Several studies have linked mutations in the genes encoding
cytochrome P450 2C9 (
CYP2C9) and
vitamin K epoxide reductase complex 1 (VKORC1) to a reduced VKA dose requirement and an increased risk of
bleeding. Nevertheless, implementation of genotyping as a routine practice is still controversial. Our study was conducted in order to investigate the impact of genetic factors, presence of VKORC1-c.1639A,
CYP2C*2 and
CYP2C*3 among outpatients referred to Anticoagulation Service due to extremely unstable
anticoagulant therapy. From 2008 to 2011, 68 patients, mean age 65.9, were included in the study. They were referred from primary care physicians due to inability to sustain the therapeutic range in the period of initiation of
anticoagulant therapy. Genotyping results showed that 17 (25%) of them were carriers of both
CYP2C9 and VKORC1 variant alleles, 38 (55.9%) were carriers of VKORC1 c.1639AA, 6 (8.8%) were carriers of
CYP2C9 variant alleles, while 7 (10.3%) of them were carriers of wild type alleles. INR control upon admission showed that 34 (50%) of them were over-anticoagulated, while 12 (17.6%) of them had subsequent
bleeding complications. Among over-anticoagulated patients, 32 were carriers of mutated alleles in both
CYP2C9 and VKORC1 gene or VKORC1 alone, while 2 of patients carried wild type alleles. In addition to presence of
CYP2C9 or VKORC 1 alleles, older age was an important factor related to a lower dose and risk for over-anticoagulation. Genotype (
CYP2C9/VKORC1) and age are the most important factors that could predispose an extreme response and subsequent
bleeding complications during the initiation of VKA.