Thalass. Rep., Volume 13, Issue 1 (March 2023) – 10 articles

The human hemochromatosis protein HFE is encoded by the HFE gene and participates in iron regulation. The aim of this study was to detect the most frequent HFE gene mutations in a control population and in β-thalassemia trait (BTT) carriers, and to study their relationship with iron metabolism. Total blood count, hemoglobin electrophoresis at alkaline pH, HbA₂ quantification, iron (Fe), total Fe binding capacity and ferritin were assayed. HFE gene mutations were analyzed by real-time PCR. A total of 119 individuals (69 normal and 50 BTT) were examined. In the control group, 9% (6/69) presented a codon 282 heterozygous mutation (C282Y), and 19% a codon 63 mutation (H63D) (13/69, 11 heterozygotes and 2 homozygotes). In the BTT group, 3 carriers (6%) were heterozygous for C282Y, 14 (28%) for H63D, 1 (2%) for a codon 65 mutation and 1 (2%) was H63D and C282Y double heterozygous. Control group Fe metabolism did not show significant differences (p > 0.05) according to whether or not they carried an HFE gene mutation; while the BTT group with and without HFE mutation showed higher Fe and ferritin than the control group (p < 0.05). However, no increases in iron parameters were detected in BTT carriers that simultaneously exhibited an H63D mutation compared to BTT subjects without a mutation. Therefore, the iron metabolism alterations observed in BTT carriers could not be attributed to the presence of HFE gene mutations. It is likely that BTT individuals have other genetic modifiers that affect their iron balance. Full article

Genetic polymorphisms in Quantitative Trait Loci (QTL) genes such as BCL11A, HBS1L-MYB and KLF1 have been reported to influence fetal hemoglobin (HbF) levels. This prospective study was planned to evaluate the role of genetic polymorphisms in QTL genes as determinant of HbF levels in beta thalassemia major patients. The study was carried out on 100 thalassemia major patients. Blood samples were collected in EDTA and plain vials for biochemical and molecular evaluation. The BCL11A, HBS1L-MYB and KLF1 genotypes were determined using a polymerase chain reaction (PCR)-based method. Red Blood Cell (RBC) indices and HbF levels were assessed. In silico analysis was assessed using loss-of-function tool (Lof Tool). Statistical difference and genetic comparisons between groups were evaluated by using SPSS for Windows, version 16.0 (SPSS Inc., Chicago, IL, USA). Comparisons between quantitative variables were carried out after data explored for normality using Kolmogorov–Smirnov test of normality. Logistic regression was used for computation of ORs and 95% CIs (Confidence Interval). We observed association of HbF levels in thalassemia major patients with the polymorphisms in BCL11A (rs11886868 rs7557939; rs1427407 and rs766432) and HBS1L-MYB (rs9399137) gene. The results of this study indicated that the presence of polymorphisms on modifier genes are strongly associated with an increase in HbF levels in thalassemia major patients. Further research with a larger sample size and with other genes of modifier genes is required. Full article

Luspatercept has been shown to act as a ligand trap, selectively suppressing the deleterious effects of GDF11 that blocks terminal erythroid maturation, restoring normal erythroid differentiation and improving anemia in animal models of β-thalassemia. Effective doses of luspatercept achieved hemoglobin increase within 7 days of the first dose, and plasma half-life supports subcutaneously administration every 21 days in adults with β-thalassemia. A Phase 3, placebo-controlled 1-year study with starting dose of 1.0 up to 1.25 mg/kg every 21 days achieved ≥33% reduction in red cell transfusion volume in 21.4% of adult transfusion-dependent β-, HbE/β-thalassemia patients on luspatercept vs. 4.5% on placebo over a fixed 12-week period, and 41.1% of patients in luspatercept vs. 2.7% placebo in any 24-week period. Luspatercept allowed ≥1.0 and ≥1.5 g/dL increase in hemoglobin from baseline in 77% and 52.1% of adult non-transfusion-dependent β-, HbE/β-thalassemia patients vs. 0% placebo over a 12-week interval. Although not significant, a greater improvement in patient-reported outcomes was observed with luspatercept. Luspatercept had a manageable safety profile with notable adverse effects of venous thromboembolism in 3.6% of transfusion-dependent β-thalassemia vs. 0.9% of placebo and extramedullary hematopoiesis in 6% of non-transfusion-dependent β-thalassemia vs. 2% of placebo. The pediatric study started patients’ enrollment. Full article

Next-generation ektacytometry provided by the osmoscan module of the Laser Optical Rotational Red Cell Analyser (LoRRca) MaxSis is, so far, one of the best complementary diagnostic tools for congenital rare anaemias due to red blood cell defects. Osmotic gradient ektacytometry (OGE) is currently considered the gold standard for the diagnosis of red cell membrane disorders, especially hereditary spherocytosis (HS). Impairment of red cell deformability, leading to a decrease in red cell survival rate, is the common trait of hereditary haemolytic anaemias; in general, it is the consequence of an abnormal cell shape, increased rigidity or dehydration. Up to now, the next-generation ektacytometry has been mainly used for the differential diagnosis of red blood cell membranopathies, but experience with structural hemoglobinopathies and thalassemia is still scarce. However, recently, many new forms of therapy are being developed for the treatment of hemoglobinopathies, particularly sickle-cell disease and β-thalassemia; clinical interest in ektacytometry is increasing and should be further explored. Here, we have evaluated the OGE profiles provided by the osmoscan module of the LoRRca ektacytometer in 96 patients with different hemoglobinopathies, both structural and thalassemia, with the aim of analysing their usefulness for the early diagnosis of these disorders either individually or in co-inheritance with other hereditary RBC defects. In addition, this study aims to improve our knowledge of the contribution of red cell deformability, osmotic fragility and intracellular viscosity to the physiopathology of haemolysis, especially when these disorders are a cause of rare anaemia. From this study, we conclude that the osmoscan profile provides complementary information on red cell deformability and hydration homeostasis that may contribute to the better understanding of the physiopathology of decreased red cell survival and hemolysis which is present in some patients. Full article

β-Thalassemia is an inherited hematological disorder that results from genetic changes in the β-globin gene, leading to the reduced or absent synthesis of β-globin. For several decades, the only curative treatment option for β-thalassemia has been allogeneic hematopoietic cell transplantation (allo-HCT). Nonetheless, rapid progress in genome modification technologies holds great potential for treating this disease and will soon change the current standard of care for β-thalassemia. For instance, the emergence of the CRISPR/Cas9 genome editing platform has opened the door for precision gene editing and can serve as an effective molecular treatment for a multitude of genetic diseases. Investigational studies were carried out to treat β-thalassemia patients utilizing CRISPR-based CTX001 therapy targeting the fetal hemoglobin silencer BCL11A to restore γ-globin expression in place of deficient β-globin. The results of recently carried out clinical trials provide hope of CTX001 being a promising one-time therapeutic option to treat β-hemoglobinopathies. This review provides an insight into the key scientific steps that led to the development and application of novel CRISPR/Cas9–based gene therapies as a promising therapeutic platform for transfusion-dependent β-thalassemia (TDT). Despite the resulting ethical, moral, and social challenges, CRISPR provides an excellent treatment option against hemoglobin-associated genetic diseases. Full article

Beta thalassemia is an inherited disorder resulting in abnormal or decreased production of hemoglobin, leading to hemolysis and chronic anemia. The long-term complications can affect multiple organ systems, namely the liver, heart, and endocrine. Myocardial iron overload is a common finding in β-thalassemia. As a result, different cardiovascular complications in the form of cardiomyopathy, pulmonary hypertension, arrhythmias, and vasculopathies can occur, and in extreme cases, sudden cardiac death. Each of these complications pertains to underlying etiologies and risk factors, which highlights the importance of early diagnosis and prevention. In this review, we will discuss different types of cardiovascular complications that can manifest in patients with β-thalassemia, in addition to the current diagnostic modalities, preventive and treatment modalities for these complications. Full article

Thalassaemia International Federation (TIF), representing the united voice of people with thalassaemia and their families globally, has been striving for more than three decades to empower research, by academic communities and industry, to focus on developing a safe and effective curative approach for thalassaemia. Such a cure would lead to new lives with equal opportunities and challenges, as for every other person not suffering from a severe chronic disease. A gene therapy product was finally authorised in May 2019 by the European Medicinal Agency, thus marking a milestone in the history of the disease. However, after this conditional authorization, everyone focused on numbers and opted for cost of illness and cost-effectiveness studies, inadmissibly ignoring patients’ voices and needs. The product was finally withdrawn from Europe, despite the fact that all implicated stakeholders, including governments, academia and industry always knew that an innovative and complex therapy would be expensive but always supported and fought for its development. In this article, TIF expresses its view on this issue, including some thoughts on how to address the high cost of innovative therapies. Full article

Background: Since the first year of the COVID-19 global pandemic, a hypothesis concerning the possible protection/immunity of beta-thalassemia carriers has remained in abeyance. Methods: Three databases (Pubmed Central, Scopus, and Google Scholar) were screened and checked in order to extract all studies about the incidence of confirmed COVID-19 cases, mortality rate, severity assessment, or ICU admission among patients with beta-thalassemia minor, were included in this analysis. The language was limited to English. Studies such as case reports, review studies, and studies that did not have complete data for calculating incidences were excluded. Results and discussion: a total of 3 studies out of 2265 were selected. According to our systematic-review meta-analysis, beta-thalassemia carriers could be less affected by COVID-19 than the general population [IRR = 0.9250 (0.5752; 1.4877)], affected by COVID-19 with a worst severity [OR = 1.5933 (0.4884; 5.1981)], less admissible into the ICU [IRR = 0.3620 (0.0025; 51.6821)], and more susceptible to die from COVID-19 or one of its consequences [IRR = 1.8542 (0.7819; 4.3970)]. However, all of those results remain insignificant with a bad p-value (respectively 0.7479, 0.4400, 0.6881, and 0.1610). Other large case-control or registry studies are needed to confirm these trends. Full article

Haemoglobin disorders are hereditary, lifelong and characterised by the need for multifaceted management. The question of quality in meeting standards of care that are likely to bring the best possible outcomes for patients is a necessary consideration. The concept of reference centres supporting peripheral treatment centres in a formal networking relationship is a response to the real needs of patients and a practical solution in public health terms. In this report, a team of advisors of Thalassaemia International Federation (TIF) attempts to suggest a set of standards for haemoglobinopathy reference centres, also based on the founding principles of TIF, aiming to act as a guideline for its member associations and professional collaborators. The standards described herein can form the basis of an accreditation process and also serve as a guide for those who would advocate for quality improvement for thalassaemia services. Full article

Transfusion-dependent thalassemia is the most severe form of thalassemia; patients require regular blood transfusions to maintain their hemoglobin level. The COVID-19 pandemic has disrupted the routine measures for controlling chronic diseases like thalassemia. This study aims to measure the difference in pre-transfusion hemoglobin levels and the frequency of transfusions before and during pandemic. This retrospective cross-sectional study utilized medical record data of 101 transfusion-dependent thalassemia (TDT) patients treated in Cipto Mangunkusumo Hospital (CMH) from 2019–2021. The dependent variables of this study were pre-transfusion hemoglobin level and transfusion attendance. The pre-pandemic phase was defined as 30 March 2019 to 29 March 2020, whereas the during-pandemic phase was from 30 March 2020 to 29 March 2021. Up to 59.4% of subjects had suboptimal Hb levels of <9.0 g/dL, even before the pandemic, and this increased to 71.3% during the pandemic. The mean pre-transfusion hemoglobin level before the pandemic was 8.71 g/dL, and this decreased to 8.46 g/dL (p value < 0.001). Transfusion attendance before and during the pandemic showed no significant difference (p-value = 0.990). Our study shows poorer control of pre-transfusion Hb levels during the pandemic. This puts patients at higher risk of developing many long-term complications. Full article