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

• Published in: Blood Vol. 87; no. 10; pp. 4204 - 4213
• Main Authors: Handt, S., Jerome, W.G., Tietze, L., Hantgan, R.R.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.05.1996; The Americain Society of Hematology
• Subjects: Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Cells, Cultured; Coronary Thrombosis - drug therapy; Drug Administration Schedule; Drug Resistance; Endothelium, Vascular - metabolism; Fibrinolysis - drug effects; Fibrinolytic Agents - pharmacology; Humans; Medical sciences; Pharmacology. Drug treatments; Plasminogen Activator Inhibitor 1 - metabolism; Thrombolytic Therapy; Time Factors; Umbilical Veins; Human; Plasminogen activator inhibitor 1; Endothelial cell; Secretion; Cytokine; Anticoagulant; In vitro; Negative therapeutic reaction; Tumor necrosis factor α; Fibrinolytic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V87.10.4204.bloodjournal87104204

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-α–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.