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 discussed.
Highlights
The specific, reversible interaction between plasminogen activator inhibitor I (PAl-I) and intact fibrin polymers was studied using both purified components and isolated activated platelets as a source of PAl-I
Perfusion studies, using platelet-rich clots, revealed that the incorporation of PAI-I R346M dose dependently decreased the 500/0 clot lysis time. These data indicate that PAI-I R346M displaces fibrin-bound, endogenous PAI-I released from activated platelets
Due to the high local concentration of fibrin-bound platelet PAI-1 (50-100 p.g/ml) [10,11,12], it is conceivable that the contribution of fibrin-bound PAI-1 to the regulation of fibrinolysis prevails over that of plasma PAl-I, which is present at very low concentrations
Summary
Vol 270, No 19, Issue of May 12, pp. 11205-11208, 1995 Printed in U.S.A. The Significance of Fibrin Binding by Plasminogen Activator Inhibitor 1 for the Mechanism of Tissue-type Plasminogen Activator-mediated Fibrinolysis*. The tentative concept for the mechanism of fibrinolysis, and in particular for the contribution of fibrin-bound PAl-I, is based on the in vitro observation that PAI-1 reversibly binds to purified, intact fibrin polymers [6, 7]. The implications of our data for reducing clinical complications, which are frequently observed after thrombolytic therapy of patients suffering from acute myocardial infarction, will be discussed in relation to other approaches to manipulate the fibrinolytic system, in particular the activity of PAl-I.
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