THE SUPRAPHARMACOLOGIC DOSING OF ANTITHROMBIN CONCENTRATE FOR STAPHYLOCOCCUS AUREUS-INDUCED DISSEMINATED INTRAVASCULAR COAGULATION IN GUINEA-PIGS - SUBSTANTIAL REDUCTION IN MORTALITY AND MORBIDITY

An animal model of gram-positive septicemia was developed to evaluate the effects of antithrombin (AT) concentrates on morbidity, mortality, and laboratory consequences of disseminated intravascular coagulation (DIG). DIC was induced in guinea pigs by infusing Staphylococcus aure us (SA) isolated from blood cultures of patients with DIC (DIC-SA) or without DIC (non-DIC-SA). The non-DIC-SA animals and animals infused w ith sterile saline served as controls. Varying doses of AT were admini stered either 30 minutes or 24 hours after infusion of SA. DIC was con firmed within 4 hours by changes in prothrombin time, activated partia l thromboplastin time, fibrinogen, fibrinogen-fibrin degradation produ cts, and AT activity. Clinical bleeding was also evident. Mortality of untreated DIC-SA animals was 36% within 24 hours and up to 75% by 72 hours. Intervention with any dose of AT between 125 and 1,000 IU/kg 30 minutes after DIC-SA infusion was associated with 100% survival (P le ss than or equal to.05 in the 250 IU/kg group) and sustained increases in AT activity and fibrinogen concentrations (P less than or equal to .05). When AT was administered in combination with low molecular weigh t heparin (LMWH) or if LMWH was adminstered alone, mortality from DIC- SA was slightly, but not significantly reduced compared with untreated DIC-SA. Gross hemorrhage was observed premortem and at autopsy in all of the DIC-SA animals but in substantially fewer animals that receive d AT (P less than or equal to.001 in the 250, 500, and 1,000 IU/kg gro ups). In contrast, groups treated with LMWH, alone or with AT, experie nced hemorrhage and appeared to develop pathologic DIG. Fibrin formati on in end-organs was detected in all guinea pigs in the untreated DIC- SA group and in the groups treated with 125 IU/kg AT and LMWH alone. A T doses between 250 and 1,000 IU/kg administered 30 minutes after DIC- SA infusion prevented fibrin formation in end-organs (P less than or e qual to.001 in the 250 and 1,000 IU/kg groups). AT administered 24 hou rs after DIC-SA could not reverse pre-existing histopathologic evidenc e of DIC but favorably affected survival, which reached statistical si gnificance in the 1,000 IU/kg AT group (P less than or equal to.025). In summary, suprapharmacologic doses of AT concentrate significantly d ecreased morbidity and mortality and ameliorated adverse changes in la boratory measures induced by DIC-SA in this guinea pig model and were not associated with untoward hemorrhagic complications. These findings provide justification for studying the use of AT therapy in patients with DIC-SA. (C) 1997 by The American Society of Hematology.