A purified antithrombin III-heparin complex as a potent inhibitor of thrombin in porcine endotoxin shock

Abstract

Inhibition of activated clotting factors is an important therapeutic approach in disseminated intravascular coagulation (DIC). We examined the possible protective effect of a purified complex of human antithrombin III (AT III) and heparin in endotoxin-induced DIC in pigs. Two groups of endotoxemic pigs were studied. AT III-heparin group pigs (n=8) were pretreated with a bolus injection of 500 units AT III-heparin complex, followed by a continuous infusion of 1000 units of the complex for 6 hours given simultaneously with the infusion of 10 μg/kgh of S. abortus equi endotoxin. Controls (n=9) were given saline in addition to the continuous infusion of endotoxin. AT III activity, prothrombin and soluble fibrin in plasma were determined by chromogenic substrate methods. Fibrinogen was measured turbidimetrically. Human AT III antigen in the treated group was 64 ± 3% at 2 hours and increased to 84 ± 4% until the end of the experiment. AT III activity in the AT III - heparin group was elevated throughout the whole observation period (> 100%), whereas it was significantly lower in the controls. Prothrombin decreased similarly in both groups by approximately 35% until the end of the experiment. AT III-heparin treatment significantly attenuated the endotoxin-induced consumption of fibrinogen and completely prevented the increase in soluble fibrin in plasma. However, no significant effect of AT III-heparin was observed on endotoxin-induced mortality and dysfunction in pulmonary gas exchange. Therefore we conclude that the purified AT III - heparin complex inhibits thrombin effects and prevents development of DIC, but fails to significantly influence clinical outcome in endotoxin shock of the pig.