see also anticoagulants, historic perspectives of medicine, history of PE

• around 1900, in rural US, veterinarians were puzzled by the mysterious sweet clover disease that caused cattle to develop fatal spontaneous bleeding.
• heparin was discovered in 1915 by Jay McLean, searching for a pure procoagulant in dog liver & heart, but finding anticoagulants instead. McLean's insight & perserverence in pursuing this strange lead resulted in the discovery of heparin which became the standard Rx for a variety of thrombotic disorders in the 1940's.
• Karl Link (an agricultural researcher) was asked to develop a strain of sweet clover low in coumarin, because cattle disdained its bitter taste. When he studied the spoiled clover that a cow had died from, he isolated a pure crystalline haemorrhagic agent & then found that vitamin K completely reversed the actions of either spoiled clover or coumarin.
• this new substance was named dicoumarol & reported to the world in 1940.
• despite its use for 2400yrs, aspirin (acetylsalicylic acid) was not shown to have anticoagulant activity until 1940, after Karl Link discovered that dicoumarol breaks down to salicylic acid. By experimenting on himself, he found that aspirin was a weak anticoagulant which reduced prothrombin activity, & published his results in 1943.
• Link then developed warfarin, initially as a rodenticide, & subsequently in 1950's for Rx use in humans. Interestingly, the precise mechanism of warfarin & vit.K was not elucidated till 1974;