Antithrombin III replacement in animal models of acquired antithrombin III deficiency

Plasma antithrombin III (AT III) levels decrease early during Gram-negative septicaemia, and even a moderate decrease in this major inhibitor of the coagulation system is associated with serious disseminated intravascular coagulation (DIC). This study reports the efficacy of high dose (at least 250 units/kg) AT III replacement in three animal models of Escherichia coli endotoxaemia or bacteraemia. Highlights of our findings are: 1. Endotoxaemic rat model: DIC occurs early, before the appearance of deleterious cardiovascular abnormalities; AT III prophylaxis attenuates DIC; and AT III prophylaxis increases permanent survival. 2. Endotoxaemic sheep pulmonary dysfunction model: AT III prophylaxis prevents the typical decrease in arterial oxygen partial pressure and AT III prophylaxis combined with alpha 1-proteinase inhibitor significantly attenuates indices of pulmonary dysfunction. 3. E. coli bacteraemic baboon model: AT III prophylaxis and treatment significantly attenuates indices of DIC and organ damage, and prevents death in an otherwise 100% lethal bacterial challenge. In conclusion, prophylactic treatment with high doses of AT III may be efficacious in disease states of impending DIC such as Gram-negative septicaemia. Data presented herein demonstrate that plasma levels of AT III must be maintained at levels markedly higher than normal to be efficacious in animal models of Gram-negative endotoxaemia or bacteraemia.