The Cattle Mystery: In the 1920s and 1930s, dairy cattle in the US and Canada were dying from a mysterious bleeding disease after eating spoiled sweet clover hay.
The Breakthrough: In 1933, a farmer named Ed Carlson brought a dead cow’s unclotted blood and moldy hay to Link’s lab.
Isolation of Dicumarol: In 1939, Link’s student Harold Campbell isolated the active anticoagulant agent, dicumarol, from the spoiled hay.
Creating Warfarin: Link and his team later synthesized a more potent analog, naming it warfarin (combining the initials of the Wisconsin Alumni Research Foundation with “coumarin”)
The toxic substance that formed in the spoiled hay is called dicumarol. It was created through a chemical reaction between a natural plant compound and common fungi (molds) when the hay was stored incorrectly.
Sweet clover (Melilotus species) naturally contains high levels of coumarin, a sweet-smelling organic compound responsible for the scent of freshly cut grass. While coumarin has a bitter taste to deter animals from eating the clover, it is relatively non-toxic and does not affect blood clotting on its own.
Fungal Fermentation: The damp, trapped environment inside the dense hay bales allowed common molds (such as Aspergillus or Penicillium) to thrive. As these fungi metabolized the plant material, they triggered an oxidation and dimerization process. This fungal reaction chemically altered the harmless coumarin, fusing two coumarin molecules together (in the presence of naturally occurring formaldehyde) to synthesize dicumarol.
Because dicumarol is a potent vitamin K antagonist, it blocked the cows’ ability to recycle vitamin K, preventing their livers from producing essential blood-clotting factors and causing them to hemorrhage.
Transition to Coumadin: It was first used as a rat poison in 1948 before water-soluble warfarin sodium was approved as a human blood thinner (Coumadin) in 1954.
Building on the coumarin research, Link and his team synthesized a variety of stronger anticoagulants. In 1945, they patented compound number 42, which was named warfarin—an acronym honoring the Wisconsin Alumni Research Foundation (WARF), which funded the laboratory’s research.