Fig. 1.

Pathways inhibited by current HAE drugs and developmental treatment options. Activation of the contact system is initiated by activation of Factor XII (FXII), resulting in activated Factor XII (FXIIa). FXIIa can activate prekallikrein (PK) to plasma kallikrein (PKa), which in turn can activate FXII to produce more FXIIa. In addition, PKa cleaves bradykinin (BK) from high-molecular-weight kininogen (HK). Finally, BK ligates the bradykinin B2 receptor (BKRB2). Additionally, FXIIa and PKa can activate plasmin (PL) from plasminogen (PLG). PL further stimulates the activation of FXII. Activation is indicated by red big-dotted arrows and inhibition by HAE drugs by gray small-dotted arrows. C1-INH denotes C1 esterase inhibitor