血栓标志物在新型冠状病毒肺炎重型患者中的诊断价值

Diagnostic value of blood coagulation biomarkers in severe COVID-19 patients

目的:回顾性分析新型冠状病毒肺炎(COVID-19)普通型患者和重型患者之间血栓标志物结果的特点,为临床诊疗提供依据。方法:收集2020年2月10日至3月10日在武汉大学中南医院住院的COVID-19确诊患者,包括95例COVID-19普通型患者和29例重型患者。分析D-二聚体(DD)和血栓标志物四项指标,包括血栓调节蛋白(TM)、凝血酶抗凝血酶复合物(TAT)、纤溶酶-α2纤溶酶抑制物(PIC)和组织纤溶酶原激活物/抑制剂-1复合物(t-PAIC)。以28例健康人群作为对照组,并进行统计学分析,采用Logistic回归分析血栓四项指标与病情严重程度的关系,受试者工作特征(ROC)曲线判断各指标的诊断效能。结果:与对照组相比较,普通型COVID-19组DD和PIC指标显著升高(P<0.05),重型COVID-19组5项指标均显著升高(P<0.05);与COVID-19普通型组相比,重型COVID-19组5项指标均显著升高(P<0.05)。普通型COVID-19患者中合并有高血压(n=24)和无合并症(n=58)的患者,5项指标均不存在显著差别(P>0.05),而合并有糖尿病的普通型COVID-19患者,TM值显著升高(P<0.05)。对普通型和重型COVID-19患者血栓四项指标进行二元Logistic回归分析,结果表明血浆TM、t-PAIC和PIC能作为预测COVID-19重型化的独立因子。ROC曲线分析结果显示,TAT、PIC、TM、t-PAIC和DD预测重型COVID-19的最佳截断值分别为3.75 ng/mL、0.93μg/mL、12.15 IU/mL、13.25 ng/mL、15.25μg/mL和3.01μg/mL,曲线下面积(AUC)分别为0.716、0.795、0.833、0.597、0.813和0.975。DD+TM+PIC+PAIC联合检测对于诊断重型COVID-19具有较好效能。结论:COVID-19重型患者存在凝血及纤溶系统异常,血浆TM、t-PAIC和PIC结果对COVID-19患者的诊疗具有重要的参考价值。

Objective: To retrospectively study the changes of coagulation markers in COVID-19, and to provide references for its clinical diagnosis and treatment. Methods: Serum samples were collected from 124 COVID-19 patients, including 95 cases in common type and 29 cases in severe type, in Zhongnan Hospital of Wuhan University from January 20, 2020 to March 10, 2020. Another 28 healthy subjects were also involved as normal controls. The serum levels of D-Dimer(DD) and coagulation biomarkers, such as thrombomodulin(TM), thrombin-antithrombin Ⅲ complex(TAT), tissue plasminogen activator-plasminogen activatorinhibitor-1 complex(t-PAIC), and plasmin-α2 plasmin inhibitor complex(PIC) were assayed. Logistic regression was used to analyze the relationship between coagulation markers and COVID-19 severity. The receiver operating characteristic(ROC) curve was used to determine the diagnostic performance of each index, and the maximum value of the Youden index was the optimal cut-off value. Results: Plasma levels of DD and PIC in common COVID-19 group were significantly higher(P<0. 05), and plasma levels of DD, TM, TAT, t-PAIC, and PIC in severe COVID-19 group were significantly higher(P<0. 05), as compared with those in normal control group. Plasma levels of DD, TM, TAT, t-PAIC, and PIC in severe COVID-19 group were significantly higher than in common COVID-19 group(P<0. 05). There were no significant difference between the levels of above five biomarkers in the common COVID-19 patients with(n=24) and without hypertension(n=58)(P>0. 05). But the level of TM in COVID-19 patients with diabetes were higher than in those without comorbidities. We then use logistic regression to analyze these biomarkers in the commom and severe COVID-19 groups. The result showed that TM, t-PAIC, and PIC could be used as laboratory indicators to reflect the severity of COVID-19(P<0. 05). ROC curve result showed that the optimal cut-off values of TAT, PIC, TM, t-PAIC, and DD in the diagnosis of venous thrombosis in patients with severe COVID-19 were 3. 75 ng/L, 0. 93 μg/L, 12. 15 IU/L, 13. 25 ng/L, 15. 25 μg/L, and 3. 01 μg/L, respectively, and their area under curve(AUC)were 0. 716, 0. 795, 0. 833, 0. 597, 0. 813, and 0. 975, respectively. The AUC of combined DD+TM+PIC+PAIC in the diagnosis of severe COVID-19 was significantly higher than that of single test respectively. Conclusion: There were coagulation and fibrinolytic system abnormalities in patients with COVID-19. The changes in blood coagulation biomarkers are valuable for the early diagnosis and treatment of severe COVID-19.