Generation of C3 opsonins on PNH erythrocytes in patients treated with eculizumab. Deficiency of DAF on PNH cells results in activation of the APC on PNH erythrocytes. Eculizumab blocks MAC-mediated complement lysis, allowing accumulation of C3 opsonins on PNH cells. The opsonized erythrocytes are recognized by reticuloendothelial cells of the spleen and liver that express receptors (primarily CR2 for C3dg and CR3 for iC3b), resulting in extravascular hemolysis. The figure illustrates covalent binding of activated C3 (C3b) to glycophorin A on the erythrocyte membrane surface. The bound C3 serves as the nidus for formation of the APC C3 convertase (C3b, activated factor B [Bb], and factor P) that enzymatically activates many molecules of C3 to C3b, which then bind covalently via an exposed thioester bond to carbohydrate residues on glycophorin A. Supported by interaction with sialic acid residues on glycophorin A, the plasma protein factor H binds to C3b and serves as a cofactor for degradation of C3b to iC3b by the plasma protein factor I. CR1 also binds to C3b and to iC3b and serves as a cofactor for the degradation of C3b to iC3b and then C3dg by factor I.