Biomaterial surface–triggered activation of the plasma contact system yields a thromboinflammatory response. Contact of FXII with a biomaterial surface, adsorbed proteins (eg, fibrinogen), DNA, RNA, NETS, polyphosphate, or activated cells, induces a conformational change to generate small amounts of FXIIa. FXIIa complexed with HK activates PK to PKa, FXI to FXIa, and C1r to its active form. PKa cleaves or activates FXII and HK, generating more FXIIa and BK, the latter of which has proinflammatory properties. PKa also directly activates FB, thus promoting the alternative complement pathway and complement factors C3 and C5. FXIa leads to thrombin generation via the intrinsic pathway of coagulation, resulting in activation of adherent platelets. C1-inhibitor (C1-INH) neutralizes PKa, FXIIa, FXIa, and C1r.