Effect of Polymorphisms in the Cytochrome P450 CYP2C9 Gene on Warfarin Anticoagulation

Abstract

Warfarin is a widely used anticoagulant with efficacy in treatment and prevention of thrombosis. Patient management, however, is difficult because of interindividual variation in response to standard doses due to significant differences in metabolic rates. Warfarin metabolism is under genetic control, involving primarily the CYP2C9 gene encoding the enzyme that catalyzes the conversion of warfarin to inactive metabolites. Several polymorphisms of CYP2C9 have been reported; the variant alleles *2 and *3 have decreased enzymatic activity. The objective of this case study is to investigate the relationship between CYP2C9 genotype and warfarin anticoagulation. A case of deep vein thrombosis treated with the standard warfarin dose is investigated for intensity of anticoagulation and CYP2C9 genotype; the case illustrates the relationship between CYP2C9 variant and overanticoagulation with subsequent bleeding complication. The patient's genotype, CYP2C9*1*3, correlated with an exaggerated anticoagulant response during the initiation of warfarin therapy at standard dose, and a bleeding episode ensued. Based on heterozygosity for the *3 variant allele, it was recommended that the patient be maintained on a low-dose warfarin regimen. The practical implications of identifying genetic risk factors that lead to overanticoagulation are multiple. Genotype knowledge of the CYP2C9 variant alleles may help the clinician to individualize warfarin therapy with the ultimate goals of shortening the initial period of induction therapy, reaching a stable maintenance dose earlier, and minimizing bleeding complications in patients who are high responders and need lower warfarin doses.