2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2379-2384
Author(s):  
Mabel Koshy ◽  
Louise Dorn ◽  
Linda Bressler ◽  
Robert Molokie ◽  
Donald Lavelle ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Complete Blood Count ◽  
Fetal Hemoglobin ◽  
Therapeutic Benefit ◽  
Additional Treatment ◽  
Acute Chest Syndrome ◽  
F Cells ◽  
Pain Crisis ◽  
Globin Synthesis

Augmentation of the fetal hemoglobin (HbF) levels is of therapeutic benefit in patients with sickle cell anemia. Hydroxyurea (HU), by increasing HbF, lowers rates of pain crisis, episodes of acute chest syndrome, and requirements for blood transfusions. For patients with no HbF elevation after HU treatment, augmentation of HbF levels by 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine) could serve as an alternate mode of treatment. Eight adult patients participated in a dose-escalating phase I/II study with 5-aza-CdR at doses ranging from 0.15 to 0.30 mg/kg given 5 days a week for 2 weeks. HbF, F cell, F/F cell, γ-globin synthesis ratio, complete blood count, and chemistry were measured. The average γ-globin synthesis relative to non-α-globin synthesis prior to therapy was 3.19% ± 1.43% and increased to 13.66% ± 4.35% after treatment. HbF increased from 3.55% ± 2.47% to 13.45% ± 3.69%. F cells increased from 21% ± 14.8% to 55% ± 13.5% and HbF/F cell increased from 17% to 24%. In the HU nonresponders HbF levels increased from 2.28% ± 1.61% to 2.6% ± 2.15% on HU, whereas on 5-aza-CdR HbF increased to 12.70% ± 1.81%. Total hemoglobin increased by 1 g/dL in 6 of 8 patients with only minor reversible toxicities, and all patients tolerated the drug. Maximum HbF was attained within 4 weeks of treatment and persisted for 2 weeks before falling below 90% of the maximum. Therefore 5-aza-CdR could be effective in increasing HbF in patients with sickle cell anemia who failed to increase HbF with HU. Demonstration of sustained F levels with additional treatment cycles without toxicity is currently being performed.

2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2379-2384 ◽  
Author(s):  
Mabel Koshy ◽  
Louise Dorn ◽  
Linda Bressler ◽  
Robert Molokie ◽  
Donald Lavelle ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Complete Blood Count ◽  
Fetal Hemoglobin ◽  
Therapeutic Benefit ◽  
Additional Treatment ◽  
Acute Chest Syndrome ◽  
F Cells ◽  
Pain Crisis ◽  
Globin Synthesis

Abstract Augmentation of the fetal hemoglobin (HbF) levels is of therapeutic benefit in patients with sickle cell anemia. Hydroxyurea (HU), by increasing HbF, lowers rates of pain crisis, episodes of acute chest syndrome, and requirements for blood transfusions. For patients with no HbF elevation after HU treatment, augmentation of HbF levels by 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine) could serve as an alternate mode of treatment. Eight adult patients participated in a dose-escalating phase I/II study with 5-aza-CdR at doses ranging from 0.15 to 0.30 mg/kg given 5 days a week for 2 weeks. HbF, F cell, F/F cell, γ-globin synthesis ratio, complete blood count, and chemistry were measured. The average γ-globin synthesis relative to non-α-globin synthesis prior to therapy was 3.19% ± 1.43% and increased to 13.66% ± 4.35% after treatment. HbF increased from 3.55% ± 2.47% to 13.45% ± 3.69%. F cells increased from 21% ± 14.8% to 55% ± 13.5% and HbF/F cell increased from 17% to 24%. In the HU nonresponders HbF levels increased from 2.28% ± 1.61% to 2.6% ± 2.15% on HU, whereas on 5-aza-CdR HbF increased to 12.70% ± 1.81%. Total hemoglobin increased by 1 g/dL in 6 of 8 patients with only minor reversible toxicities, and all patients tolerated the drug. Maximum HbF was attained within 4 weeks of treatment and persisted for 2 weeks before falling below 90% of the maximum. Therefore 5-aza-CdR could be effective in increasing HbF in patients with sickle cell anemia who failed to increase HbF with HU. Demonstration of sustained F levels with additional treatment cycles without toxicity is currently being performed.

Clinical epidemiology of individuals with Sickle cell anemia using Hydroxyurea at Muhimbili National Hospital, Dar Es Salaam, Tanzania

2020 ◽  
Vol 31 (1) ◽  
pp. 106-119
Author(s):  
Elisha Osati ◽  
Edward Kija ◽  
Florence Urio ◽  
Magdalena Lyimo ◽  
Siana Nkya ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Severe Pain ◽  
Clinical Epidemiology ◽  
Fetal Hemoglobin ◽  
Dar Es Salaam ◽  
Acute Chest Syndrome ◽  
Muhimbili National Hospital ◽  
National Hospital

Background: The pathophysiology of sickle cell disease (SCD) is complex and involves nitric oxide depletion, increased inflammation/adhesion molecules and vaso-occlusion in addition to the chronic hemolytic anemia. This pathophysiology results in systemic clinical complications including recurrent episodes of severe pain, stroke, acute chest syndrome (ACS) and an increased susceptibility to infection. SCD severity varies among individuals and fetal hemoglobin (HbF) is known as a major modulator of the disease. To date, hydroxyurea (HU) is a known intervention that acts by increasing HbF in individuals with SCD. The increase in HbF reduces the risk of ‘sickling’ events and improves clinical outcomes. This is the first study on the use of HU in individuals with SCA in Tanzania.Methods: A case-control study to determine the proportion, indications, clinical and laboratory outcomes of SCD patients with HU use was conducted at Muhimbili National Hospital in Dar Es Salaam, Tanzania.Results: Forty-two patients with Sickle cell anemia (SCA) on HU treatment and 32 patients with SCA not on HU treatment were enrolled. The proportion of HU use by individuals with SCA at Muhimbili National Hospital was 10 per 1000. The mean HbF % was 9.8 ± 2.4 vs 6.2 ±1.4 for controls (P <0.001). Thirty (71.4%) were enrolled for HU treatment due to central nervous system (CNS) events, frequent painful crises 11(26.2%) and recurrent anemia 1(2.4%). Thirty-two SCA patients (76.2%) reported improvements after being on HU for at least six months. Of these, 91% reported no history of severe pain that required hospitalizations since they started HU. Twenty patients (66.7%) out of those with CNS events reported not to have experienced convulsions after HU initiation.Conclusions: HbF was higher in patients who were on HU and had positive correlation with clinical outcomes. Further clinical trials are required to evaluate more effects of HU use among SCA individuals in Tanzania. Keywords: Sickle cell anemia, HU, Fetal hemoglobin, Tanzania.

Combining Fetal Hemoglobin and Reticulocytosis to Index Clinical Severity of Sickle Cell Disease in Children.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2556-2556
Author(s):  
Emily Riehm Meier ◽  
Colleen Byrnes ◽  
Maxine Weissman ◽  
Pierre Noel ◽  
Naomi L.C. Luban ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Supportive Care ◽  
Disease Severity ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Treatment Decisions ◽  
Clinical Severity ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
F Cells

Abstract Abstract 2556 Poster Board II-533 Predictors of disease severity during infancy or childhood in patients with sickle cell disease (SCD) are needed to guide treatment decisions with therapies that have known toxicities [transfusion, hydroxyurea (HU), bone marrow transplant]. Erythrocyte fetal hemoglobin (HbF) expression levels above 20% reduce sickle hemoglobin (HbS) polymerization and decrease hemolysis. As a result of the decreased hemolysis, the survival of erythrocytes is prolonged, and the overall level of erythropoiesis is reduced. To determine if clinical markers of increased HbF production and decreased erythropoiesis may be combined to score disease severity, we developed a Fetal Hemoglobin-Reticulocytosis Index (FRI) defined as: [HbF (%) × non-transfused F-cells (%)] / [Absolute Reticulocyte Count (K/uL)]. For these studies, red cell lysates were analyzed by high power liquid chromatography (HPLC) to estimate HbA, HbS, and HbF fractions. F-cells were analyzed by flow cytometry using antibodies directed against HbF, while transfused cells were labeled with antibodies directed against HbA. Dual staining with both antibodies provided a method for accurately distinguishing transfused and non-transfused F-cells (NT F-cells). A minimum of 10,000 cells was analyzed in all samples. Absolute reticulocyte counts (ARC) were determined using a Sysmex XE 2100 hematology analyzer (Sysmex America, Mundelein, IL). Preliminary studies revealed FRI values near 100 at one month of age followed by a rapid drop before the age of 4 years. Blood from children between the ages of 4 and 21 years was also studied to determine if FRI correlates with therapeutic regimen. FRI values for three groups were compared: those treated with chronic transfusion (n=19, mean FRI=0.72±1.04), HU (n=19, mean FRI=5.61±6.24), versus supportive care alone that did not include recent transfusions (n=42, mean FRI=2.70 ±4.85). When the FRI values from each of these groups were placed in rank order, the slope of the line increased sharply from a linear to an exponential shape near the FRI value of 2. To determine if the FRI=2 inflection may be indicative of reduced disease severity, the number of SCD events were determined in the 42 study subjects treated with supportive care. Overall, twenty-eight (66.7%) patients had an FRI<2, and fourteen (33.3%) patients had an FRI≥2. Among those patients, SCD events were tallied (listed in descending order according to number of events): painful crises requiring hospitalization (FRI<2, n=128; FRI≥2, n=25), pneumonia /acute chest syndrome (FRI<2, n=74; FRI≥2, n=18), splenic sequestration (FRI<2, n=14; FRI≥2, n=0), conditional transcranial Doppler [(TCD), FRI<2, n=13; FRI≥2, n=1), silent stroke (FRI<2, n=4; FRI≥2, n=2), bacteremia (FRI<2, n=2; FRI≥2, n=1), cholecystectomy (FRI<2, n=3; FRI≥2, n=0), and nephropathy (FRI<2, n=1; FRI≥2, n=0). None of the supportive care group had an overt stroke, abnormal TCD, sickle cell retinopathy, or priapism. Age adjusted analysis showed that the FRI≥2 group had significantly fewer total events per year [events/year: FRI<2 (0.70±0.52) vs. FRI≥2 (0.38 ± 0.36), p=0.02]. These data suggest that combining the clinical parameters of fetal hemoglobin production and reticulocytosis provides a simple index for SCD severity. Based upon this retrospective data, prospective studies are underway to determine if the FRI decline during infancy or FRI levels in childhood are useful to predict clinical severity and treatment decisions in SCD patients. Disclosures: No relevant conflicts of interest to declare.

Absolute Reticulocyte Count Is Negatively Correlated with Fetal Hemoglobin during Infancy and Early Childhood in Patients with Sickle Cell Anemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4081-4081
Author(s):  
Emily R. Meier ◽  
Colleen Byrnes ◽  
Y. Terry Lee ◽  
Maxine Weissman ◽  
Jeffery L. Miller
Keyword(s):  
Steady State ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Conflicts Of Interest ◽  
Fetal Hemoglobin ◽  
Convenience Sample ◽  
Risk Of Death ◽  
Increased Risk ◽  
F Cells ◽  
Analytical Approaches

Abstract Hemoglobin switching is largely complete in healthy infants by 6 months of age. In infants with sickle cell anemia (HbSS, SCA), reticulocytosis begins early in life as fetal hemoglobin (HbF) is replaced by sickle hemoglobin (HbS). Previous studies demonstrated that patients with an ARC greater than 200 K/uL during early infancy (60-196 days of age) were at the highest risk for SCA-associated events. 1,2 The objective of this study was to determine if ARC is related to HbF levels in a cohort of pediatric SCA patients. A convenience sample of 106 children with SCA between the ages of 1 month and 20 years who were not receiving hydroxyurea or monthly blood transfusions were enrolled in this observational study [42 (39.6%) less than 1 year of age (28-362 days old), 46 (43.4%) between the ages of 1 and 10 years, and 18 (17.0%) between 10 and 20 years old]. After consent and assent were provided, discarded peripheral blood was obtained during routine clinic visits at steady state and analyzed within 48 hours of collection and storage at 40C. Steady state was defined as a sample drawn at least 30 days following an acute event and at least 60 days following a blood transfusion. Hematologic data, including ARC and HbF levels, were measured using CLIA approved methods. F-cells were enumerated by flow cytometry following intracellular staining with a fluorescent antibody directed against HbF. Correlations were calculated to determine the relationships of ARC with HbF, F-cells, and other hematologic data, while two-tailed t tests were used to compare means. Initial studies compared groups based upon ARC greater than or equal to 200 K/uL (ARC≥200) during infancy because of the previously reported utility of this threshold as a predictive marker for SCA severity.1 Over one third of the infants less than 1 year of age (n=16) had an ARC≥200. Mean HbF and F-cell levels were significantly lower in the ARC≥200 group when compared to the ARC<200 group (HbF: 29.9±10.9% vs. 53.5±17.6%, respectively, p=2.2E-05; F-cells: 83.5±13.2% vs. 96.6±5.7%, p=6.2E-05). Mean hemoglobin levels were also lower in the ARC≥200 group [8.1±1.4 g/dL vs. 9.5±1.6 g/dL (ARC<200), p=0.005]. Of the 22 (52.4%) infants who had a HbF level greater than 40%, only 2 (9.1%) had an ARC greater than 200K/uL. Enrolled patients were also grouped according to age and comparisons were made between ARC and HbF or F-cell levels. HbF and F-cell levels were negatively correlated to ARC in the infant subgroup (r=-0.696, p=3.1E-07 and r=-0.795, p=0.000, respectively). HbF and F-cell levels from children between the ages of 1 and 10 years were inversely related to the ARC, but the correlation was less significant (r=-0.626, p=3.3E-06 and r=-0.538, p=1.2E-04, respectively). The inverse relationship was no longer present in the oldest group of patients (HbF vs. ARC r=-0.203, p=0.420 and F-cells vs. ARC, r=-0.258, p=0.302). According to both analytical approaches described here, increased ARC is associated with decreased HbF and F-cell levels in infants with SCA. Less robust negative correlations are maintained through age 10 years, but no significant correlation was identified in adolescence and young adulthood. Overall, the data suggest that increased ARC levels may identify SCA infants who manifest a more rapid or greater loss of fetal hemoglobin during the later stages of the HbF-to-HbS switching phenomenon. Meier ER, Byrnes C, Lee YT, et al. Increased reticulocytosis during infancy is associated with increased hospitalizations in sickle cell anemia patients during the first three years of life. PLoS One 2013; 8(8):e70794. doi: 10.1371/journal.pone.0070794.Meier ER, Wright EC, Miller JL. Reticulocytosis and anemia are associated with an increased risk of death and stroke in the newborn cohort of the Cooperative Study of Sickle Cell Disease. Am J Hematol 2014 May 31; doi: 10.1002/ajh.23777. [Epub ahead of print] Disclosures No relevant conflicts of interest to declare.

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

2016 ◽  
Vol 91 (8) ◽  
pp. E323-E324 ◽  
Author(s):  
Florence Urio ◽  
Magdalena Lyimo ◽  
Siana Nkya Mtatiro ◽  
Sharon E. Cox ◽  
Bruno p. Mmbando ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Low Concentration ◽  
High Prevalence ◽  
F Cells

scholarly journals Clinical and Hematological Evaluation of Patients with Sickle Cell Anemia Before and After Four Years of Using Hydroxyurea

10.3823/2469 ◽  
2017 ◽  
Vol 10 ◽  
Author(s):  
Ieda Maria Gonçalves Pacce Bispo ◽  
Maria Lúcia Ivo ◽  
Valter Aragão do Nascimento ◽  
Alexandra Maria Almeida Carvalho de Pinto ◽  
Olinda Maria Rodrigues de Araújo ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Hematological Parameters ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Teaching Hospitals ◽  
Acute Chest Syndrome ◽  
Mean Values ◽  
Significant Difference ◽  
Before And After

Objective: Evaluating clinical and hematological-clinical parameters of patients with sickle cell anemia (SCA) before and after four years of using hydroxyurea (HU).  Method: A retrospective cohort study implementing a quantitative, descriptive and analytical approach developed in two public teaching hospitals located in the Central-West region of Brazil, from November 2010 to October 2011. Data collection was performed through medical records of 32 patients with SCA to assess clinical and hematological parameters before and after HU treatment. The study was approved by the UFMS Ethics Committee under protocol number 1890/2010. Results: All of the 32 patients were homozygous with a mean age in the prescription of hydroxyurea of 19.72±7.58 years, an initial dose of 15.59±4.27 mg/kg/day, and 22.48±5.35 mg/kg/day in the fourth year of treatment. Regarding the use of HU, average values of some hematological parameters presented a significant difference in the fourth year compared to the mean values prior to HU use, such as fetal hemoglobin (14.49±7.52%), red blood cells (2.54±0.38x1012/L), hematocrit (25.30±4.03%) and hemoglobin (9.22±3.34g/dL).  Conclusion: Treatment with hydroxyurea showed a significant increase in fetal hemoglobin levels, increased hemoglobin, hematocrit and average corpuscular hemoglobin concentration, with reduced episodes of pain, infection and acute chest syndrome in such a way as to reaffirm its efficiency in treating these patients. Keywords: Hemoglobin; Sickle Cell Anemia; Hydroxyurea.

scholarly journals RN-1, a Potent and Selective LSD1 Inhibitor, Induces High Levels of Fetal Hemoglobin (HbF) in Anemic Baboons (P. anubis)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 336-336 ◽  
Author(s):  
Angela Rivers ◽  
Kestis Vaitkus ◽  
Maria Armila Ruiz ◽  
Vinzon Ibanez ◽  
Tatiana Kouznetsova ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Large Fraction ◽  
Fetal Hemoglobin ◽  
In Vitro Assays ◽  
Mrna Levels ◽  
Cell Disease ◽  
F Cells ◽  
Globin Synthesis

Abstract Increased levels of fetal hemoglobin are associated with decreased symptoms and increased life span in patients with sickle cell disease (SCD). Hydroxyurea, the only drug currently approved for SCD, is not effective in a large fraction of patients and therefore new agents are currently needed. Recent evidence has shown that LSD1, an enzyme that removes monomethyl and dimethyl residues from the lys4 residue of histone H3, is a repressor of γ-globin expression. Tranylcypromine (TCP), an LSD1 inhibitor, was shown to increase γ-globin expression in human βYAC transgenic mice (Shi et al Nat Med 19:291, 2013). Because the arrangement and developmental stage-specific expression pattern of the β-like globin genes is highly conserved between man and other simian primates, the use of an simian primate animal model such as the baboon (P.anubis) is the best predictor of the activity of HbF-inducing agents in man. In this investigation we compared the effect of TCP and the more potent and selective LSD1 inhibitor, RN-1, on HbF expression in anemic baboons (P. anubis). In vitro assays have shown that the LSD1 IC50 of RN-1 is at least 1000 fold less than TCP. Animals were phlebotomized for 14d prior to drug treatment to attain an Hct=20 to induce reticulocytosis and establish baseline HbF levels and were maintained at this Hct by periodic phlebotomies during the course of the experiment. In four baboons treated with varying doses of TCP (2-6mg/kg/; 10-20d; sc) low levels of HbF (4.9-7.9% HbF) were induced that were only slightly higher than those observed at the pretreatment baseline (2.2-4.1% HbF). In contrast, treatment with varying doses of RN-1 (2.5-0.125 mg/kg/d; 5-10d) induced high levels of HbF, F reticulocytes, and F cells in 5 of 6 animals (see Table). At high doses of drug the ratio of 5'Iγ/3'Vγ synthesis was >2 demonstrating a near-complete reversion to the pattern of fetal stage expression. Peak levels of F reticulocytes and γ-globin synthesis were observed 8d and HbF and F cells 11d after the first day of drug administration. Increased γ-globin mRNA levels (γ/γ+β) in reticulocytes measured by RT-PCR showed that increased HbF levels were not due to translational effects. Bisulfite sequence analysis showed that levels of DNA methylation of the γ-globin promoter were similar in pre- and post-treatment BM erythroid precursors from two animals. Flow cytometry analysis using anti-α4-integrin and anti-baboon RBC antibodies showed that RN-1 treatment altered terminal BM erythroid differentiation by increasing the proportion of less differentiated precursors, however no changes in MCHC or total hemoglobin synthesis (α/γ+β) were observed. RN-1 treatment was associated with decreased ANC (290-870 X 103/μl nadir) and increased platelets (1092-1445 X 103/μl peak) and monocytes that were likely caused by effects on hematopoietic differentiation. The ANC nadir and peak platelet and monocyte counts were observed between d14-19 and resolved with 2-3 days. Similar changes in ANC and platelets, although not in monocytes, are observed following treatment with decitabine and can be controlled by modification of dose and schedule of administration (Lavelle et al Blood 119:1240, 2012). We conclude that RN-1, a more potent LSD1 inhibitor than TCP, is a powerful HbF-inducing drug with activity similar to decitabine and predict that LSD1 inhibitors may be useful drugs for the treatment of sickle cell disease. Table HbF, F-cells, and F-retics in Baboons Treated with RN-1 Animal RN-1 Dose (mg/kg/d) HbF (%) Globin synthesis (γ/γ+β) F-cells (%) F-retics (%) Pre Post Pre Post Pre Post Pre Post 8548 2.5 (4d) 5.8 27.3 ND 0.78 28.5 59.2 34.6 92.3 8549 0.5 (5d) 2.4 29.5 0.06 0.68 19.1 60.8 33.9 97.5 8000 0.25 (5d) 4.1 20.6 0.15 0.49 20.3 47.0 45.7 80.7 8548 0.20 (5d) 3.7 20.5 0.04 0.52 36.9 54.8 36.9 89.2 8001 0.125 (5d) 1.8 4.8 ND 0.06 13.5 21.8 22.9 31.7 8549 0.125 (10d) 3.6 16 0.04 0.22 17.6 42.7 21.0 70.0 Disclosures No relevant conflicts of interest to declare.

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 Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2269-2275 ◽  
Author(s):  
Jane S. Hankins ◽  
Russell E. Ware ◽  
Zora R. Rogers ◽  
Lynn W. Wynn ◽  
Peter A. Lane ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
White Blood Cells ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Extension Study ◽  
Acute Chest Syndrome ◽  
Event Rates ◽  
Hydroxyurea Therapy

AbstractThe long-term efficacy and toxicity of hydroxyurea for infants are undefined, and its role in preventing organ dysfunction is unknown. Short-term feasibility of hydroxyurea administration, toxicities, hematologic effects, and effect on spleen function in infants with sickle cell anemia (SCA) were reported (Hydroxyurea Safety and Organ Toxicity [HUSOFT] trial). These infants completing 2 years of hydroxyurea therapy (20 mg/kg/d) were offered study extension with dose escalation to 30 mg/kg/d. Patients were monitored with laboratory tests and biannual imaging studies. Hematologic indices were compared with predicted age-specific values and event rates compared with historic rates. All 21 subjects completing the original trial enrolled in the extension study: median age, 3.4 years old (range, 2.6 to 4.4 years); 12 females; 20 with Hb SS, 1 with Hb S/β0-thalassemia. Seventeen patients completed 4 years of hydroxyurea, and 11 completed 6 years. After 4 years, hydroxyurea was associated with increased hemoglobin concentration, percentage of fetal hemoglobin (Hb F), and mean corpuscular volume (MCV) and decreased reticulocytes, white blood cells (WBCs), and platelets (P &lt; .01). Patients experienced 7.5 acute chest syndrome (ACS) events per 100 person-years, compared with 24.5 events per 100 person-years among historic controls (P = .001). Treated patients had better spleen function than expected and improved growth rates. Infants with SCA tolerate prolonged hydroxyurea therapy with sustained hematologic benefits, fewer ACS events, improved growth, and possibly preserved organ function.

scholarly journals Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 109-116 ◽  
Author(s):  
S Charache ◽  
GJ Dover ◽  
MA Moyer ◽  
JW Moore
Keyword(s):  
Clinical Improvement ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Pharmacokinetic Studies ◽  
Cell Responses ◽  
Small Risk ◽  
F Cells ◽  
Hemoglobin Production

Five patients with sickle cell anemia were treated with hydroxyurea (HU), in hopes of augmenting their production of fetal hemoglobin. Laboratory responses in two patients treated for more than 2 years were encouraging and there were suggestions of clinical improvement. Long- term HU therapy should be considered for severely affected adults with sickle cell anemia who are willing to accept what is probably a small risk of carcinogenesis. Preliminary chromosomal analysis and knowledge of the clastogenic properties of HU suggest that conception and pregnancy should be avoided. Pharmacokinetic studies will probably be necessary to adjust individual dosage schedules so that cytotoxicity is avoided. F cell responses can be seen in 2 to 3 weeks if the HU dose is optimal, but establishment of a large number of F cells in the circulation may take a month or longer.

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