High prevalence of individuals with low concentration of fetal hemoglobin in F‐cells in sickle cell anemia in Tanzania

Urio, Florence; Lyimo, Magdalena; Nkya, Siana; Cox, Sharon E.; Mmbando, Bruno P.; Makani, Julie

doi:10.1002/ajh.24390

Cited by 8 publications

(10 citation statements)

References 6 publications

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“…In healthy persons, F cells (Fcells%) range from 0·5 to 7%, and they are derived from erythroid cells that, during differentiation, do not switch completely from γ‐ to β‐globin chain synthesis. In SCD the proportion of F cells is much higher, and may reach 80% 11,12 . The number of F cells in a patient with SCD will depend on two main factors: (i) increase in the proportion of erythroid cells that still make γ chains as a result of ‘stress erythropoiesis’; and (ii) preferential survival of F cells in the peripheral blood 13,14 because of their relative resistance to sickling.…”

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confidence: 99%

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F cell numbers are associated with an X‐linked genetic polymorphism and correlate with haematological parameters in patients with sickle cell disease

et al. 2020

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Patients with sickle cell disease (SCD) with high fetal haemoglobin (HbF) tend to have a lower incidence of complications and longer survival due to inhibition of deoxyhaemoglobin S (HbS) polymerisation by HbF. HbF-containing cells, namely F cells, are strongly influenced by genetic factors. We measured the percentage of F cells (Fcells%) in 222 patients with SCD to evaluate the association of (i) Fcells% with genetic HbF-modifier variants and (ii) Fcells% with haematological parameters. There was a different distribution of Fcells% in females compared to males. The association of the B-cell lymphoma/leukaemia 11A (BCL11A) locus with Fcells% (b = 8Á238; P < 0Á001) and with HbF% (b = 2Á490; P < 0Á001) was significant. All red cell parameters except for Hb and mean corpuscular Hb concentration levels in males and females were significantly different. The Fcells% was positively associated with mean cell Hb, mean cell volume and reticulocytes. To explain the significant gender difference in Fcells%, we tested for associations with single nucleotide polymorphisms on the X chromosomal region Xp22.2, where a genetic determinant of HbF had been previously hypothesised. We found in males a significant association with a SNP in FERM and PDZ domain-containing protein 4 (FRMPD4) and adjacent to male-specific lethal complex subunit 3 (MSL3). Thus, we have identified an X-linked locus that could account for a significant fraction of the Fcells% variation in patients with SCD.

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“…As a result the proportion of F cells and the HbF% are highly correlated 12,16 . As it is the former that produce the latter, we set out to investigate how Fcells%, rather than HbF%, correlate, on the one hand, with their polymorphic genetic determinants; on the other hand, with haematological parameters.…”

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F cell numbers are associated with an X‐linked genetic polymorphism and correlate with haematological parameters in patients with sickle cell disease

et al. 2020

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“…A recent analysis of a population of African patients found low concentrations of HbF/F-cells in sickle cell patients in Tanzania, supporting the importance of this parameter. (6) The amount of HbF/F-cell required to entirely prevent HbS polymerization was recently proposed as a therapeutic target. (1)…”

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Effects of hydroxyurea on F‐cells in sickle cell disease and potential impact of a second fetal globin inducer

et al. 2016

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“…In untreated SCA, HbF expression is variable and distributed unequally across RBCs (heterocellular expression with 10-50% F-cells). [4][5][6][7] Traditional hydroxyurea dosing strategies raise HbF with usually heterocellular induction (20-90% F-cells). [7][8][9] In contrast, compound heterozygosity for HbS and gene-deletion hereditary persistence of HbF [HbS/(db) 0 -HPFH] results in HbF levels of 30-40%, but with a pancellular distribution of HbF across RBCs (100% Fcells).…”

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Early initiation of hydroxyurea (hydroxycarbamide) using individualised, pharmacokinetics‐guided dosing can produce sustained and nearly pancellular expression of fetal haemoglobin in children with sickle cell anaemia

et al. 2021

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Hydroxyurea (hydroxycarbamide) is an effective treatment for sickle cell anaemia (SCA), but clinical responses depend primarily upon the degree of fetal haemoglobin (HbF) induction and the heterogeneity of HbF expression across erythrocytes. The number and characteristics of HbF-containing cells (F-cells) are not assessed by traditional HbF measurements. Conventional hydroxyurea dosing (e.g. fixed doses or low starting doses with stepwise escalation) produces a moderate heterocellular HbF induction, but haemolysis and clinical complications continue. Robust, pancellular HbF induction is needed to minimise or fully inhibit polymerisation of sickle haemoglobin. We treated children with hydroxyurea using an individualised, pharmacokinetics-guided regimen starting at predicted maximum tolerated dose (MTD). We observed sustained HbF induction (mean >30%) for up to 6 years, which was not dependent on genetic determinants of HbF expression. Nearly 70% of patients had ≥80% F-cells (nearpancellular), and almost half had ≥90% F-cells (pancellular). The mean HbF/F-cell content was~12 pg. Earlier age of initiation and better medication adherence were associated with high F-cell responses. In summary, early initiation of hydroxyurea using pharmacokinetics-guided starting doses at predicted MTD can achieve sustained near-pancellular or pancellular HbF expression and should be considered an achievable goal for children with SCA treated with hydroxyurea at optimal doses. Clinical trial registration number: NCT02286154 (clinicaltrials.gov).

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High prevalence of individuals with low concentration of fetal hemoglobin in F‐cells in sickle cell anemia in Tanzania

Cited by 8 publications

References 6 publications

F cell numbers are associated with an X‐linked genetic polymorphism and correlate with haematological parameters in patients with sickle cell disease

F cell numbers are associated with an X‐linked genetic polymorphism and correlate with haematological parameters in patients with sickle cell disease

Effects of hydroxyurea on F‐cells in sickle cell disease and potential impact of a second fetal globin inducer

Early initiation of hydroxyurea (hydroxycarbamide) using individualised, pharmacokinetics‐guided dosing can produce sustained and nearly pancellular expression of fetal haemoglobin in children with sickle cell anaemia

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