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Warfarin Sensitivity Genotyping

Warfarin Pharmacodynamics

Slide 15

August 2008

A second issue in warfarin sensitivity genotyping deals with warfarin pharmocodynamics. Warfarin achieves its anticoagulation effect by inhibiting the vitamin K cycle in the liver. What happens is that vitamin K is required to perform post-translational modification of the partially deficient coagulation factors that are synthesized in the hepatocytes. This is done by vitamin K being used by Gamma Glutammyl Carboxylase to perform post-translational modification of glutammyl groups in these coagulation factors.

In this process vitamin K, that is reduced, is oxidized, then it is re-reduced through the action of the vitamin K epoxide reductase complex VKORC1. When warfarin is present, S-warfarin and R-warfarin, S- being more effective at inhibiting VKORC1, it blocks the cycle, it reduces how much vitamin K can be reduced while going through the cycle. When that happens, when vitamin K is not reduced, there is a block, so vitamin K oxidized form begins to build up. When that happens, there is less vitamin K reduced-form available for the carboxylation reaction. And when that occurs, it blocks the coagulation factors from being post-translationally modified and as a result there are fewer functional coagulation factors available to perform coagulation in the body.

Warfarin Pharmacodynamics


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