DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage.
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.
Taylor
F B
FB
Cardiovascular Biology Research, Oklahoma Medical Research Foundation, Oklahoma City 73104.
Chang
A C
AC
Peer
G T
GT
Mather
T
T
Blick
K
K
Catlett
R
R
Lockhart
M S
MS
Esmon
C T
CT
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
D000590:Amino Acid Chloromethyl Ketones; D003619:Dansyl Compounds; D014409:Tumor Necrosis Factor-alpha; C030824:dansylglutamyl-glycyl-arginine chloromethyl ketone; D015951:Factor Xa