title: Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock.
abstract: Excessive coagulation is a typical response to the vascular injury occurring in gram negative sepsis. This study evaluated the pharmacological effects of the use of a recombinant Escherichia coli derived form of tissue factor pathway inhibitor (ala-TFPI) in a baboon model of septic shock. Several doses of ala-TFPI were administered either 30 or 120 min after the initiation of a lethal intravenous infusion of E. coli into baboons. Treatment at 30 min with either 2.7 or 7.4 mg/kg of ala-TFPI resulted in the same survival rates and attenuation of both the coagulation response and cellular injury, as measured by clinical chemistry. When administration of ala-TFPI was delayed for 120 min, a dose of ala-TFPI protein continued to provide a benefit to survival. Ala-TFPI reduced the drop in mean systemic arterial pressure compared to control baboons in addition to partially attenuating the coagulopathic response. Baboons given ala-TFPI also maintained lower levels of plasma interleukin-6 (IL-6) and thrombin-antithrombin. These results suggest that the site of action of the protein may involve the later stage components of the coagulation and inflammatory pathways.
authors.affiliation: G.D. Searle & Co., Chesterfield, MO 63198, USA.
authors.forename: C
authors.initials: C
authors.lastname: Carr
authors.forename: G S
authors.initials: GS
authors.lastname: Bild
authors.forename: A C
authors.initials: AC
authors.lastname: Chang
authors.forename: G T
authors.initials: GT
authors.lastname: Peer
authors.forename: M O
authors.initials: MO
authors.lastname: Palmier
authors.forename: R B
authors.initials: RB
authors.lastname: Frazier
authors.forename: M E
authors.initials: ME
authors.lastname: Gustafson
authors.forename: T C
authors.initials: TC
authors.lastname: Wun
authors.forename: A A
authors.initials: AA
authors.lastname: Creasey
authors.forename: L B
authors.initials: LB
authors.lastname: Hinshaw
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects*; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000097:blood*; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism; D007700:Kinetics; D008074:Lipoproteins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010215:Papio; D010447:Peptide Hydrolases / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012772:Shock, Septic / Q000097:blood* / Q000188:drug therapy
chemical_list: D015850:Interleukin-6; D008074:Lipoproteins; D011994:Recombinant Proteins; C046193:antithrombin III-protease complex; C051928:lipoprotein-associated coagulation inhibitor; D000990:Antithrombin III; D010447:Peptide Hydrolases