血栓标志物评估恶性肿瘤患者静脉血栓风险

Estimation of venous thromboembolism risk with thrombotic biomarkers in cancer patients

目的研究血栓标志物对恶性肿瘤患者静脉血栓栓塞（VTE）风险的评估价值。方法选择2009—2012年就诊于天津医科大学总医院的恶性肿瘤患者1473例，采用ACLTOP700型血液凝固仪测定血管性血友病因子抗原含量（vWF：Ag）、凝血因子Ⅶ活性（FⅦ：A）、凝血因子Ⅷ活性（FⅧ：A）、蛋白C活性（PC：A）、蛋白S活性（PS：A）和抗凝血酶活性（AT：A），采用法国梅里埃VIDAS荧光免疫分析仪测定血浆D-二聚体（D．D）水平。采用受试者工作特征曲线（ROC曲线）评价各项指标的诊断性能，对预后因素的分析采用Cox回归模型，采用Kaplan—Meier曲线进行生存分析。结果除其他未分型肿瘤外，各类型肿瘤患者中vWF：Ag、D—D和FⅦ：A水平均高于对照组（均P〈0.05）。除肾癌、前列腺癌、淋巴瘤和其他肿瘤外，各类型肿瘤患者中FⅧ：A水平均高于对照组（均P〈0．05）。除脑胶质瘤、乳腺癌、胃癌、肾癌和其他肿瘤外，各类型肿瘤患者中PC：A水平均低于对照组（均P〈0．05）。除脑胶质瘤、乳腺癌、前列腺癌、淋巴瘤和其他肿瘤外，各类型肿瘤患者中PS：A水平均低于对照组（均P〈0．05）。各类型肿瘤患者中AT：A水平均低于对照组（均P〈0．05）。vWF：Ag诊断恶性肿瘤患者VTE的临界值为192％时，ROC曲线下面积为0．828（95％a为0．716～0．939）；D—D临界值为1484ng／ml时，ROC曲线下面积为0．915（95％口为0．840～0．988）；PC：A临界值为75．2％时，ROC曲线下面积为0．764（95％讲为0．630～0．898）。Cox比例风险模型显示，年龄、手术、化疗和D—D水平是恶性肿瘤患者随访3个月内发生VTE的独立风险因素。血浆D—D水平高于临界值的恶性肿瘤患者VTE累计发生概率显著增高。结论恶性肿瘤患者血浆D—D水平显著增高，并与恶性肿瘤患者的血栓风险分层和VTE风险概率密切相关，具有良好的诊断性能，可作为评价恶性肿瘤患者随访3个月内VTE风险的有效指标。

Objective To assess the value of thrombotic biomarkers in estimation of venous thromboembolism （VTE） risk in cancer patients. Methods A total of 1473 cancer patients treated in the Tianjin Medical University General Hospital from 2009 to 201 were selected, including 845 males and 628 females in the age of 56±17 years. The activities of von Willebrand factor antigen （vWF：Ag） , factor VⅡ （F VⅡ ： A） , factor VⅢ （ F VⅢ ： A） , antithrombin （ AT ： A） , protein C （ PC ： A ） and protein S （ PS ： A ） were assayed using an ACL TOP 700 blood coagulation analyzer. The level of D-dimer （D-D） was assayed using the Biomerieux Mini Vidas Automated Immunoassay Analyzer. Receiver operating characteristic curve （ROC） was used to analyze the diagnostic performance of the parameters. Cox regression analysis model was applied to evaluate the effect on prognosis, and Kaplan-Meier curve was used to implement the survival analysis. Results The levels of vWF：Ag, D-D, and FVⅢ：A were significantly higher in all the specified tumor groups （ except the other tumor group ） than that of the control groups （ P 〈 0. 05 ）. F VⅢ ： A was significantly higher than that in the control group in all tumor groups except the renal carcinoma, prostatic cancer, lymphoma groups and the other tumor group （P〈0.05）. The PC：A level was significantly lower in all tumor patients groups than in the control group, except glioma, breast cancer, gastric carcinoma, renal carcinoma and the other tumors groups （P〈0.05）. The PS：A level was significantly lower in all tumor groups than in the control group, except the glioma, breast cancer, prostatic cancer, lymphoma and the other tumors groups （P〈0.05）. The AT： A level was significantly lower in all tumor groups than in the control group （P〈0.05）. When the optimum cut-off point of vWF：Ag for VTE diagnosis was 192% in the cancer group, the area under ROC curve=0.828 （95% CI： 0.716 to 0.939）. When the optimum cut-off point of D- dimer for VTE diagnosis was 1484 ng/ml in the cancer group, the area under ROC curve= 0.915 （95% confidence interval： 0. 840 to 0. 988）. When the optimum cut-off point of PC.A for VTE diagnosis was 75.2% in the cancer group, the area under ROC curve=0.764 （95% confidence interval： 0.630 to 0.898）. The Cox analysis showed that age, surgery, chemotherapy and D-dimer were independent risk factors for VTE event within three months in cancer patients. The cumulative probability of VTE was increased significantly in the cancer patients if whose plasma D-dimer level was over the cut-off value. Conclusions The plasma D- dimer level is obviously increased in cancer patients, and there is a relevance to thrombosis risk stratification and VTE cumulative probability. It is with good diagnostic performance, and may be used as an effective marker in estimation of VTE risk within 3 months in cancer patients.