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The significance of fibrin binding by plasminogen activator inhibitor 1 for the mechanism of tissue-type plasminogen activator-mediated fibrinolysis

By H. A. Stringer and H. Pannekoek

Abstract

The specific, reversible interaction between plasminogen activator inhibitor 1 (PAI-1) and intact fibrin polymers was studied using both purified components and isolated activated platelets as a source of PAI-1. A key reagent in these experiments is a PAI-1 mutant, having its P1 reactive center residue arginine replaced by methionine (PAI-1 R346M). The second-order association rate of PAI-1 R346M with tissue-type plasminogen activator is over 10,000-fold lower than that of wild-type PAI-1, whereas the ability of the variant to bind to fibrin is unaltered. Competition experiments demonstrated that PAI-1 R346M is equally effective as wild-type PAI-1 in displacing 125I-labeled PAI-1 from fibrin. Fibrinolysis, mediated by tissue-type plasminogen activator, is inhibited in a dose-dependent manner by purified PAI-1. The inhibition can be relieved in a dose-dependent manner by PAI-1 R346M, presumably due to displacement of wild-type PAI-1 by PAI-1 R346M. Perfusion studies, using platelet-rich clots, revealed that the incorporation of PAI-1 R346M dose dependently decreased the 50% clot lysis time. These data indicate that PAI-1 R346M displaces fibrin-bound, endogenous PAI-1 released from activated platelets. Implications to manipulate PAI-1 activity for the management of clinical complications, in particular reocclusion after thrombolytic therapy, are discusse

Year: 1995
DOI identifier: 10.1074/jbc.270.19.11205
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Provided by: NARCIS
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