Study of environmental and genetic factors determining warfarin toxicity

Abstract

INTRODUCTIONWarfarin is widely used anticoagulant in treatment and prevention of thrombosis, in chronic atrial fibrillation, mechanical valves, and pulmonary embolism. Despite its common use, warfarin can be associated with bleeding complications.1-3 Achieving a safe therapeutic response can be difficult because of its narrow therapeutic index (1-20mg/d) and great variability in dose required, which is mostly a consequence of individual genetic variants and environmental factors like age, gender, diet, drug interactions. To maintain a therapeutic level, warfarin therapy requires intensive monitoring via INR. Bleeding is most common effect of warfarin toxicity. 4,5 Major bleeding complications include GI haemorrhage, intracranial bleeding, and retroperitoneal bleeding. Minor bleeding complications include subconjuctival haemorrhage, haematuria, epistaxis, and ecchymoses. A review of many studies show average yearly rates of warfarin related bleeding as high as 0.5%, 4.9% , 15% for fatal, major, minor bleeding complications. In spite of ABSTRACT Background: Warfarin is widely used anticoagulant in treatment and prevention of thrombosis. Despite its common use, warfarin can be associated with bleeding complications because of its narrow therapeutic index. A review of many studies show average yearly rates of warfarin related bleeding as high as 0.5% , 4.9% , 15% for fatal, major, minor bleeding complications. The study is to determine age, gender, pharmacogenetics, drugs influencing warfarin toxicity in Indian patients. Methods: Observational and cross-sectional study was conducted over period of 1 year after obtaining institutional ethics committee permission. Written and informed consent was taken from patients admitted in tertiary care hospital who fulfilled inclusion and exclusion criteria. Results: Most common age for Warfarin toxicity in our study was between 30 to 39 years (22.5%) with mean of 42.9 years. Bleeding risk was higher in elderly with 14 out of 26 patients with age >50 years had bleeding manifestations. Toxicity was more prevalent in female (60%). 40% patients were on drugs interacting with warfarin; NSAIDS (Nonsteroidal Anti-Inflammatary Drug) and antibiotics were the most common interacting drugs. In our study, 17.5% patients had acute liver disease and one patient had deranged creatinine (2.6). 40% of patients had VKORC1 variants and 35% of patients had CYP2C9 variants. Maximum patients developed toxicity within 15-30 days of initiation of warfarin. Conclusions: Warfarin toxicity has multifactorial cause. Drugs and Genetic variation are most common factors influencing warfarin toxicity. Warfarin toxicity has low mortality rate, although it increases with (International Normalised Ratio) INR>10 and with increasing age.