title: The suprapharmacologic dosing of antithrombin concentrate for Staphylococcus aureus-induced disseminated intravascular coagulation in guinea pigs: substantial reduction in mortality and morbidity.
abstract: 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 (DIC). DIC was induced in guinea pigs by infusing Staphylococcus aureus (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 with sterile saline served as controls. Varying doses of AT were administered either 30 minutes or 24 hours after infusion of SA. DIC was confirmed within 4 hours by changes in prothrombin time, activated partial thromboplastin time, fibrinogen, fibrinogen-fibrin degradation products, 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 < or = .05 in the 250 IU/kg group) and sustained increases in AT activity and fibrinogen concentrations (P < or = .05). When AT was administered in combination with low molecular weight 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 received AT (P < or = .001 in the 250, 500, and 1,000 IU/kg groups). In contrast, groups treated with LMWH, alone or with AT, experienced hemorrhage and appeared to develop pathologic DIC. Fibrin formation 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. AT doses between 250 and 1,000 IU/kg administered 30 minutes after DIC-SA infusion prevented fibrin formation in end-organs (P < or = .001 in the 250 and 1,000 IU/kg groups). AT administered 24 hours after DIC-SA could not reverse pre-existing histopathologic evidence of DIC but favorably affected survival, which reached statistical significance in the 1,000 IU/kg AT group (P < or = .025). In summary, suprapharmacologic doses of AT concentrate significantly decreased morbidity and mortality and ameliorated adverse changes in laboratory 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.
authors.affiliation: Division of Hematology/Oncology, The George Washington University Medical Center, Washington, DC, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Kessler
authors.forename: Z
authors.initials: Z
authors.lastname: Tang
authors.forename: H M
authors.initials: HM
authors.lastname: Jacobs
authors.forename: L M
authors.initials: LM
authors.lastname: Szymanski
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D016470:Bacteremia / Q000150:complications* / Q000382:microbiology; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy* / Q000209:etiology; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006168:Guinea Pigs; D006470:Hemorrhage / Q000139:chemically induced; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D008297:Male; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D013203:Staphylococcal Infections / Q000150:complications* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000302:isolation & purification; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D000990:Antithrombin III; D005340:Fibrinogen; D013917:Thrombin