PLASMINOGEN-ACTIVATOR INHIBITOR-1 SECRETION BY ENDOTHELIAL-CELLS INCREASES FIBRINOLYTIC RESISTANCE OF AN IN-VITRO FIBRIN CLOT - EVIDENCE FOR A KEY ROLE OF ENDOTHELIAL-CELLS IN THROMBOLYTIC RESISTANCE

Time-dependent thrombolytic resistance is a critical problem in thromb olytic therapy for acute myocardial infarction. Platelets have been re garded as the main source of plasminogen activator inhibitor-1 (PAI-1) found in occlusive platelet-rich clots. However, endothelial cells ar e also known to influence the fibrinolytic capacity of blood vessels, but their ability to actively mediate time-dependent thrombolytic resi stance has not been fully established. We will show that, in vitro, tu mor necrosis factor-alpha-stimulated endothelial cells secrete large a mounts of PAI-1 over a period of hours, which then binds to fibrin and protects the clot from tissue plasminogen activator-induced fibrinoly sis. In vivo, endothelial cells covering atherosclerotic plaques are i nfluenced by cytokines synthesized by plaque cells. Therefore, we prop ose that continuous activation of endothelial cells in atherosclerotic blood vessels, followed by elevated PAI-1 secretion and storage of ac tive PAI-1 in the fibrin matrix, leads to clot stabilization. This sce nario makes endothelial cells a major factor in time-dependent thrombo lytic resistance. (C) 1996 by The American Society of Hematology.