On the procoagulant effect of fibrin

The main threat from a beginning thrombus is that it tends to grow, and hen ce become occlusive and/or embolise. Although the progressive nature of thr ombi 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 alway s adsorbed on a natural fibrin clot is not inactivated by plasmatic antithr ombins 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 adsor bed 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 rearra ngement 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 recogn ised 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 ass igns a new and hitherto to unknown role to vWf: Our results also show that fibrin is far from being the inert end-product of coagulation but is a pote nt activator of blood platelets and by this action may foster thrombin gene ration and hence further fibrin production. We surmise this mechanism to be instrumental in the progression of thrombotic processes.