(A) FVIIIa is shown (gray), and the distance between the binding sites for FX and FIXa is depicted. The cofactor activity of FVIIIa requires positioning the catalytic site of FIXa (green) so that it will hydrolyze the cleavage site on FX (purple) to generate FXa. (B) Emicizumab is a bispecific IgG that binds the epidermal growth factor–like (EGF-like) domain 1 of FIX/FIXa with one arm and the EGF-like domain 2 of FX/FXa with the other arm. It was designed to have a common light chain (brown) and mutations in the Fc portion to facilitate heavy chain heterodimerization. These modifications reduced the number of possible permutations of antibodies during IgG assembly and enabled efficient production of the asymmetric bispecific IgG. Emicizumab mimics FVIIIa cofactor activity enabling the generation of FXa (9).