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

T Kawasaki, M Dewerchin, HR Lijnen… - Blood, The Journal …, 2000 - ashpublications.org
T Kawasaki, M Dewerchin, HR Lijnen, J Vermylen, MF Hoylaerts
Blood, The Journal of the American Society of Hematology, 2000ashpublications.org
The role of plasminogen activator inhibitor-1 (PAI-1) in the plasma, blood platelets, and
vessel wall during acute arterial thrombus formation was investigated in gene-deficient mice.
Photochemically induced thrombosis in the carotid artery was analyzed via transillumination.
In comparison to thrombosis in C57BL/6J wild-type (wt) mice (113±19× 106 arbitrary light
units [AU] n= 15, mean±SEM), thrombosis in PAI-1−/− mice (40±10× 106 AU, n= 13) was
inhibited (P<. 01), indicating that PAI-1 controls fibrinolysis during thrombus formation …
Abstract
The role of plasminogen activator inhibitor-1 (PAI-1) in the plasma, blood platelets, and vessel wall during acute arterial thrombus formation was investigated in gene-deficient mice. Photochemically induced thrombosis in the carotid artery was analyzed via transillumination. In comparison to thrombosis in C57BL/6J wild-type (wt) mice (113 ± 19 × 106 arbitrary light units [AU] n = 15, mean ± SEM), thrombosis in PAI-1−/− mice (40 ± 10 × 106 AU, n = 13) was inhibited (P < .01), indicating that PAI-1 controls fibrinolysis during thrombus formation. Systemic administration of murine PAI-1 into PAI-1−/− mice led to a full recovery of thrombotic response. Occurrence of fibrinolytic activity was confirmed in 2-antiplasmin (2-AP)–deficient mice. The sizes of thrombi developing in wt mice, in 2-AP+/− and 2-AP−/− mice were 102 ± 35, 65 ± 8.1, and 13 ± 6.1 × 106 AU, respectively (n = 6 each) (P < .05), compatible with functional plasmin inhibition by 2-AP. In contrast, thrombi in wt mice, t-PA−/− and u-PA−/−mice were comparable, substantiating efficient inhibition of fibrinolysis by the combined PAI-1/2-AP action. Platelet depletion and reconstitution confirmed a normal thrombotic response in wt mice, reconstituted with PAI-1−/− platelets, but weak thrombosis in PAI-1−/− mice reconstituted with wt platelets. Accordingly, murine (wt) PAI-1 levels in platelet lysates and releasates were 0.43 ± 0.09 ng/109 platelets and plasma concentrations equaled 0.73 ± 0.13 ng/mL. After photochemical injury, plasma PAI-1 rose to 2.9 ± 0.7 ng/mL (n = 9, P < .01). The plasma rise was prevented by ligating the carotid artery. Hence, during acute thrombosis, fibrinolysis is efficiently prevented by plasma 2-AP, but also by vascular PAI-1, locally released into the circulation after endothelial injury.
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