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

Abstract

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. (Blood. 2010;116(6):1002-1010) IntroductionSevere sepsis is a multistage, multifactorial, and life-threatening clinical syndrome that arises through the innate response to infection and can appear as a complication in conditions like trauma, cancer, and surgery. 1 Despite important strides made in understanding its pathophysiology, the sepsis-related mortality and morbidity rates still remain unacceptably high. Sepsis affects approximately 700 000 people and accounts for approximately 210 000 deaths per year 2 in the United States alone. In its most fulminant form, sepsis can produce cardiovascular collapse and death within hours. More common is the development of multiple organ failure (MOF) secondary to hypoperfusion and intravascular thrombosis. The MOF may run a protracted clinical course and eventually proves fatal in 30% to 40% of patients. The mechanisms responsible for the persistent and progressive organ failure are less understood. To examine this problem we have developed nonhuman primate models of Escherichia coli sepsis, which, depending on the bacterial dose, mimic the different pathophysiologic syndromes observed in clinical practice. 3 Challenge with 10 10 cfu/kg E coli (LD100) results in an explosive inflammatory and coagulopathic response leading to irreversible shock and death. The administration of a lower dose, 10 9 cfu/kg E coli (LD50), produces transient hypotension followed by MOF, which may progress and prove fatal in approximately 50% of the animals. The pathophysiology of the LD50 mo...

Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis

“…C5a up-regulates tissue factor and PAI-1 (37) on monocytes, thereby enhancing blood thrombogenicity and decreasing dissolution of fibrin clots (38). We previously demonstrated that C3 inhibition reduced thrombocytopenia and microvascular thrombosis, and preserved endothelial anticoagulant properties (15). Here we show that C5 inhibition also substantially decreases the activation of both intrinsic and extrinsic pathways of coagulation, as well as the fibrinolytic system in septic baboons.…”

“…Similar to C3 inhibition (15), blocking C5 ameliorated sepsisinduced cardiomyopathy, one of the main predictors of poor outcome in septic patients. C5a is a major cardio-depressant (41).…”

“…In a previous study, using the C3 inhibitor compstatin, we successfully prevented multiple organ failure and markedly improved blood pressure through blocking complement activation in a less severely bacteremic (10 9 cfu/kg E. coli; LD50) model (15). This study was limited to the first 24 h postchallenge and did not monitor survival benefit.…”

“…CLP sepsis in rodents induces expression of C5aR on cardiomyocytes and increased generation of C5a causes dysfunction of cardiomyocytes (42). Complement inhibition with compstatin prevented sepsis-induced hypotension when administered at T0 in the baboon LD50 model (15).…”

“…There is also uncertainty regarding the optimal timing of such intervention to achieve maximum protection against complement-induced tissue damage, without compromising beneficial antimicrobial and tissue recovery effects. Previously, we successfully prevented multiple organ failure by blocking complement activation with a C3 inhibitor during the late stage of disease, and markedly improved blood pressure when we targeted early-stage events (15). However, blocking complement activation at the C3 level is considered unsafe because the activation fragments C3b and iC3b are required for bacteria opsonization and subsequent phagocytosis.…”