Anticoagulant Drugs

California CATHOLIC MEDICAL CENjTS* ENTRAL MEDICAL LIBRARY Medicine 88-2I5153rd STREET N~WYORK .11I432q Blood Coagulation and the Coumarin Anticoagulant Drugs PAUL M. AGGELER, M.D., San Francisco DR. LESLIE L. BENNETT*: Ladies and gentlemen, ing with clotting mechanisms, which appeared in it gives me unusual pleasure to introduce Dr. Paul 1938. Early recognizing the importance of the M. Aggeler as Faculty Research Lecturer from the work of Dam and Almquist on the bleeding dia- San Francisco Division of the Academic Senate thesis of vitamin K-deficient chicks and the prob- for 1966. There is no higher honor that the fac- able significance for human disease of the observa- ulty can bestow upon one of its colleagues than to tion of Greaves and Schmidt of the effectiveness select him to represent publicly the faculty's com- of vitamin K in controlling the bleeding of rats with mon urge toward creativity which primarily mani- biliary fistulas, he began in the late 1930's his in- fests itself in our scientific setting as research. vestigation of the role of vitamin K in controlling Dr. Aggeler is uniquely a Californian. He is one prothrombin levels in patients with jaundice and of those rare individuals, a native son. His birth hepatic disease. This is the first of his classic works occurred in Ferndale among the redwoods of Hum- referred to in the citation of the Research Com- boldt County. After attending St. Ignatius High mittee. School in San Francisco, he enrolled as a pre- In this year, 1966, when there is increased medical student at the University of California awareness of the ethical responsibilities of physi- in Berkeley in 1929 and received the M.D. cians engaged in clinical research, it is important degree from the University of California in to recall that Dr. Aggeler was unusually adept at 1937. Dr. Aggeler interned at the University of doing venipunctures on himself to obtain blood California Hospital and was successively Assistant to set up the controls necessary for his investiga- Resident, Research Fellow in Medicine and Resi- tion of the clotting mechanism in patients with dent in Medicine. Except for one year of training jaundice. His critical observation and studies of spent at the San Joaquin General Hospital, his pro- patients with hemophilia led to his discovery of fessional and scientific training was entirely at the plasma thromboplastin component deficiency and University of California; thus I say he is uniquely resulted in an explosion of knowledge about hemo- a California product. philia. Most recently, the same critical clinical acu- As a medical student, Dr. Aggeler came under men and inquiring mind resulted in his discovery the influence of Dr. Salvatore Lucia and in Dr. of a genetic control of warfarin metabolism. His Lucia's laboratory began a systematic study of national and international reputation is thoroughly factors affecting the prothrombin time as then de- established and I shall not repeat the list of editor- termined by the method devised by Armand Quick. ships he holds, advisory roles he has filled and the These studies resulted in his first publication deal- honors that have come his way. Let me simply say The Ninth Annual Faculty Research Lecture, University of Cali- that I am proud to present my colleague for over fornia San Francisco Medical Center, 23 March 1966. a quarter of a century, the man who completely Submitted 20 January 1967. requests to: Editorial Office, Room 4320, S.F. General meets the criteria for scholar and gentleman, Dr. Hospital,Reprint 1001 Potrero Avenue, San Francisco 94110. *Morris Herzstein Professor of Physiology. Paul Aggeler. CALIFORNIA MEDICINE 255 DR. PAUL M. AGGELER*1: Professor Bennett, cepts of the blood clotting mechanism as I have members of the Academic Senate, ladies and gen- seen it unfold during the past 30 years. Blood clot- tlemen: I am sensible of the very great honor ting is somewhat unusual among physiologic proc- which the Academic Senate has bestowed on me, esses in that a great deal of what we know about and I am most grateful. I am overwhelmed to be it has come from careful study of its derangement included in the illustrious company of those who in sick patients. I will stress particularly the dis- have preceded me in this distinction. What I have coveries made through investigation of coagulation done seems inconsequential in comparison with defects in such individuals. Because of the limita- their accomplishments. I am pleased, however, that tions of time this must, of necessity, be oversimpli- what I have done and what I have been has seemed fied and must ignore the enormous contributions M ritorious to my colleagues. of many investigators. During the second part of At the outset I must acknowledge, with thanks, the hour I will outline some recent work we have the great debt I owe to many associates, fellows done with a class of drugs which interferes with and technical assistants for their help in my re- blood clotting. search endeavors. I am afraid that much of what I first became interested in blood clotting during I am given credit for is really their work. I am also my internship in this hospital in the year 1936-37. grateful to the Board of Directors and Administra- During that year I was involved in the care of sev- tion of the Children's Hospital of San Francisco eral patients suffering from hemophilia. At that for providing sponsorship and space for much of time the nature of the disease was poorly under- my activities during the past 10 years. Finally, I stood, and its treatment highly unsatisfactory. I would like to express my thanks to my first men- had no special training for research and certainly tor, Dr. Salvatore Lucia, for his stimulation, en- no intention of becoming seriously involved in it, couragement and support when I worked under but I did have an urge to find out more about the him first as a research fellow and later as an In- curious inability of the hemophiliac's blood to clot. structor in the Division of Preventive Medicine. In partial explanation of why, almost 30 years I have approached this lecture with more than later, I am still involved in blood clotting problems, the ordinary amount of apprehension. It would be I would like to quote a portion of the introduction appropriate perhaps to spend some time in philoso- to their book on blood coagulation by Drs. Rose- phizing about medical research, but I do not feel mary Biggs and Roger Macfarlane: "To the un- qualified for that task. In fact, I cringe whenever initiated, the fascination that this work has for its I am referred to as a researcher. For the better devotees must seem difficult to understand. But a part of my career I have held a title in the clinical number of explicable factors operate to develop professorial series. I have been a practicing intern- this attraction, so that once involved in it the new ist specializing in hematology with special interest recruit is almost powerless to draw back. To begin in the hemorrhagic disorders. I have been a mem- with, the spontaneous transformation of fluid ber of that branch of the faculty whose principal blood to solid clot has a stimulating effect on the concern has been with the care of patients. Such curiosity like that produced by a well executed research as I have been able to accomplish has conjuring trick. One feels that so simple and strik- sprung directly from the bedside and has usually ing a phenomenon must have a simple and striking had immediate clinical relevance. With the increas- explanation and the urge to discover it is imme- ing complexity of medical science it has become diate. Next there is the deceptive ease with which more difficult to pursue this kind of career, but I the work can be started. All that is needed is a hope the opportunity will not be completely lost. few glass tubes and a watch, a supply of blood and For me it has been an exciting and rewarding way ingenuity. Later the more mechanically-minded in- of life. vestigator will discover that almost equally good results can be obtained by apparatus of limitless In attempting to shape my discussion this morn- complexity. Thereafter experiments are easy ing into a form which might have some interest for to plan and carry out, and provide unlimited op- the many disciplines represented on this campus, portunity for being most satisfyingly clever." I have decided to discuss two related topics. In the Man's fascination with the phenomenon of blood first part of the hour I will attempt to trace briefly clotting is very old. Hippocrates and Aristotle the history of the development of our present con- thought it was simply a matter of solidification on *lProfessor of Medicine. cooling. Later, a popular theory held that the blood 256 APRIL 1967 * 106 * 4 contained an accumulation of minute particles of Morawitz also recognized that the production of fibrin-like material which were kept widely dis- thrombin from its plasma precursors was in some persed by the circulation, but which would quickly way initiated or at least enhanced by contact with aggregate with the cessation of blood flow. Andrew a foreign surface. Buchanan, whose work was published in Glasgow During the early part of the Twentieth century in 1845, probably deserves credit as the founder a number of investigators including C. H. Mills, of the modern theory of blood coagulation. He was P. Nolf, A. Fischer, J. J. Mellanby, W. H. Howell the first to show that it took two substances to and others proposed conflicting theories.

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