PLASMINOGEN-ACTIVATOR INHIBITOR-1 GENE DEFICIENT MICE .2. EFFECTS ON HEMOSTASIS, THROMBOSIS, AND THROMBOLYSIS

The effects of plasminogen activator inhibitor-1 (PAI-1) gene inactiva tion on hemostasis, thrombosis and thrombolysis were studied in homozy gous PAI-1-deficient (PAI-1-/-) mice, generated by homologous recombin ation in D3 embryonic stem cells. Diluted (10-fold) whole blood clots from PAI-1-/- and from PAI-1 wild type (PAI-1+/+) mice underwent limit ed but significantly different (P < 0.001) spontaneous lysis within 3 h (6+/-1 vs 3+/-1%, respectively). A 25-mul I-125-fibrin-labeled norma l 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-def icient (PAI-1+/-), and PAI-I-/- mice, respectively (P = 0.002 for PAI- 1+/+ vs PAI-1-/- mice). Corresponding values after pretreatment with 0 .5 mg/kg endotoxin in PAI-I+I+ and PAI-1-/- mice, were 35+/-5 and 91+/ -3% within 4 h, respectively (P < 0.001 ). 11 out of 26 PAI-1+/+ but o nly 1 out of 25 PAI-1-/- mice developed venous thrombosis (P = 0.004) within 6 d after injection of 10 or 50 mug endotoxin in the footpad. S pontaneous bleeding or delayed rebleeding could not be documented in P AI-1-/- mice after partial amputation of the tail or of the caecum. Th us, disruption of the PAI-I gene in mice appears to induce a mild hype rfibrinolytic state and a greater resistance to venous thrombosis but not to impair hemostasis.