September-October 2008, Volume 5, Issue 5
Samuel I. Rapaport: Unsung Hero of Blood Coagulation
Published on: September 01, 2008
Dr. Feinstein is Professor of Medicine, Jane Anne Nohl Division
of Hematology and Center for the Study of Blood Diseases at the Keck
School of Medicine, University of Southern California.
In 1952, Samuel I. Rapaport, MD, while working at the Long Beach
Veterans Administration Hospital, was introduced to Norwegian physician
Paul Owren. Dr. Owren was giving a lecture on new developments in the
blood coagulation field. During his visit, Dr. Owren mentioned to Dr.
Rapaport that there was a Fulbright Research Scholarship in Medicine
available in Norway, and, impressed with his interest in blood
coagulation, he urged Dr. Rapaport to apply for it. After talking with
his wife, Joyce, and after giving her several reasons why he shouldn't
apply, she was persistent in urging him to submit an application. He
relented, but he did so with the proviso that she type the application.
These events were the beginning of an illustrious research career in
blood coagulation spanning four and a half decades that resulted in key
discoveries, including the discovery that factor VII existed in plasma
in two forms: VII and VIIa,1 the development of the activated partial thromboplastin time,2 the importance of a trace of thrombin to activate factor V and VIII3 and the importance of phospholipid in the interaction between factors VIII and IX,4
the identification of factor VIIa as the bypassing activity in
prothrombin complex concentrates used to treat factor VIII inhibitors,5 the activation of factor IX by tissue factor and factor VIIa,6 and the discovery that hemophilia A does not stem from a single genotype.7 In addition, Dr. Rapaport and I were responsible for naming the most common inhibitor of the APTT — the lupus anticoagulant.
Dr. Rapaport was born in Los Angeles in 1921 to Hyman and Bertha
Rapaport. His father was a distinguished local physician, and his
mother was a lawyer active in local Democratic politics. His father was
well known in Los Angeles as the "Angel of Temple Street" because of
his tireless dedication to the needs of his patients throughout the
years of the Great Depression. Dr. Rapaport attended UCLA and
thereafter the University of Southern California, School of Medicine,
graduating in 1945. After spending two years in the Air Force, he
returned to California as a resident in internal medicine at the Long
Beach VA. In 1950, Dr. Tom Brem recruited him to join the faculty and
supervise the hematology ward. This subsequently led to the meeting
with Dr. Owren and the Fulbright in Norway.
Interestingly, two weeks after Dr. Rapaport arrived in Norway, Dr.
Owren had to leave the country because he was the primary-care
physician for Crown Princess Martha, who was seriously ill and had been
sent to Florida. Thus, after two weeks in Norway Dr. Rapaport was left
alone to learn laboratory coagulation technology. He decided to
investigate blood coagulation — specifically, why was the prothrombin
time so variable in patients taking oral anticoagulants? At that time,
it was routine to place all patients who had suffered a myocardial
infarction on oral anticoagulants. Luckily, all the patients on oral
anticoagulants were monitored by a single laboratory in the hospital
where he was working. It was during these experiments that Dr. Rapaport
concluded that there were two forms of factor VII in plasma: VII and
Dr. Rapaport returned to the Long Beach VA in 1954 and established
his first coagulation laboratory. He quickly went to work, and using a
four-part original PTT assay system containing either adsorbed ox
plasma (source of factor VIII) or aged serum (source of factor IX) as
correcting agents was able to determine if a patient had hemophilia A
or B. In 1955, he was recruited to UCLA to establish a clinical and
research coagulation laboratory. Three years later Dr. Brem, his former
chairman at Long Beach VA, who in the interim had been appointed Chair
of Medicine at USC, asked Dr. Rapaport to establish a Division of
Hematology at USC.
At USC, Dr. Rapaport was in charge of a general medicine service and
a hematology consult service. In addition, he established clinical and
research coagulation laboratories. Dr. Rapaport had several questions
that he wanted to answer and started with exploration of the contact
system. Using the newly developed activated PTT system, he and Dr.
Sandra Schiffman were able to separate factor XI from factor XII.8
However, when these two factors were combined, they failed to shorten
the clotting time of an exhausted plasma substrate. Thus, they deduced
from those experiments that at least one or more clotting factors was
necessary for plasma to clot after exposure to glass (later discovered
to be prekallikrein and high-molecular-weight kininogen).8 In addition, they determined the inheritance of PTA (factor XI) deficiency and its correlation with clinical bleeding.9
Dr. Schiffman was to be the first of a long line of outstanding
biochemists who were trained by Dr. Rapaport to better understand the
many questions that he asked about the intricacies of the blood
coagulation system (Bjarne Osterud, Paul Bajaj, and L. Vijaya M. Rao).
In 1974, Dr. Rapaport was recruited by Dr. Helen Ranney at the
University of California, San Diego, where he continued his
distinguished academic career for the next 22 years, his laboratory
being continually funded until his retirement in 1996 at the age of 75.
During Dr. Rapaport's tenure at USC and UCSD, he also established
himself as an outstanding clinician and teacher. His clinical rounds
knew no bounds — often running through dinner (not an 80-hour violation
in those days). He was asked to teach "Introduction to Hematology," a
new third-year hematology pathophysiology course at USC. He spent
endless hours with a full-time laboratory assistant developing the
curriculum, syllabus, handouts, slides, and smears of the peripheral
blood and bone marrow. It was one of the first medical-school courses
based on actual clinical cases and problem-solving. Moreover, he taught
the course by himself. This course served as the basis for his
single-authored hematology text, "Introduction to Hematology," which is
still remembered and praised today by medical students, residents, and
In addition to being an outstanding investigator, master clinician,
and award-winning teacher, he was very active in various academic
societies and organizations — particularly in the formative years of
the American Society of Hematology, of which he served as president in
1977. He also served as president of several other academic and
scientific societies, as a member of the Governing Board of the
American Board of Internal Medicine, as chairman of the Council on
Thrombosis of the American Heart Association, and as a member of
various study sections and the Advisory Council of the NHLBI.
Lastly, none of us who were former fellows and colleagues will ever
forget Dr. Rapaport's attention to detail. Writing scientific papers
was best described as "painful." Moreover, every detail of the
laboratory experiments or the clinical study was examined, questioned,
and reexamined. On many occasions new questions were explored and
formulated, sometimes repeating the experiments, sometimes performing
new ones, but always seeking the truth. Whether acting as investigator,
clinician, teacher, or leader, Dr. Rapaport's goal has always been
back to top
- Rapaport SI, Aas K, Owren PA. The effect of glass upon the activity of the various plasma clotting factors. J Clin Invest. 1955;34:9-19.
- Proctor RR, Rapaport SI. The
partial thromboplastin time with kaolin. A simple screening test for
first stage plasma clotting factor deficiencies. Am J Clin Pathol. 1961;36:212-9.
- Rapaport SI, Schiffman S, Patch MJ, Ames SB. The
importance of activation of antihemophilic globulin and proaccelerin by
traces of thrombin in the generation of intrinsic prothrombinase
activity. Blood. 1963;21:221-36.
- Schiffman S, Rapaport SI, Chong MM. The mandatory role of lipid in the interaction of factors VIII and IX. Proc Soc Exp Biol Med. 1966;123:736-40.
- Seligsohn U, Kasper CK, Osterud B, Rapaport SI. Activated factor VII: presence in factor IX concentrates and persistence in the circulation after infusion. Blood. 1979;53:828-37.
- Osterud B, Rapaport SI. Activation
of factor IX by the reaction product of tissue factor and factor VII:
additional pathway for initiating blood coagulation. Proc Natl Acad Sci USA. 1977;74:5260-4.
- Feinstein D, Chong MN, Kasper CK, Rapaport SI. Hemophilia A: polymorphism detectable by a factor VIII antibody. Science. 1969;163:1071-2.
- Schiffman S, Rapaport SI, Ware AG, Mehl JW. Separation of plasma thromboplastin antecedent (PTA) and Hageman factor (HF) from human plasma. Proc Soc Exp Biol Med. 1960;105:453-5.
- Rapaport SI, Proctor RR, Patch MJ, Yettra M. The
mode of inheritance of PTA deficiency: evidence for the existence of
major PTA deficiency and minor PTA deficiency. Blood. 1961;18:149-65.