thesis
Pharmacogenetic Aspects and Drug Interactions in Anticoagulation Therapy with Coumarins
- Publication date
- 18 February 2011
- Publisher
- 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.