Complement-mediated oxidative damage of red cells impairs response to eculizumab in a G6PD-deficient patient with PNH

(Extract) The mechanism of hemolysis in glucose 6-phosphate dehydrogenase (G6PD) deficiency is oxidative damage; in paroxysmal nocturnal hemoglobinuria (PNH), instead, red blood cells (RBCs) lyse when attacked by activated complement. The exquisite susceptibility of PNH RBCs to activated complement,1,2 resulting from lack of the complement regulators CD55 and CD59 on PNH cells, is the main mechanism of intravascular hemolysis and anemia in PNH.3,4 Intravascular hemolysis and its clinical consequences are effectively controlled by monoclonal antibodies (eg, eculizumab, ravulizumab) targeting complement C5.5-7 G6PD-deficient RBCs, being hypersusceptible to oxidative damage, undergo acute hemolysis when an exogenous trigger is applied.8,9 It has been suggested that oxidative damage could play a role in PNH as well,10,11 although it is susceptibility to complement-mediated lysis that dominates the picture. PNH is a very rare disease; however, G6PD deficiency is a relatively common X-linked genetic abnormality that in some countries may affect up to 30% of the population.