Pharmacogenetic Aspects and Drug Interactions in Anticoagulation Therapy with Coumarins
Farmacogenetische aspecten en geneesmiddelinteracties bij antistollingstherapie met coumarines
The mysterious ability of blood to clot has fascinated people over millennia. In the beginning of the 20th century, the mechanisms became better understood. In 1922, the development of hemorrhagic disease in cattle caused by mouldy sweet clover was described by Schofield. The absence or delay of blood clotting was correlated to a greatly diminished quantity of prothrombin. This discovery remained unnoticed until twenty years later the ‘hemorrhagic agent’ was identified as dicoumarol, 3,3-methylene-bis. It was promptly made available for clinical studies and already one year later first experiences on the effectiveness in deep vein thrombosis as well as its hemorrhagic complications were published. From the coumarin derivates synthesized, the most potent one was warfarin, an acronym for the Wisconsin Alumni Research Foundation (WARF). As it was used successfully to fight rats, its name may also contribute to that ‘warfare’. It was patented in 1948 and is since then the most frequently used coumarin worldwide. In 1929, Dam observed haemorrhage and markedly prolonged coagulation times in chickens fed with diets from which fat was completely extracted. He concluded that the substance whose absence in the diet was responsible for the coagulation and bone growth pathologies should be a new fat-soluble vitamin which he named vitamin K (“Koagulation”). For the discovery of vitamin K and the purification, characterization and synthesis of the vitamin, Dam and Doisy were awarded the Nobel Prize in Medicine in 1943. It was known then empirically that vitamin K reversed the bleeding problem of mouldy sweet clover poisoning. However, it took three more decades until the vitamin K cycle was proposed in 1974. After another three decades, in 2004, the complex biochemical relationship between vitamin K, its epoxide, and coumarins was enlightened by identifying the VKORC1 gene. This gene encodes the protein which is the target of the coumarins. Genetically mutated variants of the gene have been shown to cause warfarin-resistance phenotypes as well as pathogenic deficiency of all vitamin K-dependent coagulation factors.