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 Table of Contents  
EDITORIAL
Year : 2018  |  Volume : 6  |  Issue : 3  |  Page : 131-132

Sickle cell disease and fetal hemoglobin


Division of Nephrology, Vascular Biology Research Center, Department of Medicine, Beth Israel Deaconess Medical Center, the Laboratory of Clinical Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA

Date of Web Publication14-Aug-2018

Correspondence Address:
Alicia Rivera
Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, Massachusetts 02215
USA
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DOI: 10.4103/sjmms.sjmms_128_18

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How to cite this article:
Rivera A. Sickle cell disease and fetal hemoglobin . Saudi J Med Med Sci 2018;6:131-2

How to cite this URL:
Rivera A. Sickle cell disease and fetal hemoglobin . Saudi J Med Med Sci [serial online] 2018 [cited 2018 Sep 23];6:131-2. Available from: http://www.sjmms.net/text.asp?2018/6/3/131/238993



Sickle cell disease (SCD) is a genetically inherited abnormality of the β-hemoglobin gene, referred to as hemoglobin S, affecting millions of people worldwide. Despite evidence that child death rates from SCD are declining, the relative burden of child morbidity and disability will increase in the coming decades. Projections by Piel et al.[1] have shown a 30% increase in SCD births by 2050, which underscores the need to develop novel and effective therapies. However, lack of suitable tools to test promising experimental drug therapies hamper further progress.

Under low-oxygen conditions and/or pH, hemoglobin S polymerizes, forming sickle-shaped rigid cells with low survivability rates.[2] These dysfunctional oxygen-carrying cells are sticky and are easily trapped within small vessels, leading to vaso-occlusion, intravascular hemolysis and tissue damage in major organs. High recurrent infections, anemia, excruciating pain in extremities, leg ulcers, priapism, organ damage and stroke are among the common characteristics of this disease – events that lead to a poor quality of life, constant transfusions and frequent hospitalization. Treatment options for SCD are nonspecific and very limited. These include bone marrow transplantation, pain medication, blood transfusions and/or two US Food and Drug Administration (FDA)-approved drug treatment options, namely, L-glutamine oral powder (Endari) and hydroxyurea (hydroxycarbamide). In this issue of the Saudi Journal of Medicine and Medical Sciences, Mozeleski et al.[3] provide an important and compelling rationale to develop a novel approach to more accurately and precisely quantify cellular levels of hemoglobin F (HbF).


  Why Target Hemoglobin F? Top


In an otherwise healthy human fetus, HbF is present during the final months of development, representing about 75% of the total hemoglobin until the newborn is 7–8 months, when HbF is significantly reduced to 1%–2% of total hemoglobin.[2] Complications of SCD are not apparent in neonates and are mainly observed when HbF levels decrease and adult forms of hemoglobin rise.

HbF levels correlate with enhanced red cell survival, reduced hemolysis and increased absolute reticulocyte count, an index of the bone marrow's response to hemolysis.[4] However, HbF is heterogeneously distributed among sickle red cells and maybe as high as 30% due to genetic factors, the number of cells expressing HbF (F-cells) and the amount of HbF per F-cell. Evidence suggests that within the F-cell population, cells with higher HbF levels survive longer and are associated with improved anemia and reduced organ damage.[4] The Cooperative Study of Sickle Cell Disease reported a significant reduction in clinical severity and mortality in SCD patients and suggested that therapeutic agents capable of inducing HbF synthesis would lead to improved clinical outcomes.[5] Assays to accurately and more precisely measure the intracellular distribution of HbF levels may lead to significant advances in therapeutic development and prognosis, as proposed by Mozeleski et al.[3] As the genetic and pathophysiological understanding of HbF regulation improves, these assays will become more important.[6],[7]

Gardner et al.[8] reported the development of a genetic marker in which seven common gene variants within BCL11A, HMIP-2A, HMIP-2B and Xmn1-HBG2 in the β-globin locus were grouped to create a single genetic quantitative variable for HbF: g(HbF). Evidence suggests that g(HbF) is associated with HbF levels determined using the Bio-Rad Variant II and markers of disease severity.[9] Mozeleski et al.[3] posit that determination of HbF/F-cell measures would improve the prognostic value of g(HbF).

Hydroxyurea increases HbF expression and reduces hematological complications, including painful crises, acute chest syndrome and transfusion rates, with limited side effects. A multicenter study of hydroxyurea showed that use of hydroxyurea reduced painful crises by about 40%.[10] In addition, hydroxyurea recently received FDA approval for use in SCD children aged ≥2 years with moderate to severe painful crises, and thus its use is expected to increase worldwide.[11]


  State-Of-The-Art and Limitations of Current Techniques Top


High-performance liquid chromatography is the gold standard assay for HbF detection and analyses. It provides measures of HbF as a percent of total hemoglobin, but does not provide a full cellular distribution. Imaging flow cytometry is a useful tool for HbF analysis but is not suitable for quick clinical diagnostics. Standard flow cytometry may be used to develop a test assay to provide the percentage, level and distribution of F-cells. Other measures used to provide qualitative assessments of HbF include hemoglobin electrophoresis, isoelectric focusing and/or capillary electrophoresis.

In conclusion, precise and quantitative measures of cellular HbF levels will improve diagnosis and prognosis and increase our understanding of SCD's pathophysiology. Successful development of Mozeleski el al.'s [3] assay could lead to an improved ability to more precisely measure HbF/F-cell levels, and thus properly evaluate new and current therapies in SCD worldwide.



 
  References Top

1.
Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN. Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLoS Med 2013;10:e1001484.  Back to cited text no. 1
    
2.
Steinberg MH, Forget BG, Higgs DR, Nagel RL. Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management. 1st ed. Cambridge: Cambridge University Press; 2001.  Back to cited text no. 2
    
3.
Mozeleski BM, Al-Rubaish A, Al-Ali A, Romero J. Perspective: A novel prognostic for sickle cell disease. Saudi J Med Med Sci 2018;6:133-6.  Back to cited text no. 3
  [Full text]  
4.
Franco RS, Yasin Z, Palascak MB, Ciraolo P, Joiner CH, Rucknagel DL. The effect of fetal hemoglobin on the survival characteristics of sickle cells. Blood 2006;108:1073-6.  Back to cited text no. 4
    
5.
Biologic Specimen and Data Repositories Information Coordinating Center (BioLINCC). Cooperative Study of Sickle Cell Disease (CSSCD). Available from: https://biolincc.nhlbi.nih.gov/studies/csscd/. [Last accessed on 2018 Aug 02].  Back to cited text no. 5
    
6.
Shiao SY, Ou CN, Pierantoni H. The measurement of accurate fetal hemoglobin and related oxygen saturation by the hemoximeter. Clin Chim Acta 2006;374:75-80.  Back to cited text no. 6
    
7.
Mosca A, Paleari R, Leone D, Ivaldi G. The relevance of hemoglobin F measurement in the diagnosis of thalassemias and related hemoglobinopathies. Clin Biochem 2009;42:1797-801.  Back to cited text no. 7
    
8.
Gardner K, Fulford T, Silver N, Rooks H, Angelis N, Allman M, et al. g(HbF): A genetic model of fetal hemoglobin in sickle cell disease. Blood Adv 2018;2:235-9.  Back to cited text no. 8
    
9.
Quinn CT, Smith EP, Arbabi S, Khera PK, Lindsell CJ, Niss O, et al. Biochemical surrogate markers of hemolysis do not correlate with directly measured erythrocyte survival in sickle cell anemia. Am J Hematol 2016;91:1195-201.  Back to cited text no. 9
    
10.
Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;332:1317-22.  Back to cited text no. 10
    
11.
US Food and Drug Administration. FDA approves hydroxyurea for treatment of pediatric patients with sickle cell anemia. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590096.htm. [Last accessed on 2018 Jul 28].  Back to cited text no. 11
    




 

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