Did You Know That the Diagnosis of Sweet Clover Disease in Bleeding Cattle in the 1920’s Led to the Discovery of Vitamin K Antagonists?

Did you know that the diagnosis of sweet clover disease in bleeding cattle in the 1920’s led to the discovery an effective rat poison and, subsequently, the most widely used in vivo anticoagulant in humans? Two veterinarians, Frank Schofield (in Canada) and Lee Roderick (in North Dakota), reported that massive hemorrhage and death occurred when cattle and sheep were fed moldy sweet clover hay. They reported that the bleeding defect could be corrected by blood transfusion or removing the moldy sweet clover from the diet. The acquired coagulation disorder, that prevented blood from clotting, was described as a “plasma prothrombin defect.” In 1940, biochemist Karl Link and colleagues at the University of Wisconsin isolated a natural substance called coumarin in sweet clover that was oxidized to 3,3’-methylene-bis (4-hydroxy coumarin), also known as dicoumarol, in moldy sweet clover. Dicoumarol was used with limited success as an experimental anticoagulant in humans. Link’s group prepared and studied many coumarin modifications and isolated an especially potent one that was named Warfarin in honor of the Wisconsin Alumni Research Foundation (WARF) funding agency. Warfarin was first marketed as rodenticide in 1948 and was first approved for use in humans as an anticoagulant in 1954. Although vitamin K administration was recognized as an effective treatment for warfarin toxicity, the mechanism of action of warfarin, as an inhibitor of the enzyme vitamin K epoxide reductase, was not documented until 1978. More potent anticoagulant rodenticides were developed to combat resistant rodents. These second-generation anticoagulants have a longer half-life in the body; consequently, a rodent need only eat the anticoagulant-containing bait once to result in bleeding and death several days after ingestion. Unfortunately, these newer anticoagulants are also more lethal to other animals that eat the rodent bait and/or eat a rodent that has eaten the bait. Animals that have been poisoned with anticoagulant rodenticides include dogs, cats and wild mammals, as well as birds that ingest anticoagulant-containing grain and raptor and scavenger birds that eat poisoned rodents. Because of the slow clearance of second-generation anticoagulants, treatment with vitamin K must be continued for several weeks. Learn more here.