title: DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage.
abstract: One of the aims of research in the area of thrombosis has been to design an effective anticoagulant that would function in a predictable and direct manner. In evaluating the role of coagulation in sepsis we used factor Xa blocked in the active center with [5-(dimethylamino)1-naphthalenesulfonyl]-glutamylglycylarginyl+ ++ chloromethyl ketone (DEGR-Xa). We infused 1 mg/kg of DEGR-Xa together with LD100 concentrations of Escherichia coli (4 x 10(10) organisms/kg) into five baboons. As controls, we infused E coli alone into five baboons. The inflammatory, coagulant, and cell injury responses to E coli of both the treated and control groups were lethal and were similar in every respect except for the complete inhibition of the consumption of fibrinogen in the DEGR-Xa group. The half life of DEGR-Xa was approximately 10 hours and 2 hours, as determined by isotopic and enzyme-linked immunosorbent assays, respectively. These results for the first time demonstrate that, although coagulation occurs in E coli sepsis, fibrin formation per se did not influence the lethal outcome in this model. These results also show the effectiveness of DEGR-Xa as an anticoagulant and raise the possibility that it could serve as an alternative to anticoagulants currently in use.
authors.affiliation: Cardiovascular Biology Research, Oklahoma Medical Research Foundation, Oklahoma City 73104.
authors.forename: F B
authors.initials: FB
authors.lastname: Taylor
authors.forename: A C
authors.initials: AC
authors.lastname: Chang
authors.forename: G T
authors.initials: GT
authors.lastname: Peer
authors.forename: T
authors.initials: T
authors.lastname: Mather
authors.forename: K
authors.initials: K
authors.lastname: Blick
authors.forename: R
authors.initials: R
authors.lastname: Catlett
authors.forename: M S
authors.initials: MS
authors.lastname: Lockhart
authors.forename: C T
authors.initials: CT
authors.lastname: Esmon
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D000818:Animals; D001777:Blood Coagulation; D001794:Blood Pressure; D002417:Cattle; D003619:Dansyl Compounds; D004211:Disseminated Intravascular Coagulation / Q000517:prevention & control*; D004927:Escherichia coli Infections / Q000150:complications / Q000503:physiopathology*; D015951:Factor Xa / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D005260:Female; D006339:Heart Rate; D006801:Humans; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D010215:Papio; D010976:Platelet Count; D012769:Shock / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D003619:Dansyl Compounds; D014409:Tumor Necrosis Factor-alpha; C030824:dansylglutamyl-glycyl-arginine chloromethyl ketone; D015951:Factor Xa