New insights into the molecular mechanisms of the fibrinolytic system

Abstract

To cite this article: Rijken DC, Lijnen HR. New insights into the molecular mechanisms of the fibrinolytic system. J Thromb Haemost 2009; 7: 4-13.See also Lijnen R. Retirement of Dé siré Collen. This issue, pp 2-3; Van de Werf FJ, Topol EJ, Sobel BE. The impact of fibrinolytic therapy for ST-segment-elevation acute myocardial infarction. This issue, pp 14-20; Loges S, Roncal C, Carmeliet P. Development of targeted angiogenic medicine. This issue, pp 21-33.Summary. Fibrinolysis is regulated by specific molecular interactions between its main components. Activation of plasminogen by tissue-type plasminogen activator (t-PA) is enhanced in the presence of fibrin or at the endothelial cell surface. Urokinase-type plasminogen activator (u-PA) binds to a specific cellular u-PA receptor (u-PAR), resulting in enhanced activation of cell-bound plasminogen. Inhibition of fibrinolysis occurs at the level of plasminogen activation or at the level of plasmin. Assembly of fibrinolytic components at the surface of fibrin results in fibrin degradation. Assembly at the surface of cells provides a mechanism for generation of localized cellassociated proteolytic activity. This review includes novel proteins such a thrombin-activatable fibrinolysis inhibitor (TAFI) and discusses new insights into molecular mechanisms obtained from the rapidly growing knowledge of crystal structures of proteins.

Inhibition of thiol isomerase activity diminishes endothelial activation of plasminogen, but not of protein C

“…These interactions are optimised by binding of the key proteins to relevant surfaces, either the surface of a fibrin clot or the surface of endothelial cells lining the blood vessel [26]. Recent research has identified the annexin A2 heterotetramer (AIIt), comprising two molecules of annexin A2 and two of the protein S100A10, as the key endothelial receptor bringing together both plasminogen and tPA to optimise plasmin generation at the surface of the vascular wall [27].…”

Venous thromboembolism in systemic autoimmune diseases: A narrative review with emphasis on primary systemic vasculitides

“…Thrombin activates thrombin-activatable fibrinolysis inhibitor, which inhibits fibrinolysis. 21 In patients with RA and ankylosing spondylitis, TNF-α inhibition reduced PAI-1 and decreased the PAI-1/t-PA ratio. This means that TNF-α is likely involved in inhibition of the fibrinolytic system among patients with chronic rheumatologic conditions.…”

Characterization of a Small Molecule Inhibitor of Plasminogen Activator Inhibitor Type 1 That Accelerates the Transition into the Latent Conformation

“…Inhibition of the fibrinolytic system in vivo may occur either at the level of plasmin by ␣ 2 -antiplasmin or ␣ 2 -macroglobulin. Inhibition can also be at the level of tPA/ uPA (3,4), mainly by plasminogen activator inhibitor type-1 (PAI-1), which forms a suicide complex with tPA or uPA (5).…”