Analysis of the mechanism to enhance fibrinolysis by a neutralization of the activity of plasminogen activator inhibitor type 1.

血管系统中的总纤溶活性通过组织纤溶酶原激活物（tPA）和纤溶酶原激活物抑制剂1型（派-1）之间的平衡来精细调节。尽管派-1靶向PA，但它也与其他丝氨酸蛋白酶如凝血酶和因子Xa反应。这些活化的凝血因子对派-1活性的中和作用被证明强烈参与了凝血相关的纤溶活性增强。凝血酶和派-1之间的相互作用被可溶性血栓调节蛋白（TM）淬灭，其成熟形式存在于正常血管内皮细胞上并改变凝血酶的底物特异性。结果，可溶性TM可以淬灭凝血酶依赖性派-1中和所导致的t-PA诱导的纤维蛋白凝块溶解时间的缩短。我们还发现，Ca^++和磷脂对优球蛋白凝块溶解时间（ECLT）的缩短也是由Ca^++结合因子Xa和凝血酶对派-1活性的中和作用引起的。这种依赖Ca^<++>的ECLT缩短也被可溶性TM部分淬灭。激活的凝血因子中和派-1导致的凝血相关纤溶增强似乎发生在凝血因子持续激活的生长血栓上，而在表达血栓调节蛋白的完整血管内皮细胞上不发生。这种机制似乎在控制血栓的形成、维持和溶解的顺序事件中发挥重要作用。这也参与了弥散性血管内凝血中纤溶活性升高的发病机制。

Total fibrinolytic activity in the vasculature is finely tuned by the balance between tissue plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1). Although PAI-1 targets PAs, it also reacts with other serine proteases such as thrombin and factor Xa. Such neutralization of PAI-1 activity by these activated coagulation factors was shown to be strongly involved in the coagulation-associated enhancement of fibrinolytic activity. The interaction between thrombin and PAI-1 was quenched by soluble thrombomodulin (TM), whose mature form exists on normal vascular endothelial cells and modifies thrombin's substrate specificity. As a result, soluble TM quenched the shortening of t-PA-induced fibrin clot lysis time obtained by thrombin-dependent PAI-1 neutralization. We have also shown that the shortening of euglobulin clot lysis time (ECLT) by Ca^<++> and phospholipid was also induced by the neutralization of PAI-1 activity by Ca^<++>-bound factor Xa and thrombin. This Ca^<++>-dependent shortening of ECLT was also partially quenched by soluble TM.Coagulation associated enhancement of fibrinolysis due to PAI-1 neutralization by activated coagulation factors seems to take place on the growing thrombus where coagulation factors are continuously activated, whereas it does not take place on intact vascular endothelial cells where thrombomodulin is expressed. This mechanism seems to play an important role to control the sequential events of the formation, maintenance and dissolution of thrombus. This is also involved in the pathogenesis of elevated fibrinolytic activity in disseminated intravascular coagulation.