Crossregulation of DAMPs by the complement and coagulation pathways. Circulating protein sensors (eg, C3, C1q, mannose-binding lectin [MBL], or FVII) bind injury-associated ligands (eg, microbial surfaces, microbial proteins, or TF) to trigger a biochemical response, amplified through a protease cascade and reinforced by cross talk between pathways. The final protein product mounts the requisite injury responses of cytotoxicity or coagulation. This is subjected to homeostatic regulation by noninjured surfaces, which suppresses these responses. As part of the injury signal, DAMPs modulate both complement and coagulation. (A) DAMPs can enhance complement activation. HMGB-1 binds to C1q and activates C2 and C4. (B) Conversely, DAMPs also neutralize complement-associated inflammatory signaling to prevent excessive collateral damage. HMGB1–receptor for advanced glycation end product and C1q–LAIR-1 complexing on monocyte surfaces promotes anti-inflammatory differentiation. (C) Binding of CFH at the level of C4 inhibits downstream complement activation. CFH-C4 binding reciprocally neutralizes CFH toxicity. (D) FIIa and APC can also neutralize DAMPs via proteolysis. (E) Anticoagulant surfaces can bind and sequester DAMPs, although higher DAMP doses competitively inhibit these anticoagulant properties. LAIR-1, leucocyte-associated immunoglobulin-like receptor-1MAC, membrane attack complex.