vW因子联合D-二聚体预测非瓣膜性心房颤动患者抗凝治疗后发生血栓风险的研究

von Willebrand factor and D-dimer to evaluate the thrombosis risk in patients with nonvalvular atrial fibrillation in anti-coagulant therapy

目的研究血管性血友病因子抗原(vWF:Ag)含量和D-二聚体预测接受抗凝治疗的非瓣膜性心房颤动(NVAF)患者血栓风险的性能。方法收集2017年3月至2019年3月间就诊的NVAF患者256例,其中男152例,女104例,年龄(57.9±20.4)岁;根据随访期内终点事件情况,将患者分为无事件组227例,血栓事件组29例。选择同期健康体检者作为对照组共50名,其中男30名,女20名,年龄(45.0±5.3)岁。用血液凝固仪测定血浆vWF:Ag水平,采用荧光免疫分析仪测定血浆D-二聚体水平。任意两组间数据比对采用Mann-Whitney U检验,多组间数据比对采用Kruskal-Wallis H检验,用Logistic回归对分类资料做多元相关性分析获得优势比(OR);用受试者工作特征(ROC)曲线评价vWF:Ag和D-二聚体预测血栓事件的性能;用Kaplan-Meier曲线进行生存分析;用Cox比例风险回归模型获得风险比(HR)。结果对照组的vWF:Ag和D-二聚体为103%(86%~131%)和249(90~522)μg/L,患者组为234%(102%~623%)和744(100~3352)μg/L;在患者组中,无事件组为225%(102%~623%)和650(100~3281)μg/L,血栓事件组为333%(210%~494%)和1325(487~3352)μg/L;患者组的vWF:Ag和D-二聚体高于与健康对照组(P均<0.001),无事件组高于健康对照组(P均<0.001),血栓事件组高于无事件组(P均<0.001)。NVAF患者血浆vWF:Ag和D-二聚体水平均高于与对照组(P均<0.001)。无事件组患者的血浆vWF:Ag和D-二聚体水平高于健康对照组,差异有统计学意义(P均<0.001);血栓事件组患者的血浆vWF:Ag和D-二聚体水平均高于无事件组,差异有统计学意义(P均<0.001)。ROC显示,vWF:Ag预测NVAF患者3个月内血栓事件的临界值为229%时,曲线下面积为0.839(95%CI:0.784~0.894);D-二聚体的临界值为588μg/L时,曲线下面积为0.803(95%CI:0.745~0.861);vWF:Ag联合D-二聚体,曲线下面积为0.868(95%CI:0.826~0.909)。Logistic回归分析显示,NVAF患者血浆vWF:Ag水平与年龄(OR=10.240,95%CI 2.773~37.820)、慢性心力衰竭(OR=34.779,95%CI 8.010~151.019)、高血压(OR=0.068,95%CI 0.023~0.198)和2型糖尿病(OR=6.618,95%CI 2.469~17.734)有显著相关性(P<0.001),与血管疾病(OR=4.801,95%CI 1.204~19.145)有显著相关性(P=0.026);血浆D-二聚体水平与慢性心力衰竭(OR=0.146,95%CI 0.036~0.588)、服药依从性(OR=0.114,95%CI 0.016~0.832)有显著相关性(P值分别为0.007和0.032)。生存分析显示,血浆vWF:Ag、D-二聚体或vWF:Ag联合D-二聚体评估时,血浆水平高于临界值的患者在3个月内的血栓事件累积概率显著增高(Log-rankχ2分别为11.394、17.895和32.825,P均<0.001)。Cox比例回归模型显示,vWF:Ag和D-二聚体均不能独立预测抗凝治疗期间的血栓事件(HR分别为0.866和0.834,P值分别为0.253和0.152),但两项指标联合应用可显著改善预测性能(HR=0.780,P=0.048)。结论NVAF患者血浆vWF:Ag和D-二聚体水平变化与多种临床病理因素相关,并与患者3个月内的血栓风险密切相关,联合应用可为临床预测病情提供有效依据。

Objective To investigate the performance of von willebrand factor antigen(vWF:Ag)and D-dimer in predicting thrombotic risk in nonvalvular atrial fibrillation(NVAF)patients with anticoagulant therapy.Methods From March 2017 to March 2019,256 patients were enrolled,including 152 males and 104 females,aged(57.9±20.4)years old;according to the end-point events during the follow-up period,the patient group was further divided into 227 cases in the no-event group and 29 cases in the thrombotic event group;50 cases in the control group,including 30 males and 20 females,aged(45.0±5.3)years old.vWF:Ag was detected by blood coagulation instrument and determination of D-dimer was done by fluor-euzyme linked immunoassay Analyzer.Mann-Whitney U test was used for data comparison between any two groups,Kruskal-Wallis H test was used for comparison among multiple groups and multivariate correlation analysis was done by Logistic regression to obtain odds ratio(OR).The prediction performance with thrombotic events of vWF:Ag and D-dimer was evaluated by ROC curve,Kaplan-Meier curve was used to analyze the survival curve and the hazard ratio(HR)was obtained by Cox proportional hazard regression model.Results The levels of vWF:Ag and D-dimer in the control group were 103%(86%-131%)and 249(90-522)μg/L,234%(102%-623%)and 744(100-3352)μg/L in the patient group;in the patient group,of which 225%(102%-623%)and 650(100-3281)μg/L in non-event group,333%(210%-494%)and 1325(487-3352)μg/L in thrombus event group;compared the healthy control,the levels of vWF:Ag and D-dimer were increased in patients group(P<0.001),of which non-event groups were higher than healthy controls(P<0.001),and the thrombotic event group was higher than that of the non-event group(P<0.001).Plasma vWF:Ag level and D-dimer level in NVAF patients were higher than those in the control group(P<0.001).Plasma vWF:Ag level and D-dimer level in the non-event group were significantly higher than those in the healthy control group(P<0.001).The plasma vWF:Ag and D-dimer levels of patients in the thrombotic event group were significantly higher than those in the non-event group patients(P<0.001).The result of ROC showed that the critical value of vWF:Ag for predicting thrombosis within 3 months of NVAF patients was 229%and area under the curve(AUC)was 0.839(95%CI:0.784-0.894);When the critical value of D-dimer was 588 ng/ml,AUC was 0.803(95%CI:0.745-0.861).While vWF:Ag combined with D-dimer,AUC was 0.868(95%CI:0.826-0.909).Logistic regression analysis showed that plasma vWF:Ag level in NVAF patients was significantly correlated with age(OR=10.240,95%CI 2.773-37.820),congestive heart failure(OR=34.779,95%CI 8.010-151.019),hypertension(OR=0.068,95%CI 0.023-0.198)and type 2 diabetes(OR=6.618,95%CI 2.469-17.734)(P<0.001),as well as was significantly correlated with vascular disease(OR=4.801,95%CI 1.204-19.145)(P=0.026).Plasma D-dimer level was significantly correlated with congestive heart failure(OR=0.146,95%CI 0.036-0.588)and medication compliance(OR=0.114,95%CI 0.016-0.832)(P value was 0.007 and 0.032).Survival analysis showed that the cumulative probability of thrombosis within 3 months was significantly increased(Log-rankχ2 was 11.394,17.895 and 32.825 respectively,P value<0.001)in the patients with plasma levels above the critical value of vWF:Ag,D-dimer or vWF:Ag combined with D-dimer.Cox proportional regression model showed that neither vWF:Ag nor D-dimer could independently predict thrombotic events during anticoagulant therapy(HR was 0.866 and 0.834,P-value was 0.253 and 0.152,respectively),but it could improve the prediction performance significantly(HR=0.780,P=0.048)for combined application of both vWF:Ag and D-dimer.Conclusion The changes with plasma vWF:Ag and D-dimer levels in NVAF patients were associated with a variety of clinicopathological factors and closely related to the risk of thrombosis within 3 months.Combined application could provide the effective basis for clinical prediction of the condition.