Laboratory Support for Warfarin Monitoring

Warfarin use has declined with increased adoption of oral direct thrombin and direct factor (F) Xa inhibitors, but warfarin remains an important oral anticoagulant for patients with contraindications to or indications not currently covered by direct oral anticoagulant therapy, and for those with financial constraints that limit access to these medications. Warfarin is a vitamin K antagonist, which exerts its anticoagulant effect by interfering with γ-carboxylation of glutamate residues of the N-terminus of FII, FVII, FIX, and FX through inhibition of enzymatic reduction of vitamin K, resulting in reduced coagulant activity. However, warfarin also inhibits carboxylation of the natural occurring anticoagulants, proteins C, S, and Z, producing a less dominant, paradoxical procoagulant effect.

Warfarin is available as a racemic mixture of R and S enantiomers with a half-life of 36–42 hours, and its pharmacodynamics are strongly influenced by both environmental and genetic factors. As a result, frequent monitoring is required to maintain therapeutic dosing while minimizing the risk of sub- or supratherapeutic levels. The prothrombin time (PT) calculated in the form of the international normalized ratio (INR) is traditionally used to monitor warfarin treatment and remains the mainstay of warfarin monitoring. Genetic testing, including analysis of mutations of the cytochrome P450 complex CYP2C9 and vitamin K epoxide reductase (VKOR), has led to an explanation of the extremes of physiologic warfarin responses and a potential for more individualized treatment; however, prospective pharmacogenomic testing has not widely been adopted because of discrepant results from randomized controlled trials but may be reconsidered given results from a recent study.