Fetal hemoglobin in sickle cell anemia: a glass half full?

Abstract

Fetal hemoglobin (HbF) modulates the phenotype of sickle cell anemia by inhibiting deoxy sickle hemoglobin (HbS) polymerization. The blood concentration of HbF, or the number of cells with detectable HbF (F-cells), does not measure the amount of HbF/F-cell. Even patients with high HbF can have severe disease because HbF is unevenly distributed among F-cells, and some cells might have insufficient concentrations to inhibit HbS polymerization. With mean HbF levels of 5%, 10%, 20%, and 30%, the distribution of HbF/F-cell can greatly vary, even if the mean is constant. For example, with 20% HbF, as few as 1% and as many as 24% of cells can have polymer-inhibiting, or protective, levels of HbF of ∼10 pg; with lower HbF, few or no protected cells can be present. Only when the total HbF concentration is near 30% is it possible for the number of protected cells to approach 70%. Rather than the total number of F-cells or the concentration of HbF in the hemolysate, HbF/F-cell and the proportion of F-cells that have enough HbF to thwart HbS polymerization is the most critical predictor of the likelihood of severe sickle cell disease.

Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping

“…35 Inhibition of G9a methyltransferase activity in adult erythroid cells of patients with hemoglobinopathies such as sickle cell disease and b-thalassemia should cause increased expression of HbF production, with subsequent beneficial therapeutic effect. 36 Although poor in vivo pharmacokinetic properties of UNC0638 may preclude its use as a drug, additional G9a targeting compounds are being developed, including UNC0642, with similar inhibitory properties and improved in vivo stability. 37 In addition to the identification and development of UNC0638-related compounds, recognition of the role of H3K9 methylation in globin gene regulation could advance mechanistic studies of existing or alternate drugs that augment HbF expression, including cytidine derivatives.…”

Sickle Cell Disease

“…The critical determinant of the effect of HbF on the phenotype of sickle cell disease is its level in each erythrocyte. 50 In compound heterozygotes for HbS and hereditary persistence of HbF where HBB is deleted, HbF makes up approximately 30% of total hemoglobin and is homogeneously distributed in the red-cell population, with each cell containing about 10 pg. This level is sufficient to thwart polymerization of deoxygenated HbS so that persons with this genotype have nearly normal hemoglobin levels and are mostly asymptomatic.…”

Intravascular hemolysis and the pathophysiology of sickle cell disease

“…HbF has its most robust effects on subphenotypes associated with sickle vaso-occlusion, including ACS (30)(31)(32). Failure of HbF to afford similar levels of protection for hemolysis-associated subphenotypes might be a consequence of insufficient HbF in some cells, which allows continued intravascular hemolysis and endothelial injury over long exposures (33,34).…”