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.
Emerson
T E
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Miles, Inc., Pharmaceutical Division, West Haven, CT 06516.
D000818:Animals; D000990:Antithrombin III / Q000627:therapeutic use*; D020152:Antithrombin III Deficiency; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D016905:Gram-Negative Bacterial Infections / Q000097:blood* / Q000150:complications; D008297:Male; D010215:Papio; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000097:blood* / Q000150:complications; D012756:Sheep; D012772:Shock, Septic / Q000097:blood* / Q000150:complications
D000990:Antithrombin III