细胞色素氧化酶P450基因多态性对心脏机械瓣膜置换患者术后华法林抗凝剂量的影响

Effect of cytochrome oxidase P450 gene polymorphism on postoperative anticoagulant dosage of warfarin in patients undergoing mechanical heart valve replacement

目的探讨细胞色素氧化酶P450(CYP2C9)基因多态性对心脏机械瓣膜置换患者术后华法林抗凝剂量的影响。方法择期行心脏瓣膜置换术的瓣膜性病变患者522例,采用聚合酶链反应-限制性内切酶片段长度多态性技术检测患者CYP2C9基因型,根据CYP2C9基因型进行分组,CYP2C9*1/*1为强代谢(EM)组,含有CYP2C9*2或*3为弱代谢(PM)组,记录患者术后连续6 d华法林用量、凝血酶原时间(PT)值及国际标准化比值(INR),比较两组华法林初始治疗抗凝过量的情况。结果 CYP2C9*1/*1共466例(89.3%);CYP2C9*1/*2共6例(1.15%);CYP2C9*1/*3共42例(8.05%);CYP2C9*2/*3共8例(1.53%),EM组466例,PM组56例。各组不同时间点的华法林用量比较,差异有统计学意义(P<0.05),EM组的华法林用量在术后4 d较首次剂量明显减少,PM组的华法林用量在术后3 d较首次剂量明显减少,术后4、5、6 d持续减少;术后4、5、6 d PM组华法林用量明显低于EM组(P<0.05)。两组不同时间点的PT值及INR比较,差异均有统计学意义(P<0.05),两组PT值及INR于术后2 d开始增高,术后4 d上升到最高水平;术后3、4、5 d PM组的PT值及INR高于EM组(P<0.05)。PM组出现华法林抗凝过量者比例为62.5%,高于EM组的6.0%(P<0.05)。结论CYP2C9基因多态性检测结合临床检验对心脏机械瓣膜置换术后华法林抗凝剂量的确定具有重要指导意义。

Objective To explore the effect of cytochrome oxidase P450（ CYP2C9） gene polymorphism on postoperative anticoagulant dosage of warfarin in patients undergoing mechanical heart valve replacement. Methods A total of 522 patients with valvular disease undergoing selective heart valve replacement were selected. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the CYP2C9 genotype in the patients. Then the patients were grouped according to the CYP2C9 genotypes. The patients with CYP2C9＊ 1 / ＊ 1 were enrolled as extensive metabolizer（ EM） group,and the patients with CYP2C9＊ 2 or ＊ 3 as poor metabolizer（ PM） group. The dosages of warfarin,prothrombin time（ PT） and international normalized ratio（ INR） were recorded for 6 consecutive days after surgery. The incidences of overdose of warfarin for initial anticogulation were compared between the two groups. Results CYP2C9 ＊ 1 / ＊ 1,CYP2C9 ＊ 1 / ＊ 2,CYP2C9 ＊ 1 / ＊ 3and CYP2C9＊ 2 / ＊ 3 were found in 466 patients（ 89. 3%）,6 patients（ 1. 15%）,42 patients（ 8. 05%） and 8 patients（ 1. 53%） respectively.And 466 cases were included in EM group and 56 cases in PM group. There was significant difference in the dosage of warfarin among different time points in each group（ P〈0. 05）. The dosage of warfarin in EM group reduced significantly on the postoperative 4th day compared to the initial dosage,while the dosage in PM group reduced significantly on the postoperative 3rd day compared to the initial dosage and continued to reduce on the postoperative 4th,5th and 6th day. The dosages of warfarin in PM group were less than those in EM group on the postoperative 4th,5th and 6th day（ P〈0. 05）. There were significant differences in PT and INR among different time points in each group（ P〈0. 05）. PT and INR in both groups began to increase on the postoperative 2nd day and reached the highest level on the postoperative4 th day. The levels of PT and INR in PM group were higher than those in EM group on the postoperative 3rd,4th and 5th day（ P〈0. 05）.The proportion of patients with overdose of warfarin for anticoagulation in PM group was higher than that in EM group（ 62. 5% vs. 6. 0%,P〈0. 05）. Conclusion The detection of CYP2C9 gene polymorphism in combination with clinical laboratory is significant for determining the anticogulation dosage of warfarin after mechanical heart valve replacement.