Model of eculizumab function and breakthrough hemolysis in the setting of strong complement activation. (A) In PNH, loss of CD59 and CD55 results in C3b priming of C5 on red cells and allows for cleavage of C5 into C5a and C5b. This leads to formation of the MAC on PNH red cells and results in intravascular hemolysis. (B) The patient with PNH on eculizumab. Eculizumab binds to C5, and through steric hindrance, inhibits the ability of the C5 convertase to cleave C5 into C5a and C5b. The MAC does not form, and the red cell is protected. (C) The patient with PNH on eculizumab in the setting of strong complement activation (infection, surgery, etc) experiences accumulation of C3b on the cell surface (strong activation). This results in a conformation change in C5 that disrupts the steric hindrance induced by eculizumab and leads to breakthrough intravascular hemolysis. RBC, red blood cell. Professional illustration by Patrick Lane, ScEYEnce Studios.