title: Plasminogen activator inhibitor-1 secretion of endothelial cells increases fibrinolytic resistance of an in vitro fibrin clot: evidence for a key role of endothelial cells in thrombolytic resistance.
abstract: Time-dependent thrombolytic resistance is a critical problem in thrombolytic therapy for acute myocardial infarction. Platelets have been regarded as the main source of plasminogen activator inhibitor-1 (PAI-1) found in occlusive platelet-rich clots. However, endothelial cells are also known to influence the fibrinolytic capacity of blood vessels, but their ability to actively mediate time-dependent thrombolytic resistance has not been fully established. We will show that, in vitro, tumor necrosis factor-alpha-stimulated endothelial cells secrete large amounts of PAI-1 over a period of hours, which then binds to fibrin and protects the clot from tissue plasminogen activator-induced fibrinolysis. In vivo, endothelial cells covering atherosclerotic plaques are influenced by cytokines synthesized by plaque cells. Therefore, we propose that continuous activation of endothelial cells in atherosclerotic blood vessels, followed by elevated PAI-1 secretion and storage of active PAI-1 in the fibrin matrix, leads to clot stabilization. This scenario makes endothelial cells a major factor in time-dependent thrombolytic resistance.
authors.affiliation: Department of Pathology, Aachen University of Technology, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Handt
authors.forename: W G
authors.initials: WG
authors.lastname: Jerome
authors.forename: L
authors.initials: L
authors.lastname: Tietze
authors.forename: R R
authors.initials: RR
authors.lastname: Hantgan
mesh_terms: D002478:Cells, Cultured; D003328:Coronary Thrombosis / Q000188:drug therapy; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004730:Endothelium, Vascular / Q000378:metabolism*; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D015912:Thrombolytic Therapy; D013997:Time Factors; D014471:Umbilical Veins
chemical_list: D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1