Circulation, Vol 89, 432-449, Copyright © 1994 by American Heart Association
RL Mueller and S Scheidt
The history of the antithrombotic agents--aspirin, heparin, warfarin, and
the thrombolytics--is a rich and lively odyssey of serendipity,
perseverance, vision, and conflict involving a number of striking
personalities. The history of aspirin spans ages and continents from
Hippocrates' analgesic for women in labor to the rediscovery of the white
willow bark by English country scholar Reverend Edward Stone. Bayer chemist
Felix Hoffmann reinvented aspirin for his ailing father; suburban physician
L.L. Craven pioneered the prophylactic antithrombotic uses of aspirin; and
Sir John Vane elucidated aspirin's mechanism of action as the inhibition of
prostaglandin synthetase. Heparin was discovered by McLean, working as a
medical student in 1915 in search of a pure procoagulant in dog liver. His
original impure material differed somewhat from today's heparin, but
purified heparin was rapidly accepted for a myriad of clinical uses; to
this day, diverse new properties of this complex glycosaminoglycan continue
to be elucidated. The oral anticoagulants emerged from veterinary research
in the 1920s on a hemorrhagic disorder afflicting cattle that consumed
spoiled sweet clover hay. Several chance encounters led Karl Link and his
University of Wisconsin team to the identification of dicumarol as the
offending agent in 1939 and its widespread therapeutic use by Wright and
others in the 1940s. Link later developed warfarin as a rodenticide, but
its use in humans soon followed in the 1950s. Vitamin K was discovered in
the 1930s; its involvement in the mechanism of the anticoagulant agents was
not delineated until the 1970s. The intrinsic ability of clotted blood to
liquify and the fibrinolytic properties of normal urine were noted in the
1800s. Tillett and Sherry's group stumbled on the fibrinolytic properties
of streptokinase in the 1930s and pioneered the therapeutic use of
streptokinase in the 1940s and of urokinase in the 1960s. Several teams
found tissue-type plasminogen activator in various body sites beginning in
the 1940s, leading to its cloning and widespread use in the 1980s;
anisoylated plasminogen- streptokinase activator complex is an example of
rational drug design. The discoverers of these diverse agents have not only
provided physicians with a potent armamentarium of antithrombotic drugs but
also helped elucidate much basic science and vividly demonstrated the
merits of perseverance, independent thought, and adherance to the
scientific method.
ARTICLES
History of drugs for thrombotic disease. Discovery, development, and directions for the future
Division of Cardiology, New York Hospital-Cornell Medical Center, New York 10021.
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