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

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.

[1]  T. Hosoi.  STUDIES ON HEMOGLOBIN F WITHIN SINGLE ERYTHROCYTE BY FLUORESCENT ANTIBODY TECHNIQUE. , 1965, Experimental cell research.

[2]  I. Bhan,et al.  Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin , 2012, British journal of haematology.

[3]  B. Davis,et al.  Flow cytometric method for simultaneous assay of foetal haemoglobin containing red cells, reticulocytes and foetal haemoglobin containing reticulocytes. , 2001, Clinical and laboratory haematology.

[4]  Paula J. Griffin,et al.  Sickle cell disease in Saudi Arabia: the phenotype in adults with the Arab‐Indian haplotype is not benign , 2014, British journal of haematology.

[5]  W. Schroeder,et al.  Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? , 1984, Blood.

[6]  A. Adekile.  Limitations of Hb F as a Phenotypic Modifier in Sickle Cell Disease: Study of Kuwaiti Arab Patients , 2011, Hemoglobin.

[7]  H. Kamma,et al.  Estimation of fetal hemoglobin levels in individual red cells via fluorescence image cytometry. , 1995, Cytometry.

[8]  S. Orkin,et al.  Advances in the understanding of haemoglobin switching , 2010, British journal of haematology.

[9]  A. Schechter,et al.  Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian Prospective Study on Sickle Cell Disease. , 1994, Blood.

[10]  Stephen W. Hartley,et al.  Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster. , 2010, Blood.

[11]  A. Schechter,et al.  Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes. , 1985, Blood.

[12]  J. Hofrichter,et al.  Hemoglobin S gelation and sickle cell disease. , 1987, Blood.

[13]  C. Pegelow,et al.  Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. , 2003, JAMA.

[14]  Cong Peng,et al.  Correction of Sickle Cell Disease in Adult Mice by Interference with Fetal Hemoglobin Silencing , 2011, Science.

[15]  P. Sebastiani,et al.  Fetal hemoglobin in sickle cell anemia: Molecular characterization of the unusually high fetal hemoglobin phenotype in African Americans , 2012, American journal of hematology.

[16]  Paola Sebastiani,et al.  Fetal hemoglobin in sickle cell anemia. , 2011, Blood.

[17]  A. Nienhuis,et al.  Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. , 2011, Blood.

[18]  O. Platt,et al.  Mortality in sickle cell disease. Life expectancy and risk factors for early death. , 1994, The New England journal of medicine.

[19]  S. Boyer,et al.  Fetal hemoglobin restriction to a few erythrocytes (F cells) in normal human adults. , 1975, Science.

[20]  P. Sebastiani,et al.  Genetic modifiers of sickle cell disease , 2012, American journal of hematology.

[21]  Richard J. Cleary.  Handbook of Beta Distribution and Its Applications , 2006 .

[22]  G. Rodgers,et al.  Mortality in sickle cell disease. , 1994 .

[23]  G. Dover,et al.  Quantitation of hemoglobins within individual red cells: asynchronous biosynthesis of fetal and adult hemoglobin during erythroid maturation in normal subjects. , 1980, Blood.

[24]  M. Gladwin,et al.  Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. , 2007, Blood reviews.

[25]  G. Dover,et al.  Hemoglobin determinations in single cells: Comparison of different techniques. , 1981, Progress in clinical and biological research.

[26]  M L Terrin,et al.  Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea. , 1997, Blood.

[27]  K. Ataga,et al.  The risks and benefits of long‐term use of hydroxyurea in sickle cell anemia: A 17.5 year follow‐up , 2010, American journal of hematology.