Hereditary spherocytosis (HS) is the most common, nonimmune, hereditary, chronic
hemolytic anemia after
hemoglobinopathies. The genetic defects in membrane function causing HS lead to perturbation of the RBC metabolome, with altered glycolysis. In mice genetically lacking
protein 4.2 (4.2-/-; Epb42), a murine model of HS, we showed increased expression of
pyruvate kinase (PK)
isoforms in whole and fractioned RBCs in conjunction with abnormalities in the glycolytic pathway and in the
glutathione (GSH) system.
Mitapivat, a PK activator, metabolically reprogrammed 4.2-/- mouse RBCs with amelioration of glycolysis and the GSH cycle. This resulted in improved osmotic fragility, reduced
phosphatidylserine positivity, amelioration of RBC
cation content, reduction of Na/K/Cl cotransport and Na/H-exchange overactivation, and decrease in erythroid vesicles release in vitro.
Mitapivat treatment significantly decreased erythrophagocytosis and beneficially affected
iron homeostasis. In mild-to-moderate HS, the beneficial effect of
splenectomy is still controversial. Here, we showed that
splenectomy improves
anemia in 4.2-/- mice and that
mitapivat is noninferior to
splenectomy. An additional benefit of
mitapivat treatment was lower expression of markers of inflammatory vasculopathy in 4.2-/- mice with or without
splenectomy, indicating a multisystemic action of
mitapivat. These findings support the notion that
mitapivat treatment should be considered for symptomatic HS.