Interactions between coagulation and complement—their role in inflammation

Abstract

The parallel expression of activation products of the coagulation, fibrinolysis, and complement systems has long been observed in both clinical and experimental settings. Several interconnections between the individual components of these cascades have also been described, and the list of shared regulators is expanding. The coexistence and interplay of hemostatic and inflammatory mediators in the same microenvironment typically ensures a successful host immune defense in compromised barrier settings. However, dysregulation of the cascade activities or functions of inhibitors in one or both systems can result in clinical manifestations of disease, such as sepsis, systemic lupus erythematosus, or ischemia–reperfusion injury, with critical thrombotic and/or inflammatory complications. An appreciation of the precise relationship between complement activation and thrombosis may facilitate the development of novel therapeutics, as well as improve the clinical management of patients with thrombotic conditions that are characterized by complement-associated inflammatory responses.

MASP-1 of the complement system promotes clotting via prothrombin activation

“…Both the complement and the coagulation cascade originate from the same ancestral pathways, they comprise several serine proteases with common structural characteristics, and they show a high degree of interaction between specific intermediates (Amara et al, 2010;Krem and Di Cera, 2002). As both systems serve as defense mechanism in an environment with compromised barrier setting, they often activate each other (Oikonomopoulou et al, 2012).…”

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

“…Besides lysis of bacteria, C5b-9 can damage the cells and tissues of the host. It can induce tissue factor activity on endothelial cells (8), and prothrombinase formation on platelets (9, 10) and endothelial cells (11), thus contributing to development of multiple organ failure (12). Activation of complement, inflammation, and coagulation together promote thrombocytopenia and disseminated intravascular coagulation (DIC), a potential lethal thrombo-hemorrhagic complication of sepsis (13).…”

Complement C3 is a substrate for activated factor XIII that is cross‐linked to fibrin during clot formation

“…British Journal of Haematology, 146,[538][539][540][541][542][543][544][545] Hanaoka, N., Murakami, Y., Nagata, M., Nagakura, S., Yonemura, Y., Sonoki, T., Kinoshita, T. & Nakakuma, H. (2012) Complement C3 is a substrate for activated factor XIII that is cross-linked to fibrin during clot formation Complement C3 is the main effector protein of the complement system and plays a major role in innate immunity. A growing body of evidence indicates complex interactions between the complement and coagulation cascades (Oikonomopoulou et al, 2012), which are likely to be beneficial in the context of protection following injury. We previously identified C3 as a novel clot component and demonstrated that C3 binds to fibrin with high affinity and prolongs fibrinolysis in a purified system and plasma milieu (Howes et al, 2012), consistent with results of several clinical studies (Schroeder et al, 2010;Hess et al, 2012;Howes et al, 2012).…”

“…A growing body of evidence indicates complex interactions between the complement and coagulation cascades (Oikonomopoulou et al, 2012), which are likely to be beneficial in the context of protection following injury. We previously identified C3 as a novel clot component and demonstrated that C3 binds to fibrin with high affinity and prolongs fibrinolysis in a purified system and plasma milieu (Howes et al, 2012), consistent with results of several clinical studies (Schroeder et al, 2010;Hess et al, 2012;Howes et al, 2012).…”