凝血酶生成试验在预测血管性血友病患者出血倾向中的作用

The application of thrombin generation test for assessing hemorrhagic tendency in patients with von Willebrand disease

目的:评估凝血酶生成试验(thrombin generation test,TGT)在预测血管性血友病(von Willebrand disease,vWD)患者出血倾向中的应用价值。方法:选取2018年1月至2019年7月就诊于上海交通大学医学院附属瑞金医院的vWD患者38例,并根据出血严重程度分为轻度出血组(包括8例1型患者)、中度出血组(包括8例2A型和6例2M型患者)和重度出血组(包括2例2N型、6例重型1型和8例3型患者)。另选同期相同年龄段的5名健康体检者作为正常对照组。采集乏血小板血浆,分别检测患者与正常对照者间在1 pmol/L组织因子(tissue factor,TF)和5 pmol/L TF试剂激活下的凝血酶生成能力的差异,并分析TGT各参数[凝血酶生成峰值(以下简称峰值)、凝血酶生成潜力(endogenous thrombin potential,ETP)、达峰时间(time to peak,tt Peak)等]与患者血浆血管性血友病因子(von Willebrand factor,v WF)抗原(vWF∶Ag)水平、vWF活性水平(vWF∶Act)及凝血因子Ⅷ活性(FⅧ∶C)间的相关性。结果:在1 pmol/L TF激活下,正常对照组的峰值显著高于轻度出血组、中度出血组及重度出血组(P<0.05),重度出血组的峰值显著低于轻度出血组及中度出血组(P均<0.01),ETP和tt Peak仅在重度出血组与其余各组间差异有统计学意义(P均<0.01)。在5 pmol/L TF激活下,各组间峰值差异缩小,且正常对照组与轻度出血患者组的峰值间差异无统计学意义(P>0.05),ETP、tt Peak值在各组间差异均无统计学意义(P>0.05)。此外,在1 pmol/L TF激活下的峰值与患者FⅧ:C间的相关性最好(相关系数R^2为0.65);在1 pmol/L、5 pmol/L TF激活下,TGT参数(ETP和tt Peak)与患者vWF∶Ag、vWF∶Act间的相关性较弱(R^2<0.5)。结论:1 pmol/L TF激活下TGT参数的峰值可较好地反映不同出血严重程度vWD患者的出血倾向。

Objective:To assess the value of thrombin generation test(TGT)for predicting hemorrhagic tendencyin patients with von Willebr and disease(vWD).Methods:A total of 38 vWD patients from Shanghai Ruijin Hospital during January 2018 to July 2019 were enrolled,and were divided into three groups:mild bleeding group(8 mild bleeders,type 1 patients),moderate bleeding group(14 moderate bleeders,including 8 type 2 A patients and 6 type 2 M patients)and severe bleeding group(16 severe bleeders,including 2 type 2 N patients,6 severe type 1 patients and 8 type 3 patients).Five healthy subjects in the same age were served as the control group.Platelet-poor plasma samples were prepared by centrifugation.The difference in thrombin-generating capacity between patients and controls were tested by TGT,which was activated with 1 pmol/L tissue factor(TF)and 5 pmol/L TF,respectively.The correlations of vWF∶Ag,vWF∶Act,FⅧ∶C with TGT parameters[Peak value,endogenous thrombin potential(ETP),time to peak(ttPeak)]were also studied.Results:Under 1 pmol/L TF activation,the Peak value of TGT in controls was significantly higher than those in mild,moderate and severe bleeders(P<0.0001),and the Peak value in severe bleeders was significantly lower than those in mild and moderate cases.(P=0.0001).Furthermore,ETP and tt Peakvalues showed significant difference between severe bleeding group and the other groups.While TGT was activated with 5 pmol/L TF,the difference in TGT parameters decreased between groups.There was no significant difference in Peak values between controls and mild bleeders,and ETP and tt Peakvaluesdid not differ significantly between the groups(P>0.05).In addition,FⅧ∶C levels had a good correlation with Peak values measured at 1 pmol/L TF activation(R^2=0.65),whilev WF∶Ag and vWF∶Act were weakly correlated with any of TGT parameters at 1 pmol/L or 5 pmol/LTF activation(R^2<0.50).Conclusions:Activated with 1 pmol/L TF,Peak value of TGT may serve as a useful laboratory tool to evaluate thehemorrhagic tendency in different types of vWD.