Plasmin as a complement C5 convertase

Both the complement and coagulation/fibrinolytic systems are essential components of the host defense system that evolved early in the evolution of vertebrates (Krem and Di Cera, 2002). While the coagulation and fibrinolytic systems are necessary for maintenance of the integrity of the vasculature, these systems also respond to infections, and together with the complement system, play an important role in innate and adaptive immunity. There are two pathways in mammals that initiate coagulation and three that initiate complement while fibrinolysis commences in response to the presence of a fibrin clot (Bajic et al., 2015; Smith et al., 2015). The intrinsic or contact pathway for initiation of coagulation and the alternative (properdin) and lectin pathways that initiate complement activation are activated by specific properties of some surfaces such as bacterial or yeast cell walls. Cross talk between the various systems is apparent with several well-described interactions such as that between C4-binding protein (C4BP) that regulates complement by inhibiting the classical initiation pathway and protein S, the latter being a cofactor for activated protein C, a regulator of coagulation and inflammation. There are in vitro and in vivo data that suggest coagulation cascade enzymes such as thrombin could cleave C5, carrying out the same reactions as the C5 convertase (Huber-Lang et al., 2006). The cleavage products, however, did not directly generate C5a (Krisinger et al., 2012). A new study (Foley et al., 2016) shows in a venous stasis model that C5a correlates strongly with clot weight implying that pathways initiated during clot formation lead to C5 cleavage. In contrast, there is a very weak correlation with thrombin–antithrombin complexes, suggesting that thrombin is not directly cleaving C5. They then investigated the ability of thrombin, factor Xa andplasmin to cleave C5bymeasuring formation of C5a by ELISA. Plasmin, the effector enzyme in the fibrinolytic cascade, was the only enzyme that was able to cleave complement C5 at a similar rate as the canonical C5 convertase formed from complement