Recombinant human antithrombin III improves survival and attenuates inflammatory responses in baboons lethally challenged with Escherichia coli.
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. (Blood. 2000;95:1117-1123)
Minnema
M C
MC
Sanquin Blood Supply Foundation, Amsterdam, The Netherlands; the Laboratory for Experimental and Clinical Immunology, University of Amsterdam, Amsterdam, The Netherlands. muntar@db.nl
Chang
A C
AC
Jansen
P M
PM
Lubbers
Y T
YT
Pratt
B M
BM
Whittaker
B G
BG
Taylor
F B
FB
Hack
C E
CE
Friedman
B
B
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism / Q000627:therapeutic use*; D001772:Blood Cell Count / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004334:Drug Administration Schedule; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D010215:Papio; D010447:Peptide Hydrolases / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D013534:Survival; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D016209:Interleukin-8; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C046193:antithrombin III-protease complex; D016753:Interleukin-10; D000990:Antithrombin III; D005340:Fibrinogen; D010447:Peptide Hydrolases