Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis.
Severe sepsis leads to massive activation of coagulation and complement cascades that could contribute to multiple organ failure and death. To investigate the role of the complement and its crosstalk with the hemostatic system in the pathophysiology and therapeutics of sepsis, we have used a potent inhibitor (compstatin) administered early or late after Escherichia coli challenge in a baboon model of sepsis-induced multiple organ failure. Compstatin infusion inhibited sepsis-induced blood and tissue biomarkers of complement activation, reduced leucopenia and thrombocytopenia, and lowered the accumulation of macrophages and platelets in organs. Compstatin decreased the coagulopathic response by down-regulating tissue factor and PAI-1, diminished global blood coagulation markers (fibrinogen, fibrin-degradation products, APTT), and preserved the endothelial anticoagulant properties. Compstatin treatment also improved cardiac function and the biochemical markers of kidney and liver damage. Histologic analysis of vital organs collected from animals euthanized after 24 hours showed decreased microvascular thrombosis, improved vascular barrier function, and less leukocyte infiltration and cell death, all consistent with attenuated organ injury. We conclude that complement-coagulation interplay contributes to the progression of severe sepsis and blocking the harmful effects of complement activation products, especially during the organ failure stage of severe sepsis is a potentially important therapeutic strategy.
Silasi-Mansat
Robert
R
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
Zhu
Hua
H
Popescu
Narcis I
NI
Peer
Glenn
G
Sfyroera
Georgia
G
Magotti
Paola
P
Ivanciu
Lacramioara
L
Lupu
Cristina
C
Mollnes
Tom E
TE
Taylor
Fletcher B
FB
Kinasewitz
Gary
G
Lambris
John D
JD
Lupu
Florea
F
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects* / Q000276:immunology; D001794:Blood Pressure / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects; D003169:Complement Inactivator Proteins / Q000378:metabolism / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D009102:Multiple Organ Failure / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D010215:Papio; D010456:Peptides, Cyclic / Q000494:pharmacology*; D018805:Sepsis / Q000097:blood / Q000188:drug therapy / Q000276:immunology
D015415:Biomarkers; D003169:Complement Inactivator Proteins; D016207:Cytokines; D010456:Peptides, Cyclic; C111828:compstatin
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