Complement-mediated lysis of PNH erythrocytes. Top panel shows that the C3 convertase (left blue rectangle) of the APC consists of activated C3 (C3b), activated factor B (Bb, the enzymatic subunit of the complex), and factor P (a protein that stabilizes the complex, formally called properdin). The C5 convertase (right blue rectangle) has the same components as the C3 convertase except that 2 C3b molecules are required to bind and position C5 for cleavage by activated factor B (Bb). C3a and C5a are bioactive peptides that are generated by cleavage of C3 and C5, respectively, by their specific activation convertases. The C3 and C5 convertases greatly amplify complement activation by cleaving multiple substrate molecules. The MAC (red rectangle) consists of activated C5 (C5b), C6, C7, C8, and multiple molecules of C9 (C9_n). The MAC is the cytolytic unit of the complement system. The GPI-anchored complement-regulatory protein CD55 restricts the formation and stability of both the C3 and the C5 amplification convertases by destabilizing the interaction between activated factor B (Bb) and C3b (indicated by the blue arrows), whereas GPI-anchored CD59 blocks formation of the MAC by inhibiting the binding of C9 to the C5b-8 complex (indicated by the brown arrow). Inhibition of MAC formation by the humanized anti-C5 mAb eculizumab (indicated by the red arrow) ameliorates the intravascular hemolysis of PNH. Bottom panel shows that normal erythrocytes (left) are protected against complement-mediated lysis (lightning bolts) primarily by CD55 (blue circles) and CD59 (green circles). Deficiency of these GPI-anchored complement-regulatory proteins results in APC activation on PNH erythrocytes (right). Consequently, MACs form pores in the red cell membrane, resulting in colloid osmotic lysis and release of hemoglobin (red circles) and other contents of the red cell, including LDH, into the intravascular space.