Urano T, Castellino F J, Suzuki Y
Department of Medical Physiology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
W.M. Keck Center for Transgene Research, University of Notre Dame, University of Notre Dame, Notre Dame, IN, USA.
J Thromb Haemost. 2018 May 20;16(8):1487-97. doi: 10.1111/jth.14157.
The fibrinolytic system dissolves fibrin and maintains vascular patency. Recent advances in imaging analyses allowed visualization of the spatiotemporal regulatory mechanism of fibrinolysis, as well as its regulation by other plasma hemostasis cofactors. Vascular endothelial cells (VECs) retain tissue-type plasminogen activator (tPA) after secretion and maintain high plasminogen (plg) activation potential on their surfaces. As in plasma, the serpin, plasminogen activator inhibitor type 1 (PAI-1), regulates fibrinolytic potential via inhibition of the VEC surface-bound plg activator, tPA. Once fibrin is formed, plg activation by tPA is initiated and effectively amplified on the surface of fibrin, and fibrin is rapidly degraded. The specific binding of plg and tPA to lytic edges of partly degraded fibrin via newly generated C-terminal lysine residues, which amplifies fibrin digestion, is a central aspect of this pathophysiological mechanism. Thrombomodulin (TM) plays a role in the attenuation of plg binding on fibrin and the associated fibrinolysis, which is reversed by a carboxypeptidase B inhibitor. This suggests that the plasma procarboxypeptidase B, thrombin-activatable fibrinolysis inhibitor (TAFI), which is activated by thrombin bound to TM on VECs, is a critical aspect of the regulation of plg activation on VECs and subsequent fibrinolysis. Platelets also contain PAI-1, TAFI, TM, and the fibrin cross-linking enzyme, factor (F) XIIIa, and either secrete or expose these agents upon activation in order to regulate fibrinolysis. In this review, the native machinery of plg activation and fibrinolysis, as well as their spatiotemporal regulatory mechanisms, as revealed by imaging analyses, are discussed.
纤维蛋白溶解系统可溶解纤维蛋白并维持血管通畅。成像分析的最新进展使得纤维蛋白溶解的时空调节机制及其受其他血浆止血辅助因子的调节得以可视化。血管内皮细胞（VECs）分泌后保留组织型纤溶酶原激活物（tPA），并在其表面维持高纤溶酶原（plg）激活潜能。与血浆中一样，丝氨酸蛋白酶抑制剂1型纤溶酶原激活物抑制剂（PAI-1）通过抑制VEC表面结合的plg激活物tPA来调节纤维蛋白溶解潜能。一旦形成纤维蛋白，tPA介导的plg激活在纤维蛋白表面启动并有效放大，纤维蛋白迅速降解。plg和tPA通过新生成的C末端赖氨酸残基与部分降解的纤维蛋白的溶解边缘特异性结合，从而放大纤维蛋白消化，这是该病理生理机制的核心方面。血栓调节蛋白（TM）在减弱plg与纤维蛋白的结合及相关纤维蛋白溶解中起作用，而羧肽酶B抑制剂可逆转这种作用。这表明血浆中的前羧肽酶B，即凝血酶激活的纤维蛋白溶解抑制剂（TAFI），在VEC上被与TM结合的凝血酶激活，是调节VEC上plg激活及随后纤维蛋白溶解的关键因素。血小板也含有PAI-1、TAFI、TM和纤维蛋白交联酶因子（F）XIIIa，并在激活时分泌或暴露这些因子以调节纤维蛋白溶解。在本综述中，将讨论成像分析所揭示的plg激活和纤维蛋白溶解的天然机制及其时空调节机制。
