scholarly journals Correlations with Point Mutations and Severity of Hemolitic Anemias: The Example of Hereditary Persistence of Fetal Hemoglobin with Sickle Cell Anemia and Beta Thalassemia

10.5772/36240 ◽  
2012 ◽  
Author(s):  
Anderson Ferreira da Cunha ◽  
Iran Malavazi ◽  
Karen Simone ◽  
Cintia do Couto Mascarenhas
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Point Mutations ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Hereditary Persistence

scholarly journals Fetal Hemoglobin in Sickle Hemoglobinopathies: High HbF Genotypes and Phenotypes

2020 ◽  
Vol 9 (11) ◽  
pp. 3782
Author(s):  
Martin H. Steinberg
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Point Mutations ◽  
Fetal Hemoglobin ◽  
Gene Deletions ◽  
Total Hemoglobin ◽  
Sickle Erythrocytes ◽  
Hereditary Persistence ◽  
Very High

Fetal hemoglobin (HbF) usually consists of 4 to 10% of total hemoglobin in adults of African descent with sickle cell anemia. Rarely, their HbF levels reach more than 30%. High HbF levels are sometimes a result of β-globin gene deletions or point mutations in the promoters of the HbF genes. Collectively, the phenotype caused by these mutations is called hereditary persistence of fetal hemoglobin, or HPFH. The pancellularity of HbF associated with these mutations inhibits sickle hemoglobin polymerization in most sickle erythrocytes so that these patients usually have inconsequential hemolysis and few, if any, vasoocclusive complications. Unusually high HbF can also be associated with variants of the major repressors of the HbF genes, BCL11A and MYB. Perhaps most often, we lack an explanation for very high HbF levels in sickle cell anemia.

scholarly journals Hydroxyurea increases fetal hemoglobin in cultured erythroid cells derived from normal individuals and patients with sickle cell anemia or beta-thalassemia

Blood ◽  
1993 ◽  
Vol 81 (6) ◽  
pp. 1630-1635
Author(s):  
E Fibach ◽  
LP Burke ◽  
AN Schechter ◽  
CT Noguchi ◽  
GP Rodgers
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Fold Increase ◽  
Cell Number ◽  
Model Systems ◽  
Beta Thalassemia ◽  
Mean Corpuscular Hemoglobin ◽  
Normal Individuals ◽  
Culture Procedure

Hydroxyurea (HU), an inhibitor of DNA synthesis, has been shown to increase fetal hemoglobin (HbF) levels in patients with sickle cell anemia and in some patients with beta-thalassemia. However, until now there have not been good in vitro model systems that simulate this effect for study of the molecular and cellular mechanism(s) involved in perturbing the normal ontogeny of the globin genes. We analyzed the cellular effects of HU using a two-phase liquid culture procedure (Fibach et al: Blood 73:100, 1989) in which human peripheral blood- derived progenitor cells undergo proliferation and differentiation. HU was found to have multiple effects on these cultured cells: (1) an increase in the proportion of HbF produced; (2) a decrease in cell number due to inhibition of cell proliferation; (3) an increase in hemoglobin content per cell (mean corpuscular hemoglobin [MCH]); and (4) an increase in cell size (mean corpuscular volume). The extent of these effects was related to the HU dose and time of addition. When added to cell cultures from normal individuals, 4 days following their exposure to erythropoietin (EPO), 100 mumol/L HU caused a 1.3- to 3.5- fold increase in the proportion of HbF, from 0.4% to 5.2% (mean 1.6) in untreated to 1.5% to 8.2% (mean 3.1) in HU-treated cultures and a 45% +/- 10% increase in MCH but only a 25% +/- 7% decrease in cell number on day 13. Cultures of cells derived from five patients with sickle cell anemia have shown a twofold to fivefold increase in the percentage of Hb F following addition of HU while four patients with beta- thalassemia showed a 1.3- to 6.2-fold increase. We believe that this primary cell culture procedure should prove useful in studying the cellular and molecular mechanisms of pharmacologic induction of HbF and might provide a valuable predictive assay system for evaluation of the response of individual patients with hemoglobinopathies to HU and similar agents.

scholarly journals Increased HbF in sickle cell anemia is determined by a factor linked to the beta S gene from one parent

Blood ◽  
1984 ◽  
Vol 63 (1) ◽  
pp. 64-72 ◽  
Author(s):  
PF Milner ◽  
JD Leibfarth ◽  
J Ford ◽  
BP Barton ◽  
HE Grenett ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Sickle Cell Trait ◽  
Fetal Hemoglobin ◽  
S Gene ◽  
Cell Counts ◽  
F Cells ◽  
Hereditary Persistence ◽  
Large Families ◽  
Cell Gene

Abstract Members of 7 large families, containing 20 patients with sickle cell anemia (SS) characterized by high levels of fetal hemoglobin (HbF), were studied using immunofluorescence to count F cells and a radioimmunoassay to measure small amounts of HbF. In five of these families, one of the sickle cell trait (AS) parents had a much higher HbF and F-cell count than the other; in one family, both parents had a marked increase in HbF and F cells; in the remaining family, HbF and F cells were at borderline values in both parents. Seven of 14 AS siblings, but only 1 of 8 normal hemoglobin (AA) siblings, also had HbF and F-cell counts above the “normal” range. It seems that a factor for increased F cells, linked to the beta S gene of one parent, is segregating in these families and is responsible for the greatly increased HbF and F cells in the SS subjects. HbF per F cell in AS parents and siblings was the same as that of normal AA subjects, whereas in the SS offspring it was greatly increased, suggesting that it was the result of marrow hyperplasia associated with their hemolytic anemia. The similarity of this “increased F-cell gene” to heterocellular hereditary persistence of fetal hemoglobin (HPFH). Swiss type, is discussed, and it is suggested that it may control the persistent synthesis of HbF in sickle cell anemia by its presence in early infancy.

scholarly journals A Fresh Breath of Oxygen: Red Blood Cell Exchange Transfusion in Sickle Cell and COVID-19

2021 ◽  
Author(s):  
Viva Nguyen ◽  
Paul Alcius ◽  
Shachar Peles ◽  
Katherine Hodgin
Keyword(s):  
Blood Cell ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Red Blood Cell ◽  
Exchange Transfusion ◽  
Fetal Hemoglobin ◽  
Documented Case ◽  
History Of ◽  
Hospital Stays ◽  
Hereditary Persistence

We present the first documented case of a 69 year-old female with history of sickle cell anemia with hereditary persistence of fetal hemoglobin that presented due to joint pains and COVID-19 infection. The red blood cell exchange transfusion may play an important factor in preventing intubations and longer hospital stays.

scholarly journals Increased HbF in sickle cell anemia is determined by a factor linked to the beta S gene from one parent

Blood ◽  
1984 ◽  
Vol 63 (1) ◽  
pp. 64-72
Author(s):  
PF Milner ◽  
JD Leibfarth ◽  
J Ford ◽  
BP Barton ◽  
HE Grenett ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Sickle Cell Trait ◽  
Fetal Hemoglobin ◽  
S Gene ◽  
Cell Counts ◽  
F Cells ◽  
Hereditary Persistence ◽  
Large Families ◽  
Cell Gene

Members of 7 large families, containing 20 patients with sickle cell anemia (SS) characterized by high levels of fetal hemoglobin (HbF), were studied using immunofluorescence to count F cells and a radioimmunoassay to measure small amounts of HbF. In five of these families, one of the sickle cell trait (AS) parents had a much higher HbF and F-cell count than the other; in one family, both parents had a marked increase in HbF and F cells; in the remaining family, HbF and F cells were at borderline values in both parents. Seven of 14 AS siblings, but only 1 of 8 normal hemoglobin (AA) siblings, also had HbF and F-cell counts above the “normal” range. It seems that a factor for increased F cells, linked to the beta S gene of one parent, is segregating in these families and is responsible for the greatly increased HbF and F cells in the SS subjects. HbF per F cell in AS parents and siblings was the same as that of normal AA subjects, whereas in the SS offspring it was greatly increased, suggesting that it was the result of marrow hyperplasia associated with their hemolytic anemia. The similarity of this “increased F-cell gene” to heterocellular hereditary persistence of fetal hemoglobin (HPFH). Swiss type, is discussed, and it is suggested that it may control the persistent synthesis of HbF in sickle cell anemia by its presence in early infancy.

Hydroxyurea-Mediated Reactivation of Fetal Genes in Primary Erythroid Cell Cultures from Beta-Thalassemia Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3809-3809
Author(s):  
Roberta Calzolari ◽  
Aurelio Maggio ◽  
Alice Pecoraro ◽  
Vito Borruso ◽  
Antonio Troia ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Sickle Cell ◽  
Cell Cultures ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Erythroid Cell ◽  
Beta Thalassemia ◽  
Alternative Mechanism ◽  
Rna Fish ◽  
F Cells

Abstract Fetal hemoglobin (HbF) is frequently increased in the hemoglobinopathies such as sickle cell anemia and b-thalassemia. Epidemiological studies have indicated that an increase in HbF ameliorates the clinical symptoms of these diseases (Rodgers and Rachmilewitz - Bri J. Haemat. 91: 263 -1995). In sickle cell anemia, HbF containing red blood cells have a lower concentration of sickle hemoglobin (HbS), and the HbF itself inhibits HbS polymerization, decreasing cell sickling process (Eaton and Hofrichter - Science 268:1142 -1995). In b-thalassemia patients, HbF partially compensate HbA deficiency and could potentially improve RBC survival resulting in an increase of hemoglobin levels. Hydroxyurea (HU) is one of the pharmacological agents currently used to stimulate HbF synthesis in patients with sickle cell anemia and more recently has been tested in clinical trials for b-thalassemia patients too (Olivieri et al. Ann. NY Acad Sci850:100-1998; Rigano et al. Hemogl.21(3): 219- 1997; Dixit et al. Ann. Haematol. 84: 441 -2005). The mechanism involved in the HU-mediated changes is still unclear. It may involve a selection of a minor pre-existing subpopulation of F-cells that has a growth and/or survival advantage (cellular mechanism). This mechanism may be particularly effective for cells derived from patients with hemoglobinopathies, where F-cells may be resistant to “ineffective erythropoiesis”. An alternative mechanism could involve stimulation of HbF in all or the majority of cell-population by direct induction of g genes (molecular mechanism). Here we report the analysis on thalassemia patients homozygoutes for Lepore genotype that present high levels of fetal hemoglobin. We combined the use of primary erythroid cell culture from peripheral blood stem cells of these patients, with primary transcript in situ hybridization (RNA-FISH) of the g and b globin genes to investigate the mechanism of action of hydroxyurea in adult erythroid cells. RNA-FISH on erythroid cell cultures from these patients reveals that the majority of cells express one g allele only (g: 75.2 %, g:g 19.6%). The analysis in hydroxyurea-treated cultures shows the increase of cells transcribing both g-alleles, indicating the reactivation of fetal genes (g: 58.1%, g:g 40%). This evidence suggests that the molecular mechanism is involved directly on fetal genes reactivation to increase fetal hemoglobin production in HU-treated patients.

scholarly journals Hydroxyurea increases fetal hemoglobin in cultured erythroid cells derived from normal individuals and patients with sickle cell anemia or beta-thalassemia

Blood ◽  
1993 ◽  
Vol 81 (6) ◽  
pp. 1630-1635 ◽  
Author(s):  
E Fibach ◽  
LP Burke ◽  
AN Schechter ◽  
CT Noguchi ◽  
GP Rodgers
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Fold Increase ◽  
Cell Number ◽  
Model Systems ◽  
Beta Thalassemia ◽  
Mean Corpuscular Hemoglobin ◽  
Normal Individuals ◽  
Culture Procedure

Abstract Hydroxyurea (HU), an inhibitor of DNA synthesis, has been shown to increase fetal hemoglobin (HbF) levels in patients with sickle cell anemia and in some patients with beta-thalassemia. However, until now there have not been good in vitro model systems that simulate this effect for study of the molecular and cellular mechanism(s) involved in perturbing the normal ontogeny of the globin genes. We analyzed the cellular effects of HU using a two-phase liquid culture procedure (Fibach et al: Blood 73:100, 1989) in which human peripheral blood- derived progenitor cells undergo proliferation and differentiation. HU was found to have multiple effects on these cultured cells: (1) an increase in the proportion of HbF produced; (2) a decrease in cell number due to inhibition of cell proliferation; (3) an increase in hemoglobin content per cell (mean corpuscular hemoglobin [MCH]); and (4) an increase in cell size (mean corpuscular volume). The extent of these effects was related to the HU dose and time of addition. When added to cell cultures from normal individuals, 4 days following their exposure to erythropoietin (EPO), 100 mumol/L HU caused a 1.3- to 3.5- fold increase in the proportion of HbF, from 0.4% to 5.2% (mean 1.6) in untreated to 1.5% to 8.2% (mean 3.1) in HU-treated cultures and a 45% +/- 10% increase in MCH but only a 25% +/- 7% decrease in cell number on day 13. Cultures of cells derived from five patients with sickle cell anemia have shown a twofold to fivefold increase in the percentage of Hb F following addition of HU while four patients with beta- thalassemia showed a 1.3- to 6.2-fold increase. We believe that this primary cell culture procedure should prove useful in studying the cellular and molecular mechanisms of pharmacologic induction of HbF and might provide a valuable predictive assay system for evaluation of the response of individual patients with hemoglobinopathies to HU and similar agents.

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