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.