Pharmacogenetics in the Management of Coumarin Anticoagulant Therapy The Way Forward or an Expensive Diversion 英文参考文献.docVIP

Open access, freely available online Perspectives Pharmacogenetics in the Management of Coumarin Anticoagulant Therapy: The Way Forward or an Expensive Diversion? Mike Greaves W arfarin and related coumarin- based anticoagulants are the mainstay of pharmacological life-threatening bleeding is around two per 100 patient years and more minor bleeding is common [2]. This is despite the widespread adoption of the International Normalised Ratio (INR) as the method for standardisation of the prothrombin time, the coagulation assay used to measure the anticoagulant effect of warfarin. For most clinical indications, dosing is aimed at achieving a target INR of 2.5 (range 2.0–3.0), which represents a level of anticoagulation associated with an optimal relationship between antithrombotic ef?cacy and bleeding risk. However, even with the best available management, individual sensitive, and African Americans less sensitive, than those of European ancestry [5,6]. This suggestion has now been con?rmed; a signi?cant proportion of the variation in warfarin sensitivity, including the variation between ethnic groups, can be accounted for by polymorphisms within the recently identi?ed VKORC1 gene that in?uence transcriptional regulation [7]. This ?nding complements the earlier observation that variations in the rate of coumarin metabolism, due to the functional effects of polymorphisms in Cyp2C9, also contribute to individual coumarin sensitivity [8], as may polymorphisms in the genes for coagulation factors II and VII [9]. These ?ndings raise the question of whether advances in understanding of the pharmacogenetics of oral anticoagulant therapy could management for the long-term prevention of thromboembolism. It is estimated that over 1 million residents in the United Kingdom take warfarin; in excess of 20 million prescriptions for the anticoagulant are dispensed each year in the United States of America. Despite recent advances in the development of novel, alternative, oral an