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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1117-1123
Recombinant human antithrombin III improves survival and
attenuates inflammatory responses in baboons lethally challenged
with Escherichia coli
M. C. Minnema,
A. C. K. Chang,
P. M. Jansen,
Y. T. P. Lubbers,
B. M. Pratt,
B. G. Whittaker,
F. B. Taylor,
C. E. Hack, and
B. Friedman
From the Sanquin Blood Supply Foundation, Amsterdam,
The Netherlands; the Laboratory for Experimental and Clinical
Immunology, University of Amsterdam, Amsterdam, The
Netherlands; Oklahoma Medical Research Foundation, Oklahoma
City, OK; and Genzyme Corporation, Framingham, MA.
Plasma-derived antithrombin III (ATIII) prevents the lethal effects
of Escherichia coli infusion in baboons, but the
mechanisms behind this effect are not clear. In the
present study, we evaluated the effects of recombinant human
ATIII (rhATIII) on the clinical course and the inflammatory
cytokine and coagulation responses in baboons challenged with lethal
dose of E coli. Animals in the treatment group (n = 5)
received high doses of rhATIII starting 1 hour before an E coli
challenge. Those in the control group were administered saline.
Survival was significantly improved in the treatment group
(P = .002). Both groups had similar hemodynamic responses
to E coli challenge but different coagulation and inflammatory responses. The rhATIII group had an accelerated increase of
thrombin-ATIII complexes and significantly less fibrinogen
consumption compared to controls. In addition, the rhATIII group had
much less severe thrombotic pathology on autopsy and virtually no
fibrinolytic response to E coli challenge. Furthermore, the
rhATIII group had a significantly attenuated inflammatory response as
evidenced by marked reduction of the release of various cytokines. We
conclude that the early administration of high doses of rhATIII
improves the outcome in baboons lethally challenged with E
coli, probably due to the combined anticoagulation and
anti-inflammatory effects of this therapy.
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