DAMPs and immunothrombosis. (A) In an overlay of the cell-based model, DAMPs (eg, CFHs) trigger clot formation by inducing TF expression. (B) DAMPs induce NETs, which release procoagulant material and structurally facilitates clot assembly. (C) DAMP-mediated charged interactions directly activate coagulation enzymes, for example, prothrombin activation by positively charged CFHs and contact activation of FXI and FXII by the negative charge of polyphosphates, cfDNA, and cfRNA. (D) DAMPs antagonize the innate anticoagulant system; CFH neutralizes APC. (E) CFH and HMGB1 electrostatically bind to TM, inhibiting protein C (PC) activation. CFH also binds heparin-glycosaminoglycans to inhibit AT potentiation. (F) Via DAMP receptors, cfDNA, CFHs, HMGB1, and calprotectin (S100A8/9) activate and aggregate platelets. CFHs also activate platelets by directly forming calcium ionophores on platelet membranes. (G) After activation, platelets express and secrete HMGB1 and calprotectin, which further augment the procoagulant signal in an automated/paracrine manner. (H) Integration of CFH and cfDNA into a FIB (composite) clot enhances its biomechanical properties. (I) This composite clot itself is resistant to lysis by plasmin. cfDNA also directly inhibits plasmin. EPCR, endothelial protein C receptor; FDP, fibrin degradation product; S100A8/9, calprotectin.