Complement cascade modulation on normal and PNH RBCs, with or without complement inhibitors. (A) Normal RBCs, steady state. Normal RBCs (CD55+, CD59+) are protected from complement activation by CD55, which down-regulate the C3-convertase, and by CD59, which inhibits the MAC assembly. Thus, in steady state normal RBCs can withstand the challenge of complement activation. (B) PNH RBCs, steady state. PNH RBCs (CD55−, CD59−) suffer from impaired complement regulation at the level of both C3-activation (because of the lack of CD55) and MAC assembly (because of the lack of CD59). As a result, in steady state, PNH RBCs eventually undergo intravascular hemolysis because of complement activation. (C) PNH RBCs, on eculizumab. On eculizumab treatment, PNH RBCs are protected from lysis because of the blockade of terminal effector complement; however, because of the impaired C3-convertase regulation, they suffer from continuous complement activation and subsequent membrane deposition of C3 fragments. As a result, on eculizumab, PNH RBCs may become susceptible to extravascular hemolysis secondary to removal of C3-opsonized RBCs by reticuloendothelial system (RES) macrophages, resulting in possible reduced life-span PNH RBCs. (D) PNH RBCs, on TT30. As soon as complement activation is initiated, the CR2-domain of TT30 delivers the complement-modulatory domain of fH to the RBC surface. Then, TT30 disables the C3-convertase, and, as cofactor of factor I, it promotes the conversion of active C3b into iC3b and then C3dg/C3d, preventing all downstream events because of the complement cascade (as well as additional complement activation on the red cell membrane). As a result, irrespective of the blockade of C5, TT30 may confer to PNH RBCs a normal survival even in presence of complement activation.