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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 153-160
Vascular release of plasminogen activator inhibitor-1 impairs
fibrinolysis during acute arterial thrombosis in mice
Tomihisa Kawasaki,
Mieke Dewerchin,
Henri R. Lijnen,
Jos Vermylen, and
Marc F. Hoylaerts
From the Center for Molecular and Vascular Biology, University of
Leuven, and Center for Transgene Technology and Gene Therapy, Flanders
Interuniversity Institute for Biotechnology, Leuven, Belgium
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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