Mitapivat reprograms the RBC metabolome and improves anemia in a mouse model of hereditary spherocytosis

Hereditary spherocytosis (HS) is easily the most common, nonimmune, hereditary, chronic hemolytic anemia after hemoglobinopathies. The genetic defects in membrane function causing HS result in perturbation from the RBC metabolome, with altered glycolysis. In rodents genetically missing protein 4.2 (4.2-/- Epb42), a murine type of HS, we demonstrated elevated expression of pyruvate kinase (PK) isoforms entirely and fractioned RBCs along with abnormalities within the glycolytic path as well as in the glutathione (GSH) system. Mitapivat, a PK activator, metabolically reprogrammed 4.2-/- mouse RBCs with amelioration of glycolysis and also the GSH cycle. This led to improved osmotic fragility, reduced phosphatidylserine positivity, amelioration of RBC cation content, decrease in Na/K/Cl cotransport and Na/H-exchange overactivation, and reduce in erythroid vesicles release in vitro. Mitapivat treatment considerably decreased erythrophagocytosis and beneficially affected iron homeostasis. In mild-to-moderate HS, the advantageous aftereffect of splenectomy continues to be questionable. Here, we demonstrated that splenectomy improves anemia in 4.2-/- rodents which mitapivat is noninferior to splenectomy. Another advantage of mitapivat treatment was lower expression of markers of inflammatory vasculopathy in 4.2-/- rodents without or with splenectomy, indicating a multisystemic action of mitapivat. These bits of information support the concept mitapivat treatment should be thought about for symptomatic HS.