Where did warfarin come from? Did you know that it has been around for nearly a century?
The story starts just after the Great Depression in the 1920s in the Midwest. Previously healthy cattle began dying of internal bleeding without a known cause. Ultimately, it was discovered that the cows had been fed moldy sweet clover hay. At any other time in history, farmers likely would not have been forced to give their livestock spoiled feed, but following the Depression, many had few resources and no alternative. The disease became known as “sweet clover disease” and farmers were warned to avoid feeding moldy hay to their cattle as it could kill an animal within 6 weeks.
A decade passed and there were still some farmers who didn’t believe that sweet clover disease was real as they had never had a problem. Ed Carlson was one of these farmers–until 1933 when he lost most of his herd to internal bleeding. Distressed and looking for answers late one night at the local university, he came across biochemist Karl Link at the University of Wisconsin (reportedly, the professor’s door was the only unlocked one). Professor Link wasn’t initially interested, but his senior student began experimenting with a milk can full of unclotted cow’s blood that the farmer brought with him. Timing is everything—this chance encounter between farmer and scientist triggered the evolution of oral anticoagulants.
Link and his students spent the next several years trying to isolate the compound in the moldy hay responsible for its detrimental effects. In 1941, they finally did—it would become known as dicoumerol. Dicoumerol is a product of a naturally occurring plant molecule called Coumarin (not Coumadin). Coumarin is found in many plants and is responsible for the sweet smell of freshly cut grass or hay. Coumarin itself doesn’t have anticoagulant properties—but it can be converted to the anticoagulant dicoumerol by fungus. This explains why it was only moldy hay that caused sweet clover disease. The funding for this endeavor was provided by the Wisconsin Alumni Research Foundation (WARF).
In 1945, Link had the idea of using dicoumerol as a rodenticide (yes—this is where rat poison comes in), but it was much too slow to be useful for killing rats. The professor and his students went to work to try to modify dicoumerol to change the properties. Of all of the various derivatives, Compound 42 (on a list of ~150) showed great promise as it was very fast-acting. It was named WARFarin after the Alumni group that continued to support Link’s research. It hit the market in 1948 and quickly became the most commonly used rodenticide world-wide.
After that, the transition to therapeutic use in humans under the brand name Coumadin was fast. In 1955 it was used to treat President Eisenhower after a heart attack and from there, gained wide-spread acceptance as a useful and life-saving medication (and not just rat poison). Management and monitoring proved to be quite challenging for many decades until the discovery of the role of vitamin K in the mid-70’s and the development of the INR in the early-80’s.
Warfarin, for now, continues to be the most widely-used anticoagulant in the world. With the advent of weekly home PT/INR testing, using the CoaguChek XS meter, Coumadin became much easier to manage and safer to use. After all of these years it still appears that closely monitored Coumadin therapy is the safest anticoagulation therapy to date. Will the development of the new group of oral anticoagulants push warfarin out of regular use and into the history books? Will it still be around in another century? Only time will tell…