The oral anticoagulant saga: past, present, and future.
Oral anticoagulation originated with the discovery of the harmful agent causing "sweet clover disease" in cattle in North America in the 1920s. The causative agent dicoumarol was isolated in Link's laboratory in 1940. A range of related compounds was then synthesized, the most popular of which proved to be warfarin. Oral anticoagulant administration posed problems of individual variation in response to these drugs and the need for regular laboratory monitoring by prothrombin time (PT). Monitoring problems arose from the introduction in the 1950s of some poorly responsive commercial tissue extracts for use as tissue extract thromboplastin reagent in the PT. More oral anticoagulant drug was then needed to prolong the test to the required therapeutic targets, with a resultant increase in bleeding. It was not until 1983 that the problem was resolved and it was shown that the less intense UK-type regimen was just as effective as the higher North American type dosage in the prevention of venous thrombosis but caused much less bleeding. This study led to the widespread adoption of the "low-dose warfarin" regimen that, combined with the World Health Organization PT standardization scheme using the international normalized ratio (INR), has led to improved effectiveness and safety of oral anticoagulation. This has permitted increased administration of warfarin in a widening spectrum of clinical disorders. The last remaining problem is the limited success of doctors in achieving the therapeutic INR targets, which may be improved by computer-assisted dosage.