The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons.
The hypotension and disseminated intravascular coagulation (DIC) in bacteremia is thought to be mediated by the combined actions of cytokines, prostaglandins, and complement. The contact system, via the release of bradykinin and the activation of Factor XI, has been postulated to be contributing to the observed hypotension and DIC. Using a mAb to Factor XII (C6B7), we blocked the activation of the contact system in an established experimental baboon model in which Escherichia coli was infused to produce lethal bacteremia with hypotension. The untreated group (n = 5) displayed contact activation, manifested by a significant decrease in high molecular weight kininogen (HK) and a significant increase in alpha 2 macroglobulin-kallikrein complexes (alpha 2M-Kal). The C6B7-treated group (n = 5) showed an inactivation of Factor XII and the changes in HK and alpha 2M-Kal complexes were prevented. Both groups developed DIC manifested by a decrease in platelet, fibrinogen, and Factor V levels. The untreated group developed irreversible hypotension. The treated group experienced an initial hypotension that was reversed and extended the life of the animals. This study suggests that irreversible hypotension correlates with prolonged activation of the contact system, and specific antibody therapy can modulate both the pathophysiological and biochemical changes.
Pixley
R A
RA
Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
De La Cadena
R
R
Page
J D
JD
Kaufman
N
N
Wyshock
E G
EG
Chang
A
A
Taylor
F B
FB
Colman
R W
RW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D016470:Bacteremia / Q000097:blood* / Q000503:physiopathology*; D001794:Blood Pressure; D004211:Disseminated Intravascular Coagulation / Q000503:physiopathology*; D004927:Escherichia coli Infections / Q000097:blood* / Q000503:physiopathology*; D005174:Factor XII / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D005340:Fibrinogen / Q000378:metabolism*; D006339:Heart Rate; D006801:Humans; D007022:Hypotension / Q000209:etiology*; D007610:Kallikreins / Q000378:metabolism*; D007700:Kinetics; D007704:Kininogens / Q000378:metabolism*; D010215:Papio; D010976:Platelet Count; D000511:alpha-Macroglobulins / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D007704:Kininogens; D000511:alpha-Macroglobulins; D005174:Factor XII; D005340:Fibrinogen; D007610:Kallikreins