One Rare Warfarin Resistance Case and Possible Mechanism Exploration

Li Zhao,1 Zhenguo Zhai,2 Pengmei Li1 1Pharmacy Department, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of ChinaCorrespondence: Pengmei Li, Pharmacy Department, China-Japan Friendship Hospital, No. 2 Yinghua East Road, Beijing, People’s Republic of China, Tel +86-1084205661, Email lipengmei@yeah.netAbstract: One 59-year-old female patient with deep venous thrombosis (DVT) and pulmonary embolism (PE) was treated with 6 mg warfarin once daily as an anticoagulant. Before taking warfarin, her international normalized ratio (INR) was 0.98. Two days after warfarin treatment, her INR did not change from baseline. Due to the high severity of the PE, the patient needed to reach her target range (INR goal = 2.5, range = 2~3) rapidly, so the dose of warfarin was increased from 6 mg daily to 27 mg daily. However, the patient’s INR did not improve with the dose escalation, still maintaining an INR of 0.97– 0.98. We drew a blood sample half an hour before administering 27 mg warfarin and detected single nucleotide polymorphism for the following genes, which were identified to be relevant with warfarin resistance: CYP2C9 rs1799853, rs1057910, VKORC1 rs9923231, rs61742245, rs7200749, rs55894764, CYP4F2 rs2108622, and GGCX rs2592551. The trough plasma concentration of warfarin was 196.2 ng/mL after 2 days of warfarin administration with 27 mg QD, which was much lower than the therapeutic drug concentration ranges of warfarin (500– 3,000 ng/mL). The genotype results demonstrate that the CYP4F2gene has rs2108622 mutation which can explain some aspect of warfarin resistance. Further investigations are necessary to fully characterize other pharmacogenomics or pharmacodynamics determinants of warfarin dose-response in Chinese.Keywords: anticoagulation, warfarin resistance, CYP2C9, VKORC1, CYP4F2, GGCX, warfarin plasma concentration