RECOMBINANT E-COLI-DERIVED TISSUE FACTOR PATHWAY INHIBITOR REDUCES COAGULOPATHIC AND LETHAL EFFECTS IN THE BABOON GRAM-NEGATIVE MODEL OF SEPTIC SHOCK

Excessive coagulation is a typical response to the vascular injury occ urring in gram negative sepsis. This study evaluated the pharmacologic al effects of the use of a recombinant Escherichia coli derived form o f tissue factor pathway inhibitor (ala-TFPI) in a baboon model of sept ic 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 c oagulation response and cellular injury, as measured by clinical chemi stry. When administration of ala-TFPI was delayed for 120 min, a dose of ala-TFPI protein continued to provide a benefit to survival. Ala-TF PI reduced the drop in mean systemic arterial pressure compared to con trol baboons in addition to partially attenuating the coagulopathic re sponse. 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 com ponents of the coagulation and inflammatory pathways. (c) 1995 Wiley-L iss, Inc.