Female heterozygotes have intermediate values because the normal gene on one X chromosome and the defective allele on the other are both expressed. Heterozygous females will pass the defect to half of their sons. Affected males will have normal sons because they pass only their Y chromosome to them, and they will have heterozygous daughters because they pass the defective X chromosome to all of them. The precise mechanism whereby G6PD deficiency leads to hemolysis is not fully understood. Perturbations of intracellular thiol and calcium ion homeostasis may be important early events in the development of toxicity in cells of many types.
Many substances require metabolic activation before they can produce hemolysis.
It is therefore quite likely that toxic intermediates of many agents directly cause red cell damage. It is clear that extraerythrocytic factors, including hepatic drug metabolism, are important for hemolysis in vivo. Although high concentrations of primaquine may cause lysis of G6PD-deficient erythrocytes in vitro , normal cells are equally susceptible. Active metabolites produced principally in the liver must be sufficiently stable to reach the erythrocyte before the red cell can be injured. Additional intraerythrocyte catalytic activities probably play a role in the pathogenesis of hemolysis.