探讨CYP2C9及VKORC高活性对华法林抗凝的影响及对策

目的探讨细胞色素P450 2C9酶（CYP2C9）及维生素K环氧化物还原酶（VKORC）高活性患者对心瓣膜置换术后华法林抗凝的影响及对策。方法 2010年2月至2013年5月郑州大学第一附属医院心外科对CYP2C9及VKORC高活性40例患者行心瓣膜置换术,其中男18例、女22例,年龄40～51（45.18±2.93）岁。行二尖瓣置换术（MVR）18例,二尖瓣置换＋三尖瓣成形术（TVP）14例,双瓣膜置换术（DVR）8例。根据术前是否行CYP2C9和VKORC1基因多态性检测,分为两组,A组：20例,术前未行CYP2C9和VKORC1基因多态性检测;B组：20例,术前已行CYP2C9和VKORC1基因多态性检测。术后定期复查国际标准化比值（INR）,调整华法林用量,统计达到预期值时用药时间及并发症。随访时间3～12个月,出院后,每月1次电话随访,记录每次复查INR值、并发症发生及恢复情况。结果 A组2例术后发生脑梗死,2例发生腘动脉血栓,1例发生肺栓塞,1例出现瓣环血栓形成;14例分别于第15～20 d达到预期INR值,无明显血栓并发症。术后3个月行CYP2C9和VKORC1基因多态性检测,其中17例为CYP2C9＊1/＊1（＊2CC/＊3AA）阳性,VKORC1-1639 GA阳性;3例为CYP2C9＊1/＊1（＊2CC/＊3AA）阳性,VKORC1-1639 GG阳性。B组患者术后第2 d给予华法林推荐量的同时给予阿司匹林（100 mg/d）及低分子肝素（0.4 ml/d）,分别于第5～9 d达到华法林预期值,后停用阿司匹林及低分子肝素;随访6个月无明显血栓并发症,仅1例出现鼻腔出血并发症,经鼻孔填塞后好转。结论术前行CYP2C9和VKORC1基因多态性检测,对心瓣膜置换术后华法林抗凝治疗有重要的指导意义。

Influence of High Activity of CYP2C9 and VKORC on Warfarin Anticoagulation after Heart Valve Replacement

Objective To investigate the influence of high activity of CYP2C9 （Cytochrome P450 proteins 2C9） and VKORC （Vitamin K epoxide reductase C ） on warfarin anticoagulation of patients after heart valve replacement （HVR）. Methods From February 2010 to May 2013, 40 patients with high activity of CYP2C9 and VKORC underwent HVR in the Department of Cardiac Surgery, the First Affiliated Hospital of Zhengzhou University. There were 18 male and 22 female patients with their age of 40-51 （45.18 ± 2.93 ） years. There were 18 patients receiving mitral valve replacement （MVR）, 14 patients receiving MVR and tricuspid valvuloplasty （TVP）, and 8 patients receiving double valve replacement （DVR）. Depen- ding on whether they received preoperative genetic polymorphism detection of CYP2C9 and VKORC 1, all the patients were divided into 2 groups with 20 patients in each group. Patients in group A didn＇t receive preoperative genetic polymorphism detection of CYP2C9 and VKORC 1, while patients in group B received preoperative genetic polymorphism detection of CYP2C9 and VKORC1. Postoperatively, periodic examination of international normalized ratio （INR） was performed to adjust warfarin dosage. Time to reach expected INR value and morbidity were collected. All the patients were followed up for 3-12 months after discharge. Monthly telephone follow-up was performed to record INR values, morbidity and general recovery. Results Postoperatively, in group A, 2 patients had cerebral infarction, 2 patients had popliteal artery throm- bosis, 1 patient had pulmonary embolism, and 1 patient had thrombosis in the annulus. Expected INR was achieved 15-20 days after warfarin treatment among the other 14 patients without thromboembolism. Three months after surgery, CYP2C9 and VKORC1 gene polymorphism was examined to find 17 patients with positive CYP2C9＊ 1/＊1 （＊2CC/＊3AA） and positive VKORC 1-1639 GA, and 3 patients with positive CYP2C9＊ 1/＊ 1 （＊2CC/ 3AA ）and positive VKORC 1-1639 GG. In Group B,