Pharmacogenetics of warfarin: challenges and opportunities

Abstract

Since the introduction in the 1950s, warfarin has become the commonly used oral anticoagulant for the prevention of thromboembolism in patients with deep vein thrombosis, atrial fibrillation or prosthetic heart valve replacement. Warfarin is highly efficacious; however, achieving the desired anticoagulation is difficult because of its narrow therapeutic window and highly variable dose response among individuals. Bleeding is often associated with overdose of warfarin. There is overwhelming evidence that an individual's warfarin maintenance is associated with clinical factors and genetic variations, most notably polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase subunit 1. Numerous dose-prediction algorithms incorporating both genetic and clinical factors have been developed and tested clinically. However, results from major clinical trials are not available yet. This review aims to provide an overview of the field of warfarin which includes information about the drug, genetics of warfarin dose requirements, dosing algorithms developed and the challenges for the clinical implementation of warfarin pharmacogenetics.

VKORC1-1639G/A and 1173 C/T Genetic Polymorphisms Influence Individual Differences in Warfarin Maintenance Dose

“…W arfarin is a common oral anticoagulant to prevent thromboembolic diseases in patients with recurrent stroke, deep vein thrombosis, atrial fibrillation (AF), and cardiac valve replacement (CVR) (Lee and Klein, 2013). Warfarin antagonizes the action of vitamin K-dependent coagulation factors II, VII, IX, and X by inhibiting vitamin K epoxide reductase complex 1 (VKORC1), thereby lowering the vitamin K amount available as a cofactor for clotting proteins, effectively preventing clotting (de Visser et al, 2011;Eriksson and Wadelius, 2012).…”

Systems-Based Approach to Drug Response

“…The final treatment decision requires cooperation between physicians and patients. By guiding the initial warfarin dose, PGx algorithms incorporating genetic and clinical factors may improve the safety of initiation of warfarin therapy [16,17]. Patients should be provided with appropriate and sufficient explanations by scientists and physicians as to why they should, or should not, select a specific drug.…”

Nichtkardiochirurgische operative Eingriffe bei Patienten nach Implantation eines „ventricular assist device“

“…Verschiedene Erkrankungen, wie z. B. Vorhofflimmern oder künstli-che Herzklappen, erfordern eine dauerhafte Antikoagulation [30]. Ein zusätz-liches Blutungsrisiko besteht jedoch für VAD-Patienten durch die häufig auftretende Entwicklung des Von-WillebrandSyndroms (vWS) [6].…”