Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysisduring acute arterial thrombosis in mice

The role of plasminogen activator inhibitor-1 (PAI-1) in the plasma, blood platelets, and vessel wall during acute arterial thrombus formation was inv estigated in gene-deficient mice. Photochemically induced thrombosis in the carotid artery was analyzed via transillumination. In comparison to thromb osis in C57BL/6J wild-type (wt) mice (113 +/- 19 x 10(6) arbitrary light un its [AU] n = 15, mean +/- SEM), thrombosis in PAI-1(-/-) mice 140 +/- 10 x 10(6) AU, n = 13) was inhibited (P < .01), indicating that PAI-1 controls f ibrinolysis during thrombus formation, Systemic administration of murine PA I-1 into PAI-1-/- mice led to a full recovery of thrombotic response. Occur rence of fibrinolytic activity was confirmed in (alpha(2)-antiplasmin (alph a(2)-AP)-deficient mice. The sizes of thrombi developing in wt mice, in alp ha(2)-AP(+/-) and alpha(2)-AP(-/-) mice were 102 +/- 35, 65 +/- 8.1, and 13 +/- 6.1 x 10(6) AU, respectively (n = 6 each) (P < .05), compatible with f unctional plasmin inhibition by alpha(2)-AP. In contrast, thrombi in wt mic e, t-PA(-/-) and u-PA(-/-) mice were comparable, substantiating efficient i nhibition of fibrinolysis by the combined PAI-1/ alpha(2)-AP action. Platel et depletion and reconstitution confirmed a normal thrombotic response in w t mice, reconstituted with PAI-1(-/-) platelets, but weak thrombosis in PAI -1(-/-) mice reconstituted with wt plate lets. Accordingly, murine (wt) PAI -1 levels in platelet lysates and releasates were 0.43 +/- 0.09 ng/10(9) pl atelets and plasma concentrations equaled 0.73 +/- 0.13 ng/mL. After photoc hemical injury, plasma PAI-1 rose to 2.9 +/- 0.7 ng/mL (n = 9, P < .01). Th e plasma rise was prevented by ligating the carotid artery. Hence, during a cute thrombosis, fibrinolysis is efficiently prevented by plasma alpha(2)-A P but also by vascular PAI-1, locally released into the circulation after e ndothelial injury. (Blood. 2000;95:153-160) (C) 2000 by The American Societ y of Hematology.