Prediction of bleeding risk in patients taking vitamin K antagonists using thrombin generation testing

Until recently, vitamin K antagonists (VKAs) were the mainstay of oral anticoagulant treatment with bleeding as the most prevalent adverse effect. One to four percent of patients experience major bleeding episodes, while clinically relevant bleeding occurs in up to 20%. At this moment no laboratory assays are available to identify patients at risk for bleeding. With this study we aimed to investigate whether thrombin generation tests might identify a bleeding risk in patients taking VKAs. This prospective cohort study included 129 patients taking VKAs for more than three months. Calibrated automated thrombinography (CAT) was performed in whole blood, platelet rich and platelet poor plasma. Hematocrit, hemoglobin concentrations and the International Normalized Ratio (INR) were defined and coagulation factor levels were measured. Forty clinically relevant bleeding episodes were registered in 26 patients during follow-up. No differences were found in plasma CAT parameters or INR values. Bleeding was not associated with age, sex, hematocrit, hemoglobin levels or coagulation factor levels. In whole blood a significantly lower endogenous thrombin potential (ETP) and peak were found in patients with bleeding (median ETP: 182.5 versus 256.2 nM.min, p = 0.002; peak: 23.9 versus 39.1 nM, p = 0.029). Additionally, the area under the receiver operating curve (AUC ROC) was significantly associated with bleeding (ETP: 0.700, p = 0.002; peak: 0.642, p = 0.029). HAS-BLED scores were also significantly higher in bleeding patients (3 versus 2, p = 0.003), with an AUC ROC 0.682 (p = 0.004). In conclusion, bleeding in patients taking VKAs is associated with a decreased whole blood ETP and peak as well as with an increased HAS-BLED score.

直至近期，维生素K拮抗剂（VKAs）仍是口服抗凝治疗的主流方案，出血是其最常见的不良反应。1%~4%的患者会发生大出血事件，而临床相关出血的发生率最高可达20%。目前尚无实验室检测方法可识别出血风险人群。本研究旨在探讨凝血酶生成试验是否可识别服用VKAs患者的出血风险。本前瞻性队列研究共纳入129例服用VKAs超过3个月的患者。对全血、富血小板血浆及乏血小板血浆进行校准自动化凝血酶生成法（CAT）检测。测定血细胞比容、血红蛋白浓度、国际标准化比值（INR）以及凝血因子水平。随访期间，26例患者共发生40例次临床相关出血事件。血浆CAT参数及INR值未发现组间差异。出血与患者年龄、性别、血细胞比容、血红蛋白水平或凝血因子水平均无关联。但在全血样本中，发生出血的患者其内源性凝血酶潜能（ETP）及峰值均显著降低（ETP中位数：182.5 vs 256.2 nM·min，p=0.002；峰值：23.9 vs 39.1 nM，p=0.029）。此外，受试者工作特征曲线下面积（AUC ROC）与出血风险显著相关（ETP：0.700，p=0.002；峰值：0.642，p=0.029）。出血患者的HAS-BLED评分也显著更高（3 vs 2，p=0.003），其AUC ROC为0.682（p=0.004）。综上，服用VKAs患者的出血事件与全血ETP及峰值降低、HAS-BLED评分升高显著相关。