动脉瘤性蛛网膜下腔出血后迟发性脑缺血的早期凝血及纤溶生物标志物变化

Coagulative and fibrinolytic markers in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

目的通过对动脉瘤性蛛网膜下腔出血(aSAH)后早期血液凝血和纤溶相关标志物进行动态分析,探讨其与迟发性脑缺血(DCI)之间的关系,尝试从临床角度阐述微血栓形成机制在DCI发生发展中可能的潜在影响。方法前瞻性连续纳入2016年12月至2018年6月北京天坛医院发病3 d内的aSAH住院患者165例。入院后按照统一标准化方案分别采集患者入院时、发病后(4±1)、(7±1)、(10±1)、(13±1)d的血液样本,记录DCI患者及非DCI患者各时间点的部分血液凝血[包括凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、血小板计数、血管性血友病因子(vWF)抗原定量和vWF活性]及纤溶相关标志物参数(D-二聚体、纤维蛋白原)。PT、APTT、纤维蛋白原水平通过凝血酶测定,D-二聚体含量通过乳胶光度法测定,vWF抗原定量和vWF活性检测分别采用vWF抗原检测试剂盒和vWF活性检测试剂盒,并对两组间不同时间点各参数进行重复测量方差分析。结果DCI发生率为31.5%(52/165)。凝血及纤溶标志物相关结果显示,DCI患者在aSAH后早期即出现血管性血友病因子(vWF)抗原含量和活性升高,并在发病后(7±1)d达到高峰,DCI患者vWF抗原及活性水平较非DCI患者更高,两组间差异具有统计学意义(F值分别为6.873、5.784,P值分别为0.017、0.021),同时vWF抗原及活性水平与时间相关(F值分别为105.448、89.141,均P<0.01),且存在组别与采样时间之间的交互效应(F值分别为9.525、10.114,P值分别为0.022、0.016)。此外,DCI与不同采样时间对PT、APTT、血小板计数、D-二聚体、纤维蛋白原等水平无明显影响(均P>0.05),并且两组别与时间不存在交互作用(均P>0.05)。结论DCI患者vWF抗原含量及活性明显高于非DCI患者,提示可能存在微血栓形成,动态监测vWF抗原含量及活性有助于早期发现DCI。

Objective To explore the relationship between early blood coagulative and fibrinolytic markers and delayed cerebral ischemia( DCI) through the dynamically analyzing the change of early blood coagulative and fibrinolytic markers after aneurysmal subarachnoid hemorrhage( aSAH),aiming to explain the potential effect of the mechanism of micro-thrombosis in the development of DCI. Methods The trial was a prospective study that continuously enrolled 165 patients who had onset of aSAH within 3 days in Beijing Tiantan Hospital from December 2016 to June 2018. Blood samples were collected from each patient on admission and on day 4 ± 1,7 ± 1,10 ± 1,and 13 ± 1 after admission according to a unified,standardized protocol,a part of coagulative markers such as prothrombin time( PT),activated partial thromboplastin time( APTT),platelet count,von Willebrand factor( vWF) antigen and vWF activity,and fibrinolytic markers such as D-dimer,fibrinogen( Fbg),were examined by blood samples of included DCI patients and no-DCI patients at point of aforementioned time. PT,APTT and Fbg were measured by thrombin examination,D-dimer was measured by latex spectrophotometry,and vWF antigen and vWF activity were measured using the vWF antigen kit and vWF activity kit,respectively. These paraments in various time points between the DCI group and the non-DCI group were analyzed with the variance analysis of repeated measurement. Results The incidence rate of DCI was 31. 5%( 52/165). According to the analysis results of blood coagulative and fibrinolytic markers,the level and activity of vWF antigen in patients with DCI were increased in the early stage after aSAH and reached a peak on day 7 ± 1. The level and activity of the vWF antigen were higher in patients with DCI compared to non-DCI patients,which were significantly different( F = 6. 873,P = 0. 017;F = 5. 784,P = 0. 021,respectively. Meanwhile,the level and activity of the vWF antigen were relative to time( F = 105. 448,P < 0. 01;F = 89. 141,P < 0. 01,respectively) and these paraments had an interaction effect between the groups and sampling time points( F = 9. 525,P =0. 022;F = 10. 114,P = 0. 016,respectively). In addition,there was no statistical significance in PT,APTT,platelet count,D-dimer and Fbg in DCI group and at different sampling time points( All P > 0. 05)and these paraments didn't have an interaction effect between the two groups and sampling time point( All P > 0. 05). Conclusions Patients with DCI has a higher level and activity of vWF antigen compared to non-DCI patients,which indicates the possibility of microthrombosis. Therefore,it is contributed to early detect DCI by dynamically monitoring the level and activity of vWF.