Accordingly, administration of C1-INH replacement therapy during an HAE attack restores regulation of the cascade systems producing bradykinin by inhibiting the same targets as endogenous C1-INH (i.e., plasma kallikrein, factors XIIa and XIIf, and elements of the complement pathway, including MASP-1; Figure 1) (5, 13, 16). Here, KLK4 is linked to hereditary angioedema.