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Evaluation of oral anticoagulants with vitamin K epoxide reductase in its native milieu

Xuejie Chen, Da-Yun Jin, Darrel W. Stafford and Jian-Ke Tie

Key points

  • Acenocoumarol is the most efficient oral anticoagulant with the least variation of resistance among naturally occurring VKOR mutations.

  • Warfarin and fluindione are equipotent for anticoagulation control but have different mechanisms of action on VKOR inactivation.

Abstract

Warfarin, acenocoumarol, phenprocoumon, and fluindione are commonly prescribed oral anticoagulants for the prevention and treatment of thromboembolic disorders. These anticoagulants function by impairing the biosynthesis of active vitamin K-dependent coagulation factors through the inhibition of vitamin K epoxide reductase (VKOR). Genetic variations in VKOR have been closely associated with the resistant phenotype of oral anticoagulation therapy. However, the relative efficacy of these anticoagulants, their mechanisms of action, and their resistance variations among naturally occurring VKOR mutations remain elusive. Here, we explored these questions using our recently established cell-based VKOR activity assay with the endogenous VKOR function ablated. Our results show that the most-to-least efficacy of these anticoagulants on VKOR inactivation are: acenocoumarol > phenprocoumon > warfarin > fluindione. This is consistent with their effective clinical dosages for stable anticoagulation control. Cell-based functional studies of how each of the twenty-seven naturally occurring VKOR mutations responds to these four oral anticoagulants indicate that phenprocoumon has the largest resistance variation (up to 199-fold), while the resistance of acenocoumarol varies the least (<14-fold). Cell-based kinetics studies show that fluindione appears to be a competitive inhibitor of VKOR, while warfarin is likely to be a mixed-type inhibitor of VKOR. The anticoagulation effect of these oral anticoagulants can be reversed by the administration of a high dose of vitamin K, apparently due to the existence of a different enzyme that can directly reduce vitamin K. These findings provide new insights into the selection of oral anticoagulants, their effective dosage management, and their mechanisms of anticoagulation.

  • Submitted May 7, 2018.
  • Accepted August 5, 2018.