Department of Pharmacy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Key Laboratory of Assessment of Clinical Drugs Risk and Individual Application (Beijing Hospital), Beijing, P.R. China.
Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, P.R. China.
Clin Transl Sci. 2022 Apr;15(4):923-929. doi: 10.1111/cts.13205. Epub 2021 Dec 13.
Rivaroxaban is an oral anticoagulant that inhibits thrombin and blocks coagulation cascade through directly inactivating factors Xa. Despite rivaroxaban is widely used for prevention and treatment of venous thrombosis, and its common adverse reactions have been reported, including abnormal coagulation, mucosal hemorrhage, hematuria, and intracranial hemorrhage. To explore potential drivers of individual differences in adverse reactions induced by rivaroxaban, we performed whole-exome sequencing and found that AKR7A3 rs1738023/rs1738025 and ABCA6 rs7212506 are susceptible sites for rivaroxaban-related bleeding in aged patients treated with rivaroxaban. Gene functional annotation and signaling pathway enrichment indicated that homozygous mutations in AKR7A3 and ABCA6 might alter normal rivaroxaban transport and metabolism, and lead to continuous accumulation of activated drugs and toxic substances in vivo. Our results suggested that interindividual differences in bleeding events induced by rivaroxaban may be potentially driven by genetic alterations related to abnormal metabolism and transport of rivaroxaban.
利伐沙班是一种口服抗凝剂，通过直接灭活因子 Xa 来抑制凝血酶并阻断凝血级联反应。尽管利伐沙班被广泛用于预防和治疗静脉血栓形成，但其常见的不良反应已被报道，包括凝血异常、黏膜出血、血尿和颅内出血。为了探索利伐沙班相关不良反应个体差异的潜在驱动因素，我们进行了全外显子组测序，发现 AKR7A3 rs1738023/rs1738025 和 ABCA6 rs7212506 是接受利伐沙班治疗的老年患者发生利伐沙班相关出血的易感位点。基因功能注释和信号通路富集分析表明，AKR7A3 和 ABCA6 的纯合突变可能改变利伐沙班的正常转运和代谢，导致体内激活药物和有毒物质的持续积累。我们的研究结果表明，利伐沙班引起的出血事件的个体间差异可能是由与利伐沙班异常代谢和转运相关的遗传改变所驱动的。
