scXIIa proteolytic activity. Initiation of contact activation may arise when zymogen FXII interacts with polyphosphates, a negatively charged surface, to evolve proteolytic activity for small-molecular-mass chromogenic substrates (not shown) and proteins, PK, FXII, or FXI (XI). This form of FXII, which is the subject of the study by Ivanov et al in this issue of Blood, is newly appreciated and can be designated single-chain FXIIa, or scXIIa. Propagation of contact activation occurs when scXIIa activates PK to plasma Kal, FXII to a 2-chain αFXIIa (αXIIa), and FXI to active FXIa. Amplification of formed Kal and αXIIa occurs by reciprocal activation and results in induction of inflammatory, complement, and fibrinolytic pathways. In addition, αXIIa activates more XI, leading to thrombin formation via the intrinsic pathway of blood coagulation. Professional illustration by Patrick Lane, ScEYEnce Studios.