Efficacy of antithrombin III supplementation in animal models of fulminant Escherichia coli endotoxemia or bacteremia.
Plasma antithrombin III (ATIII) levels decrease early during gram-negative septicemia, and even a moderate decrease in this major inhibitor of the coagulation system is associated with serious disseminated intravascular coagulation (DIC). Herein the efficacy of high-dose (at least 250 units/kg) ATIII supplementation in animal models of Escherichia coli endotoxemia or bacteremia is reported. An endotoxemic rat model demonstrated that: (1) DIC occurs very early, before the appearance of deleterious cardiovascular abnormalities; (2) ATIII prophylaxis attenuates DIC, metabolic dysfunction, and organ damage; (3) ATIII prophylaxis increases permanent survival; (4) ATIII treatment one hour after endotoxin challenge attenuates DIC, metabolic dysfunction, and organ damage, although not as well as when given prophylactically, and survival is not increased. An endotoxemic sheep pulmonary dysfunction model demonstrated that: (1) ATIII prophylaxis prevents the typical decrease in arterial oxygen partial pressure; (2) ATIII prophylaxis combined with alpha-1-proteinase inhibitor significantly attenuates indices of pulmonary dysfunction. An E. coli bacteremic baboon model demonstrated that ATIII prophylaxis and treatment significantly attenuate indices of DIC and organ damage and prevent death in an otherwise completely lethal dose bacterial challenge. In conclusion, prophylactic treatment with high doses of ATIII may be efficacious in disease states of impending disseminated intravascular coagulation, such as primary or secondary gram-negative septicemia.
Emerson
T E
TE
Department of Experimental Therapeutics, Cutter Biological, Miles Inc., Berkeley, California 94710.
Fournel
M A
MA
Redens
T B
TB
Taylor
F B
FB
D000818:Animals; D000990:Antithrombin III / Q000627:therapeutic use*; D004211:Disseminated Intravascular Coagulation / Q000517:prevention & control*; D004731:Endotoxins; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000628:therapy*; D008297:Male; D010215:Papio; D051381:Rats; D011919:Rats, Inbred Strains; D018805:Sepsis / Q000628:therapy*; D012756:Sheep
D004731:Endotoxins; D000990:Antithrombin III