Detection of residual complement activity in PNH patients on eculizumab, with their pathogenic and therapeutic implications. (A) Residual CH50 activity in PNH on eculizumab (see Figure 2A in the article by Peffault de Latour et al that begins on page 775). (B) Mechanism of residual intravascular hemolysis on eculizumab: lack of complete C5 blockade may be due to low plasma level of eculizumab (PK breakthrough) and extra complement activation (PD breakthrough) or rare C5 polymorphisms. Residual intravascular hemolysis may benefit from changes in eculizumab schedule and novel terminal complement inhibitors.¹⁰  (C) Mechanism of supervening extravascular hemolysis: due to the lack of CD55, proximal complement activation on RBC remains impaired, eventually leading to C3 opsonization and subsequent C3-mediated extravascular hemolysis.⁶  C3-mediated extravascular hemolysis may benefit from novel inhibitors of the proximal complement targeting C3 and other proteins involved in the activation of the complement alternative pathway.^8-10