Sickle cell anemia: targeting the role of fetal hemoglobin in therapy

Sickle cell anemia results from the single amino acid substitution of valine for glutamic acid in the beta-chain owing to a nucleotide defect that causes the production of abnormal beta-chains in hemoglobin S. Abnormal hemoglobin chains form polymers in the deoxygenated state, leading to the characteristic sickle cells. The polymerization 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 polymerization process. Fetal hemoglobin production may be induced pharmacologically or by the use of gene therapy and genetic engineering techniques.     

Chemotherapy to increase fetal hemoglobin in patients with sickle cell anemia

The obvious beneficial effects of hemoglobin F on sickling have motivated numerous investigators to increase this type of hemoglobin artificially in patients with sickle cell anemia. Various chemotherapeutic agents including 5-azacytidine, hydroxyurea, and cytosine arabinoside, have been used successfully in patients. All of these drugs can increase the level of hemoglobin F in sickle cell anemia (SS) patients, but the kinetics and magnitude of the responses are highly individual and variable. The mechanism or mechanisms responsible for the increased synthesis of hemoglobin F remain unknown. Further controlled studies in a limited number of patients with severe sickle cell disease will be necessary in order to work out a rational, safe treatment program suitable for wider use.     

Coinheritance of sickle cell anemia and hereditary spherocytosis

To date only three siblings with coinheritance of sickle cell anemia (SCA) and hereditary spherocytosis (HS) have been reported. We here describe a 17-year-old boy who experienced episodes of hemolysis and had a large spleen. The diagnosis of SCA was confirmed by hemoglobin electrophoresis (HbS 88.9%) and genetic analysis (homozygote HbSS mutation). The diagnosis of HS was established by an osmotic fragility test, performed twice. A splenectomy was performed, and following surgery the hemoglobin concentration was maintained between 9 and 11 g/dl without further transfusion requirements. This patient was the fourth reported case with co-existence of two different genetically transmitted hemolytic anemias.     

Interpretation of fetal hemoglobin only on newborn screening for hemoglobinopathy

Newborn screening for hemoglobinopathies rarely produces a fetal hemoglobin only result; it is most consistent with beta-thalassemia major, although other diagnoses are possible. The authors describe two unrelated African-American babies born in North Carolina whose newborn screening revealed fetal hemoglobin only. Both had a relatively benign clinical and hematologic picture. Molecular analyses indicated that both children are compound heterozygotes for beta-thalassemia and pancellular (deletional) hereditary persistence of fetal hemoglobin, a rare and apparently benign condition. Accurate interpretation of the fetal hemoglobin only result on newborn screening requires thorough evaluation, including family studies and molecular analysis.     

Induction of fetal hemoglobin synthesis in children with sickle cell anemia on low-dose oral sodium phenylbutyrate therapy

This study was designed to determine if low doses of oral sodium phenylbutyrate (SPB) induce hemoglobin F (HbF) synthesis in children with hemoglobin SS (HbSS). We treated 8 children with HbSS over a period of 5-30 weeks. The initial dose (1.0 g/d) was increased weekly (by 1.0 g/d) until F-reticulocytes doubled. All patients showed an increase in F-reticulocytes (P = 0.002) that was dose-dependent (P = 0.001). Three of 5 patients who continued oral SPB for more than 10 weeks had substantial increases in HbF. We conclude that lower dose SPB is effective in inducing HbF synthesis in some children with HbSS. Further trials are warranted to determine the optimal treatment regimen.     

Prevalence of beta-thalassemia and sickle cell anemia trait in premarital screening in Konya urban area, Turkey

Thalassemias and sickle cell anemia (SCA) are common disease in Turkey. To determine the prevalence of beta-thalassemia and SCA traits in Konya urban area of Turkey, all couples applied for marriage procedures were screened. Screening tests included complete blood count and quantitation of hemoglobin for both partners. The subjects were considered to have the beta-thalassemia trait if they had a mean corpuscular volume of less than 80 fL and/or a mean corpuscular hemoglobin level of less than 27 pg and a hemoglobin A2 level of more than 3.2% or a hemoglobin F level of more than 2%. Subjects were considered to have an SCA trait if they were positive for sickle hemoglobin. During the study, premarital screening of hemoglobinopathies was evaluated retrospectively in 72,918 subjects; the thalassemia trait was detected in 1465 subjects (2%), and the SCA trait was detected in 37 subjects (0.05%). Of the carriers of the beta-thalassemia trait, 820 (56%) people had high hemoglobin A2, 513 (35%) people had high hemoglobin F, and 132 (9%) people had both high hemoglobin F and hemoglobin A2. Our results are very similar to Turkey's beta-thalassemia and SCA trait averages.     

Amelioration of clinical severity through raised fetal hemoglobin in sickle cell anaemia

In the present study, the levels of fetal hemoglobin (HbF) in sickle cell anemia patients were compared with sickle cell trait, beta thalassemia major and control. The mean HbF levels in beta thalassemia major and sickle cell anemia were 51.62 and 19.63% respectively. However, when the amount of HbF was expressed in terms of gram hemoglobin per deciliter whole blood, the mean values were 2.88 and 1.81 respectively between the two groups, suggesting that the genetic mechanism controlling the different threshold levels of increased HbF in these disorders could probably be similar. The elevated. HbF level in sickle cell anemia along with moderate hematologic profile observed in the present study is suggested to provide amelioration of the clinical severity unlike in beta thalassemia major where despite raised HbF levels, the severe clinical implications are attributed to marked imbalance in the globin chain synthesis.     

Effect of hydroxyurea in sickle cell anemia: a clinical trial in children and teenagers with severe sickle cell anemia and sickle cell beta-thalassemia.

This study evaluated the efficacy of hydroxyurea treatment in the prevention of vaso-occlusive crises among children and teenagers with severe sickle cell anemia and sickle cell beta-thalassemia. Nineteen children and young adults with severe sickle cell disease were enrolled to the hydroxyurea treatment trial. The incidence of vaso-occlusive crises, acute chest syndrome, hemolytic crises, splenic sequestration episodes, blood transfusions, and hospital days in the 2 years before hydroxyurea (HU) treatment were compared with the same parameters in the first 2 years of treatment. The patients received a mean dose of 21.3 mg/kg/day daily and were treated during a mean period of 40.3 +/- 14 months (range 20 to 68 months). Significant increases were observed after 1 month in the Hgb, MCV, MCH, and MCHC levels and were more notable after 3 months. The increase in the Hgb F level became important after 3 months of HU therapy and was highly significant (p < .001) beyond 6 months. No differences were observed in the RDW, reticulocyte count, Hgb S, and Hgb A2. Severe neutropenia was observed in one case. A decrease in the frequency of vaso-occlusive crises, acute chest syndrome, hemolytic crises, blood transfusions, and days spent in the hospital was demonstrated during the HU treatment period compared to the same period before. The clinical and laboratory response to HU was dramatic in severely affected sickle cell anemia (SCA) patients. The response to HU in children and teenagers with severe sickle cell anemia is similar to the response in adults, and no severe adverse effects were observed.     

Physiologic decline in fetal hemoglobin parameters in infants with sickle cell disease: implications for pharmacological intervention.

PURPOSE: Fetal hemoglobin (HbF) is an important determinant in the clinical severity of patients with sickle cell disease. The physiologic decline in HbF parameters in a cohort of infants with sickle cell disease was investigated. PATIENTS AND METHODS: The percent HbF and F cells were quantitated, and the HbF per F cell was then calculated. One hundred thirty-eight blood samples from 44 infants with homozygous sickle cell anemia (HbSS) and 56 samples from 24 infants with sickle cell hemoglobin (HbSC) were studied. RESULTS: Infants with HbSS had a logarithmic decline in HbF parameters; at 24 months, the average HbF was 14.6%+/-7.3% and the % F cells was 64.7%+/-16.9%. The amount of HbF in each F cell (HbF per F cell) was <15 pg/cell, a suggested threshold for intracellular sickle polymerization, by age 12 months. Infants with HbSC had a more rapid decline: at 12 months the average % HbF was 12.2%+/-9.3%, the % F cells was 60.5%+/-18.7%, and the HbF per F cell was <10 pg/cell. CONCLUSIONS: By age 2 years, HbF parameters including the % HbF, % F cells, and the HbF per F cell decrease to levels insufficient to inhibit sickling. Pharmacologic intervention designed to enhance HbF production and prevent chronic organ damage should be considered during infancy.