Effect of heparin and/or antithrombin III on the generation of endotoxin-induced plasminogen activator inhibitor

It has been experimentally shown that endotoxin induces a significant increase in the blood levels of a plasminogen activator inhibitor (PAI). We evaluated the effect of different doses of heparin (5 to 20 IU kg-1 h-1), antithrombin III (10 to 40 U kg-1 h-1 and 240 U/kg as bolus) and of a combination of the two on: 1) the elevation of PAI activity, 2) fibrin deposition in kidneys and 3) mortality in rabbits infused with E. coli lipopolysaccharide. Our results show that heparin plus AT III is able to significantly reduce the generation of endotoxin-induced PAI activity in rabbits' circulation. Low dose of heparin and a bolus injection of AT III both cause a decrease in the generation of PAI at 2 but not at 6 hours of endotoxin infusion. Moreover, fibrin deposits in kidneys of animals receiving heparin plus AT III or a bolus injection of AT III were significantly reduced as compared to control rabbits. The association between low levels of PAI and decreased fibrin deposits is strengthened by the significant correlation (p less than 0.05) found between these two parameters. Finally, the plasma levels of PAI activity at 2 and 6 hours of endotoxin infusion in surviving animals were lower than those observed in animals that died within 2 hours after the end of treatment. We conclude that heparin plus AT III partially prevents the endotoxin-induced generation of PAI activity which seems to correlate with the reduced presence of fibrin deposits in kidneys and with a reduced mortality