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The accumulation of unbound α-globin chains in red blood cells is a crucial pathophysiology of β-thalassemia. IOX1 (5-carboxy-8-hydroxyquinoline) is a broad-spectrum 2-oxoglutarate (2OG)-dependent oxygenase inhibitor that can reduce α-globin mRNA expression in human cord blood erythroid progenitor cells. Therefore, IOX1 has been proposed as a potential compound for β-thalassemia treatment through the decrease in α-globin chain synthesis. However, there is no empirical evidence regarding the consequences of IOX1 in β-thalassemia. In this study, the therapeutic effects of IOX1 were investigated in β 0 -thalassemia/hemoglobin E (HbE) erythroid progenitor cells during in vitro erythropoiesis. The results indicated that IOX1 had no impact on α-globin gene expression, but it led instead to significant decreases in γ-globin and fetal hemoglobin (HbF, α 2 γ 2 ) production without affecting well-known globin regulators: KLF1, BCL11A, LRF, and GATA1. In addition, differential mRNA expression of several genes in the hypoxia response pathway revealed the induction of EGLN1, the PHD2-encoding gene, as a result of IOX1 treatment. These findings suggested that IOX1 fails to lower α-globin gene expression; on the contrary, it mediates γ-globin and HbF silencing in β 0 -thalassemia/HbE erythroid progenitor cells. Because of the negative correlation of EGLN1 and γ-globin gene expression after IOX1 treatment, repurposing IOX1 to study the hypoxia response pathway and γ-globin regulation may provide beneficial information for β-thalassemia., Competing Interests: Conflict of Interest Disclosure The authors declare no competing interests., (Copyright © 2022 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Although not regularly transfused, patients with non-transfusion-dependent thalassemia (NTDT) are prone to iron overload and its complications. Their molecular, phenotypical and laboratory characteristics vary in different populations and there is a need to document local prevailing patterns. We have reviewed the records of our patients with NTDT in Kuwait and documented their clinical and molecular characteristics in addition to iron status [serum ferritin and liver magnetic resonance imaging (MRI) T2*], management and complications. There were 41 patients, made up of 20 with β-thalassemia intermedia (β-TI), 18 with Hb H (β4) disease and three with Hb E (HBB: c.79G > A)-β-thalassemia (Hb E-β-thal); their ages ranged from 3 to 36 years (mean 12.5 ± 7.7). While 18 (43.9%) had been transfused at least once, only three (7.3%) had been transfused on multiple occasions. Three patients had serum ferritin >500 ng/mL; while four of 38 had mild or moderate liver iron overload. Seven (35.0%) of the β-TI patients were managed with hydroxyurea (HU) with good response. Other complications included five patients with gallstones and one each of hypothyroidism and moyamoya. The most common mutations among the β-TI patients were IVS-II-1 (G > A) and IVS-I-6 (T > C), while among the Hb H patients, the Saudi α2-globin gene polyadenylation (polyA) (AATAAA > AATAAG) mutation was responsible for all cases either as homozygotes (61.1%) or compound heterozygotes with the α-thal-2 (-α(3.7)) allele (33.3%). Although the pattern of NTDT in Kuwaiti patients is generally mild, there is a need to follow them to adulthood as the complications are cumulative and more prevalent in this group.

The national screening policy for hemoglobinopathies uses the cutoffs for red cell indices mean corpuscular volume >80 and mean corpuscular hemoglobin >27, a strategy known to miss some individuals with Hb E trait (EBT), the most common abnormal hemoglobin in Sri Lanka. We wanted to determine if red cell distribution width (RDW) cutoff values would help in increasing the sensitivity of screening for Hb E trait. High-performance liquid chromatography was carried out as the gold standard to detect hemoglobinopathies and red blood cell parameters with colter counter. Receiver operating characteristic curve was drawn to determine the cutoff value for EBT against β-trait (BTT) and other anemias. Of the 504 patients, 246 had BTT, 110 had EBT, and 151 had other types of anemias. Mean (SD) RDW among patients with BTT was 16 (2.8), with EBT 14.5 (2.9), and with other anemias 15.8 (4.2) (P>0.001). With 14.45 as the cutoff for RDW and considering accepted values for mean corpuscular volume >80 and mean corpuscular hemoglobin >27, it gave a predictive sensitivity of 98.2% for EBT. By using RDW cutoff at 14.45 in addition to the accepted screening indices, sensitivity of Hb E trait detection went up to 98.2% from 86.6%. This study highlights the importance of taking RDW into consideration for screening.

Allogeneic HSCT is the only curative treatment for severe thalassemia disease. MC occurs in one-third of these patients within the first two months after HSCT; this is a major risk factor of graft rejection, especially when RHCs are more than 25%. There is still no consensus for the management of MC, especially in the early phase of HSCT. The DLI has also been described in the treatment of MC following HSCT for hemoglobinopathies, but its success is still not guaranteed. The second HSCT has been an approach used in an attempt to cure patients who reject their graft. Concern about toxicity of conditioning regimen, the second HSCT is usually delayed for at least a year after the first HSCT. We would like to demonstrate the successful use of the second mini-allogeneic HSCT in hemoglobin E/β-thalassemia with evidence of unstable MC in the first 100 days after allogeneic HSCT to prevent further graft loss after allogeneic HSCT., (© 2011 John Wiley & Sons A/S.)

Purpose: In (hemoglobin, Hb) HbEβ-thalassemia, HbE (β-26 Glu→Lys) interacts with β-thalassemia to produce clinical manifestation of varying severity. This is the first proteomic effort to study changes in protein levels of erythrocytes isolated from HbEβ-thalassemic patients compared to normal., Experimental Design: We have used 2-DE and MALDI-MS/MS-based techniques to investigate the differential proteome profiling of membrane and Hb-depleted fraction of cytosolic proteins of erythrocytes isolated from the peripheral blood samples of HbEβ-thalassemia patients and normal volunteers., Results: Our study showed that redox regulators such as peroxiredoxin 2, Cu-Zn superoxide dismutase and thioredoxin and chaperones such as α-hemoglobin stabilizing protein and HSP-70 were upregulated in HbEβ-thalassemia. We have also observed larger amounts of membrane associated globin chains and indications of disruption of spectrin-based junctional complex in the membrane skeleton of HbEβ-thalassemic erythrocytes upon detection of low molecular weight fragments of β-spectrin and decrease in β-actin and dematin content., Conclusion and Clinical Relevance: We have observed interesting changes in the proteomic levels of redox regulators and chaperons in the thalassemic hemolysates and have observed strong correlation or association of the extent of such proteomic changes with HbE levels. This could be important in understanding the role of HbE in disease progression and pathophysiology., (Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Despite large populations carrying traits for thalassemia in countries implementing universal iron fortification, there are few data on the absorption and utilization of iron in these persons., Objective: We aimed to determine whether iron absorption or utilization (or both) in women heterozygous for beta-thalassemia, alpha-thalassemia 1, or hemoglobin E (HbE) differed from that in control subjects and compound HbE/beta-thalassemia heterozygotes., Design: In Thai women (n = 103), red blood cell indexes, iron status, non-transferrin-bound iron, and growth differentiation factor 15 were measured, and body iron was calculated. Fractional iron absorption was measured from meals fortified with isotopically labeled ((57)Fe) Fe sulfate, and iron utilization was measured by the infusion of ((58)Fe) Fe citrate., Results: Iron utilization was approximately 15% lower in alpha-thalassemia 1 or beta-thalassemia heterozygotes than in controls. When corrected for differences in serum ferritin, absorption was significantly higher in the alpha- and beta-thalassemia groups, but not the HbE heterozygotes, than in controls. HbE/beta-thalassemia compound heterozygotes had lower iron utilization and higher iron absorption and body iron than did controls. Nontransferrin-bound iron and growth differentiation factor 15 were higher in the compound heterozygotes, but not in the other groups, than in the controls., Conclusions: In alpha-thalassemia 1 and beta-thalassemia heterozygotes with ineffective erythropoesis, dietary iron absorption is not adequately down-regulated, despite a modest increase in body iron stores. In populations with a high prevalence of these traits, a program of iron fortification could include monitoring for possible iron excess and for iron deficiency.

The antioxidant status of hemoglobin-E carriers was studied pre- and post-treatment with vitamin E for 3 months. Fourteen hemoglobin-E carriers (age = 21.36 +/- 1.08 years, BMI = 18.32 +/- 1.22 kg/m2) were treated with vitamin E 200 I.U. daily for 3 months. Fasting blood samples were collected and analyzed for erythrocyte superoxide dismutase activity, total antioxidant activity, hemoglobin concentration, hematocrit, MCV, Heinz body formation and osmotic fragility test. The blood parameters before and after vitamin E treatment were compared. The results showed that superoxide dismutase activity in the erythrocytes was significantly decreased, while total antioxidant activity in plasma, and the osmotic fragility of the erythrocytes, was significantly increased after vitamin E supplementation. However, hematocrit, MCV, and Heinz body formation did not change significantly. This demonstrated that vitamin E 200 IU could be used as a lipophilic antioxidant in red blood cells and could help increase the level of antioxidant in hemoglobin-E carriers.

Accurate and precise hemoglobin separation and the quantitation of Hb A2 and Hb F are essential for the diagnosis of the thalassemias and hemoglobinopathies. Presented in this study is the validation of the the Hb A2 assay of the HbGold analyzer, a fully automated liquid chromatography system for hemoglobin separation and quantitation. Variability of Hb A2 quantitation was quite low; the CV's of within-run, between-run and interlaboratory studies were 1.8-3.1%, 3.4-6.0% and 6.8-8.8% respectively. The results of the %Hb A2 quantitated by HbGold analyzer correlated well with those given by the Bio-Rad Variant Hb testing system (r=0.98). The application of the HbGold analyzer for the diagnosis of the thalassemia phenotypes frequently observed in Thailand is considered. In conclusion, the Hb A2 assay of the HbGold analyzer could be used for the quantitation of Hb A2 and Hb F and the presumptive identification of abnormal hemoglobins.

Successful pregnancy outcome is described in a patient with hemoglobin E/beta(0)-thalassemia which is expressed as thalassemia major. A 21 year-old Laotian female complicated by severe anemia became pregnant. The diagnosis of hemoglobin E/beta (0)-thalassemia was made by hemoglobin analysis. The fetal weight estimated by abdominal echogram decreased during pregnancy. She received blood transfusions, in order to improve intrauterine growth retardation. Hemoglobin concentration was maintained at the level greater than 9 g/dl. Fetal growth was improved by the treatment. A normal full-term male infant was born by a caesarean section, and splenectomy was performed at the same time.

Red blood cell (RBC) antioxidant defense was investigated in eight individuals with hemoglobin E (Six EE and two E-B(+) thalassemia) and compared to that in six individuals with thalassemia and ten normal subjects. Individuals with hemoglobin E had increased incubated Heinz body formation (68% +/- 18%; p less than 0.001) compared to normal and thalassemic RBC (10% +/- 2% and 11% +/- 5%, respectively). Stimulated pentose phosphate shunt activity was increased in the thalassemic and decreased in the hemoglobin E RBC as compared to normal. The 2,3-diphosphoglycerate (DPG) content of the EE RBC was increased to 5.59 +/- 0.69 mumol/ml RBC as compared to normal (4.51 +/- 0.77; p less than 0.001). In the EE RBC, there was a direct correlation between Heinz body formation and DPG content (r = 0.73). Ascorbic and dehydroascorbic acid (0.1 and 1.0 mM) were able to decrease the degree of Heinz body formation in the hemoglobin E RBC. Ascorbic acid (0.1 mM) prolonged the response of the pentose shunt. Thus impaired antioxidant defense may account for the persistence of the hemoglobin E gene in areas where malaria is endemic. Oxidant medications should be used with caution in individuals of Southeast Asian origin.

Generalized epileptiform seizures developed in a 23-year-old patient with beta-thalassemia-hemoglobin E. A computed tomographic scan suggested an intracranial mass. Surgery disclosed an extramedullary hematopoietic mass compressing the brain. Removal of the mass followed by irradiation of the area resulted in disappearance of the convulsions.

The mean +/- S.D. of LAP score in neutrophil of the normal control, non splenectomised patients and splenectomised patients were 116 +/- 78, 94 +/- 48 and 37 +/- 23 Kaplow units, respectively. The significant reduction in the leukocyte alkaline phosphatase level (P less than 0.05) was found in beta thalassemia/HbE patients. The degree of reduction was greater in the splenectomised patients (P less than 0.05). The decreased LAP levels in PMN was persistent. This was in contrast to the LAP in PMN of other patients where as LAP returned to normal after splenectomy. The relevance to the increased susceptibility to infection and low LAP in beta thalassemia/HbE should be further investigated.