Fig. 2.

The contact system in disease states. FXII is activated into FXIIa either by endogenous activator (nucleic acids RNA/DNA, neutrophil extracellular traps (NETs), polyphosphate, and heparin) or artificial surfaces. FXIIa then activates 4 different pathways: (1) The inflammation kallikrein-kinin pathway by converting plasma prekallikrein (PPK) into active plasma kallikrein (PK), which cleaves both FXII into FXIIa and high molecular weight kininogen (HK) to bradykinin (BK). The latter binds to kinin receptors (B2 and B1 receptors) and triggers inflammation. (2) The complement system by activation of the C1qrs complex subunits C1r and C1s leading formation of the membrane attack complex by the classical complement pathway. (3) The fibrinolytic system by PK activation of prourokinase into urokinase that in turn cleaves plasminogen into plasmin, an enzyme that degrades fibrin clots. (4) The intrinsic coagulation pathway by FXI activation into FXIa leading to thrombin activation and fibrin generation. The contact system is controlled mainly by C1 inhibitor (C1-Inh) that inhibits both FXIIa and PK. Other endogenous inhibitors including antithrombin III (ATIII), α-2-macroglobulin (α2M), and α-2-antiplasmin (α2AP) contribute in controlling contact system proteases and new synthetic “exogenous” inhibitors have been developed to interfere with contact system-mediated diseases. Green arrows indicate activation, and red arrows inhibition. Protein in bold is the result of proteolytic cleavage of their precursors. Boxed text indicates pathways (underlined) and related disease states (reproduced by permission of Elsevier from: Weidmann H, Heikaus L, Long AT, Naudin C, Schluter H, Renne T. The plasma contact system, a protease cascade at the nexus of inflammation, coagulation and immunity. Biochim Biophys Acta Mol Cell Res. 2017;1864(11 Pt B):2118–27).