II. Effects on Hemostasis, Thrombosis, and Thrombolysis

The effects of plasminogen activator inhibitor-l (PAI-1) gene inactivation on hemostasis, thrombosis and thrombolysis were studied in homozygous PAI-i-deficient (PAT-I- ) mice, generated by homologous recombination in D3 embryonic stem cells. Diluted (10-fold) whole blood clots from PAI-1i-- and from PAI-1 wild type (PAI-i 1+) mice underwent limited but significantly different (P< 0.001 ) spontaneous lysis within 3 h (6±1 vs 3±1%, respectively). A 25-A1I '25-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 PAT-i-deficient (PA-i +1-), and PAT-i - mice, respectively (P = 0.002 for PAI-i 1+ vs PAI-1-i- mice). Corresponding values after pretreatment with 0.5 mg/kg endotoxin in PA-i +'+ and PAT-I- mice, were 35±5 and 91±3% within 4 h, respectively (P< 0.001).11 out of26 PA-i +'+ but only 1 out of 25 PAI-1-i- mice developed venous thrombosis (P = 0.004) within 6 d after injection of 10 or 50 ,ug endotoxin in the footpad. Spontaneous bleeding or delayed rebleeding could not be documented in PA -I - mice after partial amputation of the tail or of the caecum. Thus, disruption of the PAI-i gene in mice appears to in