基因指导华法林相关颅内出血术后重启抗凝的临床观察

Genotype-guided postoperative anticoagulant therapy in patients with warfarin-associated intracranial hemorrhage

目的探讨细胞色素P4502C9（CYP2C9）和维生素K环氧化物还原酶1（VKORC1）基因型在华法林相关颅内出血（WICH）术后患者重启抗凝中的作用。方法前瞻性纳入首都医科大学附属北京安贞医院神经外科2015年5月至2017年1月心脏瓣膜置换术后发生WICH的汉族患者28例，所有患者于颅内出血术后14 d重启华法林治疗。按照是否接受基因检测，分为基因组（12例）和对照组（16例）。基因组根据患者的CYP2C9和VKORC1基因型，计算华法林初始剂量；对照组按照常规治疗方法，初始华法林剂量为3 mg/d。两组均根据国际标准化比值（INR）调整华法林用量（INR目标值为1.8～2.4）。随访3个月（91 d），对比两组INR达到目标值所需的时间、INR达目标值持续的时间在91 d中所占的百分比（达标时间百分比）及颅内外出血或缺血事件的发生率。结果28例患者中共有21例患者完成随访，其中基因组9例，对照组12例。基因组中，8例基因型为CYP2C9 CC/AA ＋VKORCl AA，1例为CYP2C9 CC/AA ＋VKORCl GA。基因组和对照组INR达到目标值所需时间分别为（7.0±3.2）d、（12.0±5.9）d，INR达标时间百分比分别为（76±13）%、（56±14）%，差异均有统计学意义（P＝0.032，P＝0.006）。对照组再发硬膜下血肿2例，无缺血事件发生；基因组无一例发生出血和缺血事件，两组出血事件发生率差异无统计学意义（P＝0.314）。结论与传统抗凝比较，采用基于个体化基因型指导的WICH术后重启华法林治疗模式，INR达标时间短、在达标范围时间更久，安全有效。

ObjectiveTo evaluate the efficacy and safety of genotype-guided postoperative anticoagulant therapy in patients with warfarin-associated intracranial hemorrhage （WICH）.MethodsClinical and genetic data of 28 patients were investigated in this prospective study who developed WICH following cardiac valve surgery at Beijing Anzhen Hospital from May 2015 to January 2017. Warfarin treatment was restarted 14 days after surgical operation of intracranial hemorrhage. Based on whether genetic testing was conducted with consent, 28 patients were divided into genome and control groups. In the genome group, genotypes of CYP2C9 and VKORC1 were detected by pre-detection. The guideline dose was decided based on the genetic test results. Doses of warfarin were prescribed according to pharmacogenetic-based algorithms in genome group, while conventional standard doses （3 mg/d） of warfarin were administered in control group. In both groups, the doses were adjusted according to international normalized ratio （INR） and the values were monitored routinely and maintained in the range of 1.8-2.4. All patients were followed up for 3 months to compare the time to target INR, the time percentage of standard anticoagulation and major bleeding/thromboembolic events between 2 groups.ResultsA total of 21 patients completed follow-up including 9 in genotype group and 21 cases in control group. The genotypes in genotype group were CYP2C9 CC/AA ＋ VKORCl AA in 8 cases and CYP2C9 CC/AA ＋ VKORCl GA in 1 case. The time required for INR to reach the target value was 7.0 ± 3.2 days in the genome group and 12.0 ± 5.9 days in control group. The genotype group had a shorter time to target INR （P=0.032）. The time percentages of satisfied anticoagulation was 76±13% in genome group and 56±14% in control group, which were significantly different （P=0.006）. In the control group, there were 2 cases of subdural hematoma and no ischemic events. There was no bleeding or ischemic events in the genotype group. There was no significant difference in the incidence of major hemorrhagic events between 2 groups （P=0.314）.ConclusionsGenotype-guided anticoagulant therapy seems safe, effective and advantageous to conventional one for postoperative re-initiation of warfarin administration in patients with WICH in terms of time to target INR and its duration.