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Research Article Free access | 10.1172/JCI116893

Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis.

P Carmeliet, J M Stassen, L Schoonjans, B Ream, J J van den Oord, M De Mol, R C Mulligan, and D Collen

Center for Molecular and Vascular Biology, University of Leuven, Belgium.

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Center for Molecular and Vascular Biology, University of Leuven, Belgium.

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Center for Molecular and Vascular Biology, University of Leuven, Belgium.

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Center for Molecular and Vascular Biology, University of Leuven, Belgium.

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Center for Molecular and Vascular Biology, University of Leuven, Belgium.

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Center for Molecular and Vascular Biology, University of Leuven, Belgium.

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Center for Molecular and Vascular Biology, University of Leuven, Belgium.

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Center for Molecular and Vascular Biology, University of Leuven, Belgium.

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Published December 1, 1993 - More info

Published in Volume 92, Issue 6 on December 1, 1993
J Clin Invest. 1993;92(6):2756–2760. https://doi.org/10.1172/JCI116893.
© 1993 The American Society for Clinical Investigation
Published December 1, 1993 - Version history
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Abstract

The effects of plasminogen activator inhibitor-1 (PAI-1) gene inactivation on hemostasis, thrombosis and thrombolysis were studied in homozygous PAI-1-deficient (PAI-1-/-) mice, generated by homologous recombination in D3 embryonic stem cells. Diluted (10-fold) whole blood clots from PAI-1-/- and from PAI-1 wild type (PAI-1+/+) mice underwent limited but significantly different (P < 0.001) spontaneous lysis within 3 h (6 +/- 1 vs 3 +/- 1%, respectively). A 25-microliters 125I-fibrin-labeled normal murine plasma clot, injected into a jugular vein, was lysed for 47 +/- 5, 66 +/- 3, and 87 +/- 7% within 8 h in PAI-1+/+, heterozygous PAI-1-deficient (PAI-1+/-), and PAI-1-/- mice, respectively (P = 0.002 for PAI-1+/+ vs PAI-1-/- mice). Corresponding values after pretreatment with 0.5 mg/kg endotoxin in PAI-1+/+ and PAI-1-/- mice, were 35 +/- 5 and 91 +/- 3% within 4 h, respectively (P < 0.001). 11 out of 26 PAI-1+/+ but only 1 out of 25 PAI-1-/- mice developed venous thrombosis (P = 0.004) within 6 d after injection of 10 or 50 micrograms endotoxin in the footpad. Spontaneous bleeding or delayed rebleeding could not be documented in PAI-1-/- mice after partial amputation of the tail or of the caecum. Thus, disruption of the PAI-1 gene in mice appears to induce a mild hyperfibrinolytic state and a greater resistance to venous thrombosis but not to impair hemostasis.

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