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Samuel I. Rapaport: Unsung Hero of Blood Coagulation

By Donald I. Feinstein, MD, MACP

2008-09-01

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,¹the 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,⁶and the discovery that hemophilia A does not stem from a single genotype.⁷In addition, Dr. Rapaport and I were responsible for naming the most common inhibitor of the APTT — the lupus anticoagulant.

Drs. Oscar D. Ratnoff, Marshall A. Lichtman, Joseph F. Ross, Eugene P. Cronkite, Philip W. Majerus, Helen M. Ranney, Ernst R. Jaffé, Y.W. Kan, and John W. Harris. Bottom row, from left to right: Drs. David G. Nathan, E. Donnall Thomas, Jane F. Desforges, Alvin M. Mauer, Ernest Beutler, and Samuel I. Rapaport.

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 VIIa.¹

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 colleagues.

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 excellence.