Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
J Thromb Thrombolysis. 2013 Jan;35(1):90-4. doi: 10.1007/s11239-012-0769-8.
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, CYP2C2 and CYP2C3 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.
一些研究已经将细胞色素 P450 2C9（CYP2C9）和维生素 K 环氧化物还原酶复合物 1（VKORC1）基因编码的突变与降低 VKA 剂量需求和增加出血风险联系起来。然而，将基因分型作为常规实践的实施仍然存在争议。我们的研究旨在调查遗传因素、VKORC1-c.1639A、CYP2C2 和 CYP2C3 的存在对因抗凝治疗极不稳定而被转诊到抗凝服务的门诊患者的影响。2008 年至 2011 年，共有 68 名平均年龄为 65.9 岁的患者纳入研究。他们是由初级保健医生转诊过来的，因为他们在开始抗凝治疗期间无法维持治疗范围。基因分型结果显示，17 名（25%）患者为 CYP2C9 和 VKORC1 变异等位基因的携带者，38 名（55.9%）患者为 VKORC1 c.1639AA 携带者，6 名（8.8%）患者为 CYP2C9 变异等位基因携带者，而 7 名（10.3%）患者为野生型等位基因携带者。入院时的 INR 控制表明，其中 34 名（50%）患者存在过度抗凝，而 12 名（17.6%）患者随后出现出血并发症。在过度抗凝的患者中，32 名患者同时携带 CYP2C9 和 VKORC1 基因或 VKORC1 突变等位基因，而 2 名患者携带野生型等位基因。除了 CYP2C9 或 VKORC1 等位基因的存在外，年龄较大是与低剂量和过度抗凝风险相关的重要因素。基因型（CYP2C9/VKORC1）和年龄是导致 VKA 起始时出现极端反应和随后出血并发症的最重要因素。
