Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis

Author:

Silasi-Mansat Robert1,Zhu Hua1,Popescu Narcis I.12,Peer Glenn3,Sfyroera Georgia4,Magotti Paola4,Ivanciu Lacramioara1,Lupu Cristina1,Mollnes Tom E.56,Taylor Fletcher B.12,Kinasewitz Gary3,Lambris John D.74,Lupu Florea712

Affiliation:

1. Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City;

2. Departments of Pathology and

3. Internal Medicine, Pulmonary and Critical Care Division, Oklahoma University Health Sciences Center, Oklahoma City;

4. Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia;

5. Institute of Immunology, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway; and

6. Research Laboratory, Nordland Hospital, Bodø and University of Tromsø, Tromsø, Norway

7. J.D.L. and F.L. cosupervised this study.

Abstract

AbstractSevere 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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