How do vitamin K antagonists (VKAs) work?

By William Aird

The VKAs produce their anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide), thereby modulating the gamma-carboxylation of glutamate residues (Gla) on the N-terminal regions of vitamin K-dependent proteins, which include factors II, VII, IX, and X. The vitamin K-dependent coagulation factors require gamma-carboxylation for their procoagulant activity. Carboxylation is required for a calcium-dependent conformational change in coagulation proteins that promotes binding to cofactors on phospholipid surfaces. In addition, the VKAs inhibit carboxylation of the regulatory anticoagulant proteins C, S, and Z and thereby have the potential to be procoagulant.

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The enzyme that modifies the vitamin K-dependent proteins such as factors II, VII, IX and X, is the vitamin K-dependent carboxylase (or vitamin K-dependent gamma glutamyl carboxylase [GGCX]). This enzymes results in the carboxylation of of Glu to Gla residues. Concomitant with this modification, a reduced vitamin K molecule is converted to vitamin K epoxide. Before it can be reused, this vitamin K epoxide must be converted back to reduced vitamin K by the vitamin K epoxide reductase (VKOR). It is not known whether the conversion of vitamin K to reduced vitamin K is accomplished by VKOR or a separate enzyme. Thus, the unidentified reductase is referred to simply as vitamin K reductase (VKR) or vitamin K quinone reductase. Warfarin inhibits vitamin K epoxide reductase complex subunit 1 (VKORC1), thereby dampening the carboxylation and the procoagulant potential of vitamin K–dependent coagulation factor. To the extent that VKOR contributes to the conversion of vitamin K to reduced vitamin K, warfarin inhibits both reduction steps (indicated by red line).