h~moglobin, 125 per cent.
28th. Vomiting continues unabated. Calomel, cerium oxalate, and
lavage have been ineffectual in stopping it. Analysis of the vomitus"
total acidity, 85; free HCI, 37; no lactic acid.
29th. Red blood oorl~uscles, 10,200,000; h~moglobin, 112 per cent.
30th. Lips very liwd; the general surface of the skin, inchding
face, trunk, and extremities suffused. The imprint of the hand disap-
pears very slowly, and the nails are a little cyanosed.
June lsr Patient's bowels were finally moved by a high enem0a.
The blood count was as follows: Red blood corl~usoles, 7,576,00 ;
leucocytes, 30,000 ; h~moglobin, 115 per cent.; specific gravity (chloro-
form and benzol method), 1068.
4th. The patient wasdischarged feeling greatl~r improved, the bowels
having commenced to move somewhat more freely.
The patient was admitted for the third time on April 29, 1902, com-
ulainin~ of an attack of vomiting, hiccoughing, and constipation, which
began ~even weeks previously. "~ He ha~ vomited bih several times.