Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, University of Bari, Bari, Italy.
J Thromb Haemost. 2010 Apr;8(4):790-8. doi: 10.1111/j.1538-7836.2010.03739.x. Epub 2010 Jan 17.
Anticoagulants are expected to promote fibrinolysis by counteracting the antifibrinolytic effects of thrombin, which include thrombin-activatable fibrinolysis inhibitor (TAFI) activation and clot structure enhancement. However, the efficiency of anticoagulants may vary remarkably, and the ability of direct thrombin inhibitors to facilitate clot lysis remains controversial.
To evaluate the profibrinolytic effect of dabigatran, a new, direct thrombin inhibitor, using different in vitro models.
The resistance of tissue factor-induced plasma clots to fibrinolysis by exogenous tissue-type plasminogen activator (t-PA) (turbidimetric method) was reduced by dabigatran in a concentration-dependent manner, with > or = 50% shortening of lysis time at clinically relevant concentrations (1-2 microm). A similar effect was observed in the presence of low (0.1 and 1 nm) but not high (10 nm) concentrations of thrombomodulin. Acceleration of clot lysis by dabigatran was associated with a reduction in TAFI activation and thrombin generation, and was largely, although not completely, negated by an inhibitor of activated TAFI, potato tuber carboxypeptidase inhibitor. The assessment of the viscoelastic properties of clots showed that those generated in the presence of dabigatran were more permeable, were less rigid, and consisted of thicker fibers. The impact of these physical changes on fibrinolysis was investigated using a model under flow conditions, which demonstrated that dabigatran made the clots markedly more susceptible to flowing t-PA, by a mechanism that was largely TAFI-independent.
Dabigatran, at clinically relevant concentrations, enhances the susceptibility of plasma clots to t-PA-induced lysis by reducing TAFI activation and by altering the clot structure. These mechanisms might contribute to the antithrombotic activity of the drug.
抗凝剂通过对抗凝血酶的抗纤维蛋白溶解作用来促进纤维蛋白溶解，凝血酶的抗纤维蛋白溶解作用包括血栓调节蛋白激活和纤维蛋白凝块结构增强。然而，抗凝剂的效率可能会有很大的差异，并且直接凝血酶抑制剂促进血栓溶解的能力仍然存在争议。
使用不同的体外模型评估新型直接凝血酶抑制剂达比加群对纤维蛋白溶解的促纤溶作用。
组织因子诱导的血浆凝块对组织型纤溶酶原激活物（t-PA）（浊度法）的纤溶作用的抵抗力被达比加群以浓度依赖性方式减弱，在临床相关浓度（1-2 µm）下，纤溶时间缩短>或=50%。在低浓度（0.1 和 1nm）但不是高浓度（10nm）的血栓调节蛋白存在下观察到类似的作用。达比加群加速血栓溶解与 TAFI 激活和凝血酶生成减少有关，并且被 TAFI 激活抑制剂——土豆羧肽酶抑制剂在很大程度上（尽管不是完全）消除。对凝块粘弹性的评估表明，在达比加群存在下生成的凝块更具渗透性、更柔韧，并且纤维更厚。使用流动条件下的模型研究这些物理变化对纤维蛋白溶解的影响表明，达比加群使凝块明显更容易受到流动 t-PA 的影响，其机制在很大程度上与 TAFI 无关。
在临床相关浓度下，达比加群通过减少 TAFI 激活和改变凝块结构来增强血浆凝块对 t-PA 诱导的纤溶作用的敏感性。这些机制可能有助于该药物的抗血栓活性。
