Béguin S
Département de Biochimie, Cardiovascular Research Institute Maastricht (CARIM), Université de Maastricht, Pays-Bas.
Bull Acad Natl Med. 1998;182(7):1479-91; discussion 1491-2.
The main threat from a beginning thrombus is that it tends to grow, and hence become occlusive and/or embolise. Although the progressive nature of thrombi has been recognised since a long time, the mechanisms behind thrombus growth remain only partially resolved. In order to investigate in what ways thrombi can themselves become foci of further thrombin -and hence fibrin-formation, we studied the effect of fibrin clots on thrombin generation in platelet poor--and platelet rich plasma (PPP and PRP). The thrombin always adsorbed on a natural fibrin clot is not inactivated by plasmatic antithrombins and could be shown to retain its ability to enhance further thrombin formation by activation of clotting factors V and VIII as well as of blood platelets. To our surprise, fibrin clots without any active thrombin adsorbed, because they were obtained by a snake-venom enzyme or because thrombin had been inhibited, retained their capacity to activate blood platelets and make them procoagulant. The activation could be shown to be due to a rearrangement of cell-membrane phospholipids, by which the procoagulant species (phosphatidyl serine and phosphatidyl ethanolamine) became available at the outer cell surface. The platelet membrane receptor involved could be recognised as glycoprotein Ib, interacting with fibrin through the plasma protein von Willebrand factor (vWf). In fact it appeared that vWf is indispensable for the generation of thrombin in PRP, with or without added clot. This assigns a new and hitherto unknown role to vWf. Our results also show that fibrin is far from being the inert end-product of coagulation but is a potent activator of blood platelets and by this action may foster thrombin generation and hence further fibrin production. We surmise this mechanism to be instrumental in the progression of thrombotic processes.
初始血栓的主要威胁在于其易于生长，进而变得阻塞血管和/或形成栓子。尽管血栓的进展特性早已为人所知，但血栓生长背后的机制仍未完全阐明。为了研究血栓自身如何成为进一步生成凝血酶——进而生成纤维蛋白——的病灶，我们研究了纤维蛋白凝块对乏血小板血浆和富血小板血浆（PPP和PRP）中凝血酶生成的影响。吸附在天然纤维蛋白凝块上的凝血酶不会被血浆抗凝血酶灭活，并且可以证明它通过激活凝血因子V和VIII以及血小板，仍保留增强进一步凝血酶形成的能力。令我们惊讶的是，没有吸附任何活性凝血酶的纤维蛋白凝块，无论是因为它们是由蛇毒酶获得的，还是因为凝血酶已被抑制，都保留了激活血小板并使其具有促凝作用的能力。可以证明这种激活是由于细胞膜磷脂的重排，通过这种重排，促凝物质（磷脂酰丝氨酸和磷脂酰乙醇胺）出现在细胞外表面。所涉及的血小板膜受体可被识别为糖蛋白Ib，它通过血浆蛋白血管性血友病因子（vWf）与纤维蛋白相互作用。事实上，似乎无论是否添加凝块，vWf对于PRP中凝血酶的生成都是不可或缺的。这赋予了vWf一个新的、迄今未知的作用。我们的结果还表明，纤维蛋白远非凝血的惰性终产物，而是血小板的强效激活剂，通过这种作用可能促进凝血酶的生成，进而进一步产生纤维蛋白。我们推测这种机制在血栓形成过程的进展中起作用。
