1 Sickle Cell Anemia: Targeting the Role of Fetal Hemoglobin in Therapy Emma Coleman, BSc, and Baba Inusa, MBBS, FRCPCH, DCP (Haem), FMCPaed, MRCP deformable and, hence, to become trapped, thus blocking small vessels of the microcirculation. 4-6 The degree of HbS polymerization in the circula- tion determines how likely the individual is to have a vasoocclusive crisis or other adverse event. It is of interest that cells are less prone to sickling in individ- uals who retain a high level of fetal Hb (HbF). Hemoglobin F (α2γ2) inhibits the polymerization of the HbS owing to its high oxygen affinity. Hemoglobin F dissociates to a dimer, which when combined with a1s1, gives an α2β s 1γ1 tetramer that does not form a polymer. This is in contrast to HbA, which dissociates to a dimer that combines to give an α2β s 1β1 tetramer that has a 50% chance of polymerizing. 2 Thus, high proportions of HbF are even better than high propor- tions of HbA in preventing the formation of hemoglo- bin polymers and thus, sickled cells. The role of HbF on the clinical phenotype is variable and inconsistent, such that even levels nearing 20% may be found in patients with severe disease. 3-6 The modulation of symptoms and complications becomes more consistent when a certain level of HbF threshold has been achieved. The threshold for significant reduction in acute episodes of pain, chest syndromes, and priapism is 20%, and for organ dam- age, 10%. The symptoms of sickle cell disease (SCD) are almost completely eliminated with HbF levels Introduction S ickle cell anemia is an inherited disorder of hemoglobin caused by a single nucleotide sub- stitution thymidine for adenine (GAG→GTG) of the β-chain that results in the amino acid valine instead of glutamic acid. 1-3 This is responsible for alteration in the properties of the hemoglobin tetramer, with the tendencies to polymerize in the deoxygenated state. 1 In homozygotes or when there is co-inheritance of a double heterozygous state (with hemoglobin C, β-thalassemia, D or O), the nor- mal β-chains are replaced by the modified form of the β-chain. Increasing accumulation of hemoglobin S (HbS) polymers occurs within the red cell in the deoxygenated state. This causes it to be less Sickle cell anemia results from the single amino acid substitution of valine for glutamic acid in the β-chain owing to a nucleotide defect that causes the production of abnormal β-chains in hemoglobin S. Abnormal hemoglobin chains form polymers in the deoxygenated state, leading to the characteristic sickle cells. The poly- merization of deoxygenated hemoglobin S accounts for the pathologic changes in sickle cell disease. The main- stay of therapy in sickle cell disease aims to reduce the amount of sickled hemoglobin present through the prevention of polymerization and reversal of this process. One way of discouraging polymerization is to increase the level of fetal hemoglobin, which because of its high oxygen affinity, does not participate in the poly- merization process. Fetal hemoglobin production may be induced pharmacologically or by the use of gene therapy and genetic engineering techniques. Keywords: sickle cell anemia; fetal hemoglobin; hydroxyurea therapy; anemia; painful crisis From St Thomas Hospital, London, United Kingdom. Address correspondence to: Baba Inusa, MBBS, FRCPCH, DCP (Haem), FMCPaed, MRCP, Lead Consultant, Paediatric Hemoglobinopthies, St Thomas Hospital, London SE1 7EH, UK; e-mail: Baba.Inusa@gstt.nhs.uk Editor’s comment: This scholarly review was written by a fourth- year medical student at St. Thomas Hospital in London. We have encouraged participation by residents in our “Resident Rounds” section of the journal and invite individuals in all stages of medical education and training to contribute reviews such as this one. Clinical Pediatrics Volume 46 Number X Month 2007 1-6 © 2007 Sage Publications 10.1177/0009922806297751 http://clp.sagepub.com hosted at http://online.sagepub.com Commentary