(A) In normal blood, when complement is activated, red cells are protected from lysis in several ways: primarily by the 2 glycosylphosphatidylinositol (GPI)-linked surface proteins CD55 (prevents binding of C3 fragments) and CD59 (prevents the membrane attack complex [MAC] from inserting into the membrane). (B) PNH red cells are deficient in CD55 and CD59 because the GPI biosynthetic pathway is blocked as a result of a PIGA mutation; therefore, C3 fragments, particularly C3d,¹⁰ bind to their surface, and the red cells are rapidly lysed by the action of the MAC. (C) With drugs (monoclonal antibodies) that bind to C5 and prevent it splitting into C5a and C5b, the entire distal pathway from C5 onward is blocked, MAC is not formed, and IVH is abrogated. However, red cells opsonized by C3d will be destroyed in the spleen and elsewhere; this drug-induced EVH varies in severity between patients. The Coombs test, which is characteristically negative in PNH, becomes positive (provided that a “broad spectrum” or an anticomplement reagent is used). (D) With a drug that targets C3, C3b formation is inhibited, and the distal pathway is not triggered by C3b. Therefore, again, no MAC is formed (abrogating IVH), and, at the same time, opsonization of red cells by C3d is prevented, so that EVH is also curbed. The same is largely true for drugs that target factor B or factor D, although C3b can still be formed through the classical pathway. This figure does not do justice to the complexity of the complement system (eg, see Mastellos et al⁸). fB, factor B; fD, factor D. Professional illustration by Patrick Lane, ScEYEnce Studios.