The kallikrein-kinin system and HAE. Activation of FXII to FXIIa leads to conversion of plasma prekallikrein (PK) to active plasma kallikrein (PKa). PKa can cleave high- and low-molecular-weight kininogens (K) to release bradykinin. Under normal conditions, C1-INH inhibits FXIIa and prevents propagation of the pathway. Many cases of HAE are caused by insufficient or inactive C1-INH. The article by Dickeson et al shows that a methionine-to-lysine missense mutation in kininogen (K-Lys), identified in a family of patients with HAE, renders it susceptible to cleavage by the fibrinolytic protease plasmin. This mutation thus causes excessive bradykinin formation and can lead to HAE.