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

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-μl 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 μg 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.