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The suprapharmacologic dosing of antithrombin concentrate for
Staphylococcus aureus-induced disseminated intravascular coagulation in
guinea pigs: substantial reduction in mortality and morbidity
CM Kessler, Z Tang, HM Jacobs and LM Szymanski
Division of Hematology/Oncology, The George Washington University Medical
Center, Washington, DC, USA.
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.
Volume 89,
Issue 12,
pp. 4393-4401,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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