Samuel I. Rapaport, creator of the partial thromboplastin time and other landmark blood coagulation discoveries: 19 November 1921–20 December 2011
Article first published online: 4 SEP 2012
© 2012 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 10, Issue 9, pages 1719–1721, September 2012
How to Cite
FEINSTEIN, D. I., ØSTERUD, B. and RAO, L. V. M. (2012), Samuel I. Rapaport, creator of the partial thromboplastin time and other landmark blood coagulation discoveries: 19 November 1921–20 December 2011. Journal of Thrombosis and Haemostasis, 10: 1719–1721. doi: 10.1111/j.1538-7836.2012.04849.x
- Issue published online: 4 SEP 2012
- Article first published online: 4 SEP 2012
- Accepted manuscript online: 13 JUL 2012 02:00PM EST
Samuel I. 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 Party 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 – often caring for patients without pay. Samuel Rapaport attended the University of California at Los Angeles (UCLA) and thereafter the University of Southern California (USC) School of Medicine, graduating in 1945. After spending 2 years in the Air Force, he returned to California as a resident in internal medicine at the Long Beach Veterans Administration Hospital in 1950. Subsequently, the Chief of Medicine recruited him to join the faculty and supervise the hematology ward. In 1952 he was introduced to a famous Norwegian physician, Paul Owren, while he was visiting the Los Angeles and the Long Beach VA Hospital. Owren gave a lecture on new developments in the blood coagulation field. Rapaport asked Owren some very insightful questions and impressed with his interest in blood coagulation, Owren urged him to apply for a Fulbright Research Scholarship in Medicine that was available in Norway. After discussing this 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 finally relented, but he did so with the proviso that she typed the application.
Interestingly, 2 weeks after Rapaport arrived in Norway, Owren had to leave the country as he was the primary care physician for Crown Princess Martha, who was seriously ill and had been sent to Florida. Thus, after 2 weeks in Norway, Rapaport was left alone to learn laboratory technology. Initially, he asked the question why the prothrombin time test was so variable in patients who were taking oral anticoagulants. Luckily, all the patients on oral anticoagulants in Norway were monitored in a single laboratory in the hospital where he was working. It was from these experiments that he concluded that there were two forms of factor VII in plasma, factors VII (FVII) and VIIa (FVIIa) .
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 partial thromboplastin assay system containing either adsorbed ox plasma (source of FVIII) or aged serum (source of FIX) 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, but 3 years later, Thomas Brem, his former chairman at the Long Beach VA, who in the interim had been appointed the Chairman of Medicine at USC, asked Rapaport to establish a Division of Hematology at USC.
At USC, Rapaport established a Hematology Consult Service and clinical and research coagulation laboratories. He was awarded a Hematology Training Grant from the National Institutes of Health, and his very productive research career was on its way to being one of the most productive in blood coagulation history. Initially, he thought that it would be important to develop a good screening assay for the intrinsic coagulation system. Working with one of his first fellows, Bob Proctor, he developed the activated partial thromboplastin time test , which is still used today in the world’s clinical laboratories for screening, and, in addition, a modification of the test is used for many of the quantitative assays for various coagulation factors. Using this new assay, he and Sandra Schiffman then discovered that when they combined purified FXI with purified FXII, they failed to shorten the clotting time of an exhausted plasma substrate. They deduced from those experiments that at least one or more clotting factors were necessary for plasma to clot after exposure to glass (later discovered to be prekallikrein and high-molecular-weight kininogen) . In addition, using the quantitative assay for factor XI, they determined the inheritance of factor XI deficiency and its correlation with clinical bleeding . Schiffman was to be the first of a long line of outstanding biochemists who were trained by Rapaport to better understand the many questions that he asked about the many intricacies of the blood coagulation system. He and Schiffman subsequently discovered that a trace of thrombin was necessary to activate FVIII and FV  and that phospholipid was important in the interaction between FVIII and FIX .
Rapaport was always puzzled by the fact that hemophiliac patients had a severe bleeding disorder despite the presence of a powerful extrinsic blood coagulation system that did not require either FVIII or FIX. Bjarne Østerud and he postulated that the extrinsic system must be required to trigger the intrinsic blood coagulation system, and they set out to prove such. Using a set of elegant experiments they were able to show that tissue factor (TF) and FVIIa directly activated FIX to FIXa, thus establishing the key link between the extrinsic and intrinsic systems . This was a paradigm shift in blood coagulation research and finally made sense of the dual systems.
Working with Uri Seligsohn, Carol Kasper and Bjarne Østerud, FVIIa was identified as probably the ‘bypassing activity’ in activated prothrombin complex concentrates used to treat hemophilia A patients with inhibitors . This served as a very important clue to the possibility of FVIIa as a pro-hemostatic agent. Both Kasper (at USC) and Seligsohn (Israel) went on to establish their own laboratories and developed distinguished research careers.
Natalie Sanders and Paul Bajaj working in the Rapaport laboratory reported that FX and another moiety present in the lipopoprotein fraction of plasma was necessary for the inactivation of TF/FVIIa  and later working with Vijay Rao provided the mechanism of its inhibitory action and named it the extrinsic pathway inhibitor (later designated as tissue factor pathway inhibitor or TFPI) . Subsequently working with Bonnie Warn-Cramer, Per Morten Sandset and Rao provided evidence for a physiological role for TFPI as a natural anticoagulant [11,12]. Thus, this balanced system clarified how blood coagulation was initiated and controlled, why the extrinsic system could not compensate for defects in the intrinsic system, and why hemophilia A and B patients bled excessively. Østerud, Bajaj and Rao all have continued to head highly productive coagulation research laboratories, particularly focusing on the mechanisms of the initiation and control of blood coagulation.
Working with Don Feinstein and Kasper, Rapaport discovered that hemophilia A did not stem from a single genotype  and working with Feinstein in studying a large number of patients with systemic lupus erythematosus noted the high incidence of an inhibitor of the intrinsic blood coagulation system, which they named the ‘lupus anticoagulant’ . Rapaport’s extensive and other important research contributions [15–24] have been documented by over 200 peer-reviewed publications, four books and 25 chapters.
In 1974 Rapaport was recruited by Helen Ranney at the University of California at San Diego, where he continued his distinguished academic career for the next 22 years, his laboratory being continually funded by the NIH until he retired in 1996 at the age of 75.
During Rapaport’s tenure at the University of Southern California and the University of California at San Diego, he also established himself as an outstanding clinician and teacher. His clinical rounds knew no bounds – often running through dinner time. He was asked to develop a new pathophysiology course in hematology in the late 1960s. He spent endless hours with a full-time laboratory assistant developing the curriculum, syllabus, handouts and slides and smears of the blood and bone marrow. It was one of the first medical school courses based on actual clinical cases and based on problem solving and critical thinking. Moreover, he taught the course by himself. The course served as the basis for his single authored hematology textbook ‘Introduction to Hematology’ , which is still remembered and praised today by medical students, residents and fellows.
In addition to being an outstanding investigator, master clinician and award-winning teacher, he was very active in various academic societies. Besides serving as President of the American Society of Hematology in 1977, he also served a leadership role in several other academic societies, including membership of the Governing Board of the American Board of Internal Medicine, as Vice-President of The International Society of Thrombosis and Haemostasis, as Chairman of the Council on Thrombosis of the American Heart Association, and as a member of various study sections and a member of the Advisory Council of the National Heart and Blood Institute.
His contributions to medicine, hematology and hemostasis have been recognized with several honors, which are too numerous to list but include more than 20 named visiting professorships, memberships of the American Society of Clinical Investigation and the American Association of Physicians, the Henry Stratton Lecture and Prize of the American Society of Hematology, a Merit Award from the NHLBI, the Robert P. Grant Medal from the International Society of Thrombosis and Hemostasis and the Wright Schulte Plenary Lecture of the International Society of Thrombosis and Hemostasis.
Finally, all of his former fellows and colleagues will never forget Rapaport’s attention to detail. Writing scientific papers could best be described as ‘painful’. Moreover, every detail of the laboratory experiments or the clinical study were examined, questioned and re-examined. On many occasions new questions were explored and formulated, sometimes repeating the experiments, sometimes performing new ones, but always seeking the scientific truth.
Sam Rapaport will be remembered by all in many different ways – as an outstanding clinician, as a great investigator who was a great listener with penetrating insight and ground-breaking ideas or as a mentor and great teacher of hematology and hemostasis. Moreover, all of his academic progeny will remember him as a close friend and kind human being who brought out the best in all who had the good fortune to be part of his life.
Disclosure of Conflict of Interests
The authors state that they have no conflict of interest.
- 11Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc Natl Acad Sci U S A 1991; 88: 708–12., , , , .
- 25Introduction to Hematology. Philadelphia: J.B. Lippincott Company, 1971..