川崎病合并冠状动脉瘤患儿应用华法林治疗的安全性

目的探讨川崎病合并冠状动脉瘤患儿应用华法林治疗的安全性和转归。方法选择2011至2020年湖南省人民医院收治的川崎病合并巨大冠状动脉瘤、1支冠状动脉血管内发生多个冠状动脉瘤或冠状动脉内发生血栓的患儿共21例进行前瞻性研究,应用华法林治疗,将国际标准化比值(INR)目标范围控制在2.0~3.0。在治疗开始时,治疗后1、2、3、4周及2、3、6、12个月,观察治疗前后冠状动脉瘤直径、数量、部位和冠状动脉内血栓的变化,并监测INR、心电图、肌酸激酶同工酶(CK-MB)、肌钙蛋白I。实施规范的华法林出血风险培训与管理,并根据家长实际落实情况,分为落实组和未落实组,比较2组患儿出血的发生情况。组间比较采用秩和检验或Fisher确切概率法。结果21例患儿男15例、女6例,发病年龄为2月龄至6岁。入组时评估冠状动脉病变为Ⅱ级有4例、Ⅲ级有7例、Ⅳ级有7例、Ⅴ级有3例。10例发生血栓的患儿临床发现血栓的时间为病程第4天至4个月。应用华法林治疗后,其剂量分布在0.06~0.10 mg/(kg·d),INR为1.80~2.59,10例有血栓的患儿有8例消失,2例未消失的Ⅴ级患儿的血栓有不同程度机化。治疗后,4例Ⅱ级病变患儿的冠状动脉均恢复正常;7例Ⅲ级病变患儿中有3例冠状动脉瘤消失,4例无改变;7例Ⅳ级病变患儿中5例冠状动脉瘤缩小为Ⅲ级,2例无改变;3例Ⅴ级病变患儿瘤体无改变。治疗后均没有新发血栓及新冠状动脉瘤出现。21例患儿治疗前后心电图无特殊改变,治疗前后肌钙蛋白I和CK-MB差异均无统计学意义[0.07(0~3.01)比0.04(0~0.29)μg/L,20.6(11.2~58.2)比29.0(16.7~47.0)U/L,Z=0.932、1.906,均P>0.05]。华法林出血风险管理落实组患儿出血发生率明显低于未落实组,差异有统计学意义(2/15比4/6,Fisher值=5.689,P=0.031)。结论应用INR 2.0~3.0为目标范围,结合川崎病并冠状动脉瘤的严重程度来调整华法林剂量,并予以规范而严格的管理与培训,可增加川崎病患儿华法林治疗的安全性,改善患儿的冠状动脉病变,治疗血栓及预防新血栓,降低出血风险。

Safety of warfarin therapy in children with coronary aneurysm due to Kawasaki disease

Objective To investigate the safety of warfarin for Kawasaki disease(KD)with coronary artery aneurysm(CAA)and its prognosis.Methods Twenty one children with KD complicated with giant CAA,multiple CAA in one coronary artery or thrombosis in coronary artery were enrolled in this prospective study.Warfarin was used to control the goal international normalized ratio(INR)ranging from 2.0 to 3.0.The CAA diameter,number,location and thrombus in coronary artery were recorded at the beginning of treatment,1,2,3,4 weeks and 2,3,6,12 months after treatment,as well as the influence on INR,electrocaroliogram,creatine kinase-MB(CK-MB),troponin I.Standardized warfarin bleeding risk training and management was implemented.Children were divided into implementation group and non-implementation group according to the status of actual implementation of their parents.The incidence of bleeding events was compared between the two groups.Comparisons between groups were performed using a Rank sum test and a Fisher exact test.Results In the 21 patients(15 males and 6 females),the age of onset ranged from 2 months to 6 years.There were 4 cases with gradeⅡ,7 cases with gradeⅢ,7 cases with gradeⅣand 3 cases with gradeⅤaccording to the severity of coronary arterial lesions before treatment.The time of clinical detection of thrombus in 10 children with thrombosis ranged from the fourth day to the fourth month.The dose distribution of warfarin was 0.06-0.10 mg/(kg·d),and the INR was 1.80-2.59.Among the 10 cases with thrombus,8 cases had disappearance of thrombi and 2 cases with gradeⅤhad thrombus organization to different degree.After treatment,the coronary artery ectasia of the 4 cases with gradeⅡall returned to normal.Among the 7 cases with gradeⅢ,3 cases of coronary artery aneurysms returned to normal,and 4 cases did not change.Among the 7 cases with gradeⅣ,5 cases of coronary artery aneurysms shrank to gradeⅢ,and 2 cases remained unchanged.Three cases with gradeⅤlesions had no changes in aneurysm.Neither new thrombus nor new CAA was detected during the treatment.There was no significant change in electrocardiogram before and after treatment.No statistically significant difference was found regarding the troponin I(0.07(0-3.01)vs.0.04(0-0.29)μg/L,Z=0.932,P>0.05)and CK-MB(20.6(11.2-58.2)vs.29.0(16.7-47.0)U/L,Z=1.906,P>0.05)before and after treatment.The incidence of bleeding events in the implementation group was significantly lower than that in the non-implementation group(2/15 vs.4/6,Fisher=5.689,P=0.031).Conclusions The application of goal INR of 2.0-3.0 and adjustment of warfarin dose according to the severity of CAA combined with standardized and strict warfarin bleeding risk training and management,can increase the safety of warfarin therapy in children with KD,improve the prognosis of coronary artery lesions,promote the dissolution of thrombi,prevent new thrombosis,and effectively reduce the incidence of bleeding complication.