The complement system as a main column of innate immunity and the coagulation system as a main column in hemostasis undergo massive activation early after injury. Interactions between the two cascades have often been proposed but the precise molecular pathways of this interplay are still in the dark. To elucidate the mechanisms involved, the effects of various coagulation factors on complement activation and generation of anaphylatoxins were investigated and summarized.
Activated clotting Factor XII (FXIIa) can activate the classical complement pathway through cleavage of the complement component C1. Similarly, thrombin, kallikrein and plasmin directly cleave complement component C3, as well as its activation fragments. Moreover, thrombin can cleave C5 into C5a, which occurs independently of C3 and therefore represents a bypass of the three traditional complement-activation pathways (that is, the classical, lectin and alternative pathways). Thrombin-activatable fibrinolysis inhibitor (TAFI) inactivates C3a and C5a in a negative-feedback loop. The complement system also amplifies coagulation through the C5a-mediated induction of expression of tissue factor and plasminogen-activator inhibitor 1 (PAI1) by leukocytes, the latter of which inhibits fibrinolysis. In addition, mannan-binding lectin serine protease 2 (MASP2) of the lectin complement-activation pathway triggers coagulation by converting prothrombin to thrombin. C4b-binding protein (C4BP) of the complement pathway inhibits protein S, which is a co-factor for the activated protein-C pathway of coagulation inhibition, which indicates that the inhibition of anticoagulant mechanisms further augments the pro-coagulant activities of complement. MAC, membrane-attack complex (C5b–C9); TPA, tissue plasminogen activator; UPA, urokinase-like plasminogen activator.
Own in vitro findings suggest, that the coagulation factors FXa, FXIa and plasmin may cleave both C5 and C3, and robustly generate C5a and C3a (as detected by immunoblotting and ELISA). The produced anaphylatoxins were found to be biologically active as shown by a dose-dependent chemotactic response of neutrophils and HMC-1 cells, respectively. Thrombin did not only cleave C5 but also in vitro-generated C3a when incubated with native C3. The plasmin-induced cleavage activity could be dose-dependently blocked by the serine protease inhibitor aprotinin and leupeptine. These findings suggest that various serine proteases belonging to the coagulation system are able to activate the complement cascade independently of the established pathways. Moreover, functional C5a and C3a are generated, both of which are known to be crucially involved in the inflammatory response.
1. Amara U, et al. (2008). Interaction between the coagulation and complement system. In Current topics in complement II (pp. 68-76). Springer US.
2. Amara U, et al. (2008). Interaction between the coagulation and complement system. In Current topics in complement II (pp. 68-76). Springer US.