Physicians have long proposed “thinning” the blood as a treatment for various maladies, and this was even considered by Hippocrates (approximately 400 BCE). The application of leeches was a common prescription by “hematologists” in earlier centuries. An improved understanding of hemostasis combined with the increasing problem of thrombotic disease in the population has provided the basis for more modern approaches to anticoagulation.

Working in 1916 with William Henry Howell, a pharmacologist at Johns Hopkins, Jay McLean, a medical student, is credited with discovery of heparin, which was extracted from animal liver (“hepar”). Clinical use was delayed until the 1930s when nontoxic, water soluble preparations were produced. Heparin that is produced commercially now is extracted from animal intestines and is very heterogeneous in composition. Extensive research into its structure and mechanism of action led to eventual identification of the pentasaccharide sequence needed for the critical interaction with antithrombin necessary for its anticoagulant effect. More recently, better preparations have been produced by controlled depolymerization and fractionation of heparin, leading to the introduction of low-molecular-weight heparins with improved pharmacological properties. Synthesis of a pentasaccharide analogue of the binding site for antithrombin eventually resulted in introduction of fondaparinux as the first synthetic heparin-like anticoagulant.

The discovery and development of oral anticoagulants is one of the most interesting in pharmaceutical history and started with a hemorrhagic disease in cattle in the Midwest US in the 1920s. This was traced to ingestion of spoiled sweet clover, and the substance responsible for bleeding was extracted and identified as a coumarin by Karl Paul Link working at the University of Wisconsin. This led to the commercialization of dicoumarol in 1941, and efforts to develop an effective rodenticide resulted in synthesis of warfarin (Wisconsin Alumni Research Foundation), which was approved for medical use in 1954. Therapy with warfarin was closely linked to development of the PT as a test to regulate its anticoagulant effect and dosage. Improved anticoagulant treatment resulted from well-designed clinical trials and development of the INR approach to standardization of the PT. However, problems with biological variation in response, food and drug interactions, long onset of action and difficulty with reversal have made therapy with warfarin very difficult and provided the impetus for new approaches. Genetic studies are now elucidating the basis for differences in individual responsiveness to warfarin, and efforts to develop new oral anticoagulants are coming to fruition as several new agents are in advanced clinical trials.

See the related ASH 50th Anniversary Review articles under the THROMBOSIS AND VASCULAR BIOLOGY section of the publication ASH 50th Anniversary Reviews: A Salute to the American Society of Hematology.