Mechanisms of failure to C5 inhibition. (A) In patients who receive anti-C5 therapy, early complement activation remains uncontrolled on PNH erythrocytes, leading to surface C3 activation and progressive opsonization, with C3 fragments of PNH erythrocytes spared from MAC-mediated hemolysis. Because C3d-opsonized erythrocytes may be recognized by professional macrophages through C3dg receptors, C3-mediated extravascular hemolysis has emerged as additional/alternative mechanism of hemolysis in patients with PNH receiving anti-C5 therapy. (B) Intravascular hemolysis is caused either by insufficient drug dosing, allowing free C5 levels to rise (i), or by complement-amplifying conditions (eg, pregnancy, infection, major surgery), resulting in excess C3b accumulation on PNH erythrocytes, which decreases the binding of C5 inhibitor to C5 because of conformation change in C5 and generates high-affinity, C3b-rich, C5 convertases that compete more efficiently with anti-C5 antibodies for their substrate C5 (ii). Professional illustration by Somersault 18:24.