Evaluation of VKORC1 and Cytochrome P450 CYP2C9 Gene Polymorphisms and Management of Warfarin Dose Using Pharmacogenetic Data

Long-term anticoagulation therapy with warfarin is recommended for patients with atrial fibrillation/flutter (AF), left atrial thrombus, deep vein thrombosis (DVT), pulmonary thromboembolism (PE), mechanical heart valve replacement, cardiomyopathy, and ischemic stroke. Warfarin, a coumarin derivative, produces an anticoagulant effect by interfering with the vitamin K 2,3 epoxide reductase (VKOR) enzyme and γ-carboxylation of vitamin K-dependent clotting factors such as II, VII, IX, and X. However, management of warfarin therapy is complicated with interindividual differences in drug response, delayed onset of action, difficulty with reversal and a narrow therapeutic window leading to increased risk of life-threatening hemorrhagic adverse events or thromboembolism. Furthermore, in order to determine safe and effective loading dose during the early phase of therapy and maintenance doses require frequent laboratory monitoring and adjustments to compensate for changes in patients' age, body size, vitamin K intake through diet, disease state, comorbidities, concomitant use of other medications, and patient-specific genetic factors.

Poor anticoagulant control may cause fatal complications such as thromboembolism with undertreatment or bleeding with excessive anticoagulation. Indeed, the risk of major bleeding in patients on warfarin is between 1% and 5% per year. Identifying the optimal therapeutic range and managing the dose of therapy to achieve the maximal time in therapeutic range are two of the most important determinants of therapeutic effectiveness and of reducing hemorrhagic risk. Currently, there have been substantial efforts to improve the safety of warfarin anticoagulation therapy. Recent warfarin pharmacogenetic studies have largely focused on two candidate genes: CYP2C9, responsible for warfarin metabolism, and VKORC1, which encodes vitamin K epoxide reductase, the site of warfarin action. Current evidence is clear that polymorphisms in either CYP2C9 or VKORC1 affect warfarin sensitivity.

We aimed to use pharmacogenetic information in clinical practise which may lead to rapid, efficient, and safe warfarin dosing in this observational prospective study. In this context, we plan to develop an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from the Turkish study population. This study is unique not only investigating clinical factors, demographic variables, CYP2C9, and VKORC1 gene variations which contribute to the variability among patients in dose requirements for warfarin but also including thrombogenic single nucleotide polymorphisms (SNP) in the same patient population. Thus, warfarin would be a good example by being the first cardiovascular drug for pharmacogenetic guided "personalized medicine" applications.