FIGURE 1.

Activation of the contact system induces thrombotic and inflammatory pathways in Alzheimer's disease (AD). Activation of coagulation factor XII (FXII) by Aβ42 can trigger the intrinsic clotting pathway as well as an inflammatory pathway. A, Intrinsic clotting occurs when activated FXII (FXIIa) activates factor XI (FXI) to FXIa. Eventually, prothrombin is cleaved to thrombin, which cleaves fibrinogen into fibrin. Aβ42 can interact with fibrinogen, and fibrin clots formed in the presence of Aβ42 are resistant to degradation. These resistant blood clots can increase the incidence of vessel occlusion, leading to microinfarcts, blood‐brain barrier (BBB) damage, and inflammation. Extravasated fibrin(ogen) can also induce cerebral inflammation. B, FXIIa cleaves prekallikrein (PK) to generate kallikrein. The proinflammatory peptide, bradykinin, is released upon high molecular weight kininogen (HK) cleavage by kallikrein. Bradykinin can induce vasodilation, edema, inflammation, and BBB damage. HK is essential for normal operation of both thrombotic and inflammatory pathways of the contact system, as PK and FXI need to bind HK to be activated by FXIIa