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 co-existence 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.

Fig. 1

Coagulation and complement cascades. a The coagulation branch of the hemostatic system. Coagulation takes place via the intrinsic and extrinsic pathways. The intrinsic pathway is initiated in vitro by contact activation of factor XII, in a plasma kallikrein-high molecular weight kininogen-dependent fashion (contact system). Triggering of the extrinsic pathway, which is considered the primary mode of in vivo coagulation, is tissue factor (TF) dependent and takes place on the surface of activated cells. The two pathways are based on the sequential activation of the coagulation factors, which converge in the catalytic generation of active thrombin by its zymogen proteinase. Thrombin is responsible for the proteolytic transformation of fibrinogen to fibrin and the subsequent generation of fibrin clots. The designation “a” following the various clotting factors represents a state of activation of the factors. Activated platelets have a major role in this process, as they can provide their negatively charged phospholipid area as a surface for initiation of coagulation. b Complement activation pathways. The components of complement system can be organized into three major pathways: the classical pathway is mainly initiated by the binding of C1q to antigen–antibody complexes, whereas the lectin pathway is triggered by binding of mannose-binding lectin (MBL) or ficolins to glycosylated surfaces on microbial cell walls. Both pathways lead to the formation of a common C3 convertase, an enzyme complex with serine proteinase trypsin-like specificity. The alternative pathway, on the other hand, can be triggered by spontaneous hydrolysis of the internal thioester bond of C3, leading to the formation of C3_H2O. This non-proteolytically activated form of C3 can lead to the formation of the alternative pathway C3 convertase by interacting with factors B and D. This convertase formation can be further induced and stabilized by properdin. C3 convertases generated by all pathways are able to cleave C3 into C3a and C3b, the latter of which forms additional convertases, thereby rapidly amplifying complement response. C3b vitally contributes to the clearance of pathogens by phagocytes (macrophages and neutrophils) and is a major component of the C5 convertase, which in turn cleaves C5 to C5a and C5b. The anaphylatoxins C3a and C5a mediate the inflammatory responses of complement. C5b subsequently takes the lead in formation of the terminal C5b-9 complement complex, also called MAC, ultimately resulting into cell lysis. Potential roles in the proteolytic activation of C3 and C5 have also been assigned to non-complement proteinases, including enzymes of the coagulation and fibrinolysis cascades

Fig. 2

Interconnections between coagulation and complement. Components of the coagulation, fibrinolysis, and complement cascades are highlighted to demonstrate the potential vital intercommunication that the three systems may exhibit in vivo. More details on these interactions are discussed in the text. Proteolytic cleavages are represented by blue lines, while black-colored lines depict non-proteolytic interactions. Related inhibitory actions on the pathway components are shown by dotted lines

Fig. 3

A potential cardinal role for the complement anaphylatoxin C5a in septicemia. In patients with sepsis, systemic activation of complement and persistent release of C5a can induce the upregulation of tissue factor (TF) by immune and endothelial cells, leading to the development of disseminated intravascular coagulation (DIC). DIC, in cooperation with the C5a-mediated release of pro-inflammatory cytokines, can lead to the multiple organ dysfunction that characterizes the systemic inflammatory response syndrome (SIRS). In advanced sepsis, C5a can elicit neutrophil dysfunction, adversely affecting the host’s immune response to opportunistic infections. C5a can also cause apoptosis of thymocytes, possibly lymphocytes, and adrenal medullary cells, resulting in immunosuppression or septic shock. C5a has further been implicated in the development of septic cardiomyopathy leading to heart failure. The aforementioned outcomes of C5a induction can potentially be triggered by cell signaling via its two receptors, C5aR and C5L2 (reviewed in [101, 102, 115])