Objective: To explore the predictive value of four items of new thrombus markers combined with conventional coagulation tests for thrombosis in antiphospholipid syndrome.
Methods: A total of 121 antiphospholipid syndrome (APS) patients who hospitalized at Peking University People's Hospital from March 2022 to January 2023 were selected and divided into thrombus group (50 cases) and nonthrombus group (71 cases) according to whether thrombosis occurred. The differences of laboratory characteristics including antiphospholipid antibodies were compared between the thrombotic and non-thrombotic groups. Chemiluminescent immunoassay was used to detect thrombomodulin (TM), thrombin-antithrombin complex (TAT), Plasmin-α2 plasmin inhibitor complex (PIC), and tissue plasminogen activator inhibitor complex (t-PAIC) in plasma from venous. The independent risk factors of thrombosis in patients with APS were determined using binary Logistic regression. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the efficacy of each index on the prediction of thrombosis.
Results: Compared with the patients without thrombosis, the patients with thrombosis were older [49 (32, 64) years vs. 36 (32, 39) years, P < 0.05]. The percentages of male, smoking, hypertension, and global antiphospholipid syndrome score (GAPSS)≥10 in the patients with thrombosis were significantly higher than those in the patients without thrombosis (P < 0.05). The positive rates of anticardiolipin antibody (aCL) and lupus anticoagulant (LA) in the thrombotic group were significantly higher than those in the non-thrombotic group (P < 0.05), and the levels of prothrombin time, activated partial thromboplastin time, fibrinogen, fibrin degradation product in the thrombotic group were significantly higher than those in the non-thrombotic group (P < 0.05).Among the thrombosis group, venous thrombosis accounted for 19 (38.00%), including deep vein thrombosis (16, 84.21%) and pulmonary embolism accounted (5, 26.32%); Arterial thrombosis accounted for 35 (70.00%), including myocardial infarction (6, 17.14%) cerebral infarction (30, 85.71%). The patients in the thrombotic group had significantly greater TM levels than those in the non-thrombotic group (P < 0.05).There were no significant dif-ferences between the two groups in TAT (Z=-1.420, P=0.156), PIC (Z=-0.064, P=0.949), and t-PAIC (Z=-1.487, P=0.137). Univariate and binary Logistic regression analysis of relevant variables showed that advanced age [OR=1.126, P=0.002], elevated TM [OR=1.325, P=0.048], prolonged prothrombin time (PT) [OR=4.127, P=0.008] were independent risk factors for thrombosis in the patients with APS. ROC curve analysis of the above three independent risk factors showed that the combined detection of age, PT and TM had the highest Yoden index (0.727) and sensitivity (83.0%), with a specificity of 89.7%.
Conclusion: TAT, PIC, TM, and t-PAIC may reflect thrombus formation from the coagulation system, fibrinolysis system, and endothelial system. The combined of age TM and PT is superior to the application of a single marker, which has diagnostic value for the early identification of APS thrombosis.
目的: 探讨新型血栓四项联合常规凝血指标在预测抗磷脂综合征(antiphospholipid syndrome, APS)患者血栓形成的早期诊断价值。
方法: 选择2022年3月至2023年1月北京大学人民医院风湿免疫科就诊的APS患者121例进行回顾性分析，根据是否发生血栓将患者分为血栓组(50例)和非血栓组(71例)。比较血栓组和非血栓组患者包括抗磷脂抗体(antiphospholipid antibodies，aPL)在内的实验室指标的差异，采用化学发光免疫分析法检测其静脉血浆中新型血栓四项[包括凝血酶调节蛋白抗原(thrombomodulin，TM)、凝血酶抗凝血酶复合物(thrombin-antithrombin complex，TAT)、血浆纤溶酶抗纤溶酶复合物(plasmin-α2 plasmin inhibitor complex，PIC)、组织纤溶酶原激活物抑制物复合物(tissue plasminogen activator inhibitor complex，t-PAIC)]水平。通过二元Logistic回归分析，筛选APS患者血栓发生的独立危险因素，应用受试者工作特征(receiver operator characteristic, ROC)曲线分析评估各指标预测血栓风险的效能。
结果: 血栓组APS患者年龄显著高于非血栓组APS患者[49(32, 64)岁vs. 36(32, 39)岁，P < 0.05]，血栓组APS患者中男性、吸烟、高血压、全面抗磷脂综合征评分(global antiphospholipid syndrome score，GAPSS)≥10分的比例均高于非血栓组APS患者(P均 < 0.05)。血栓组APS患者中抗心磷脂抗体(anticardiolipin antibcdy, aCL)、狼疮抗凝物(lupus anticoagulant, LA)阳性率更高(P均 < 0.05)，凝血酶原时间(prothrombin time，PT)、活化部分凝血活酶时间(activated partial thromboplastin time，APTT)、纤维蛋白原降解产物(fibrin degradation product，FDP)水平更高(P均 < 0.05)。血栓组静脉血栓19例(38.00%)，其中深静脉血栓16例(84.21%)，肺栓塞5例(26.32%)；动脉血栓35例(70.00%)，其中心肌梗死6例(17.14%)，脑梗死30例(85.71%)。血栓组患者的TM水平明显大于非血栓组(P＜0.05)，两组间TAT(Z=-1.420，P=0.156)、PIC(Z=-0.064，P=0.949)和t-PAIC(Z=-1.487，P=0.137)血浆浓度差异无统计学意义。对相关变量进行单因素及二元Logistic回归分析，发现高龄[OR=1.126，P=0.002]、TM升高[OR=1.325，P=0.048]、PT延长[OR=4.127，P=0.008]是APS患者血栓形成的独立危险因素，对上述3个独立危险因素进行ROC曲线分析，发现年龄、PT、TM三项联合检测对APS血栓形成的诊断性能最佳[AUC为0.916(0.862, 0.969)]，具有最高的约登(Youden)指数(0.727)和敏感性(83.0%)，特异性为89.7%。
结论: TAT、PIC、TM和t-PAIC可以从凝血系统、纤溶系统和内皮系统反映血栓形成。TM、PT联合年龄优于单一标志物的应用，对APS血栓形成的早期识别具有诊断价值。
Keywords: Antiphospholipid syndrome; Plasmin-α2 plasmin inhibitor complex; Thrombin-antithrombin complex; Thrombomodulin; Tissue plasminogen activator inhibitor complex.