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Dordevic A, Mrakovcic-Sutic I, Pavlovic S, Ugrin M, Roganovic J. Beta thalassemia syndromes: New insights. World J Clin Cases 2025; 13:100223. [PMID: 40191679 PMCID: PMC11670029 DOI: 10.12998/wjcc.v13.i10.100223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 11/06/2024] [Accepted: 12/02/2024] [Indexed: 12/19/2024] Open
Abstract
Beta thalassemia (β-thalassemia) syndromes are a heterogeneous group of inherited hemoglobinopathies caused by molecular defects in the beta-globin gene that lead to the impaired synthesis of beta-globin chains of the hemoglobin. The hallmarks of the disease include ineffective erythropoiesis, chronic hemolytic anemia, and iron overload. Clinical presentation ranges from asymptomatic carriers to severe anemia requiring lifelong blood transfusions with subsequent devastating complications. The management of patients with severe β-thalassemia represents a global health problem, particularly in low-income countries. Until recently, management strategies were limited to regular transfusions and iron chelation therapy, with allogeneic hematopoietic stem cell transplantation available only for a subset of patients. Better understanding of the underlying pathophysiological mechanisms of β-thalassemia syndromes and associated clinical phenotypes has paved the way for novel therapeutic options, including pharmacologic enhancers of effective erythropoiesis and gene therapy.
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Affiliation(s)
- Ana Dordevic
- Department of Business Development, Jadran Galenski Laboratorij, Rijeka 51000, Croatia
| | | | - Sonja Pavlovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11000, Serbia
| | - Milena Ugrin
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11000, Serbia
| | - Jelena Roganovic
- Department of Pediatric Hematology and Oncology, Children’s Hospital Zagreb, Zagreb 10000, Croatia
- Faculty of Biotechnology and Drug Development, University of Rijeka, Rijeka 51000, Croatia
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Malay J, Salama RAA, Alam Qureshi GS, Ammar ARAA, Janardhan G, Safdar M, Elshamy HAH. Gene Therapy: A Revolutionary Step in Treating Thalassemia. Hematol Rep 2024; 16:656-668. [PMID: 39449307 PMCID: PMC11503351 DOI: 10.3390/hematolrep16040064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 09/27/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
Beta thalassemia is an inherited blood disorder that results in inefficient erythropoiesis due to genetic mutation that leads to the reduction or absence of the hemoglobin beta-globulin protein. Approximately 8.5% of UAE residents suffer from β-thalassemia, a significant health and financial problem. The treatment options available for β-Thalassemia major are limited and associated with a wide range of complications. β-thalassemia gene therapy is emerging as a potential novel treatment option that eliminates the complications caused by the current long-term treatment modalities and the associated economic burden. This paper reviews the scientific literature related to emerging gene therapy for β-Thalassemia by analyzing all the articles published from January 2010 to December 2023 in the English language on Databases like PubMed, Scopus, ProQuest, and CINAHL. The use of gene therapy has demonstrated promising outcomes for a permanent cure of β-Thalassemia. To conclude, gene therapy is an innovative solution. It demonstrates a promising future, but does come with its own setbacks and is something that must be tackled in order to revolutionize it in the medical world. FDA-approved ZYNTEGLO is a potentially one-time curative treatment for β-Thalassemia. Although cutting-edge, its use is limited because of the high cost-a price of USD 2.8 million per patient.
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Affiliation(s)
- Jhancy Malay
- Department of Pediatrics, RAK Medical and Health Sciences University, Ras Al Khaimah 11127, United Arab Emirates
| | - Rasha Aziz Attia Salama
- Department of Community Medicine, RAK Medical and Health Science University, Ras Al Khaimah 11127, United Arab Emirates;
| | - Ghania Shehzad Alam Qureshi
- RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah 11127, United Arab Emirates; (G.S.A.Q.); (A.R.); (G.J.); (M.S.)
| | - Ali Raafat Ali Ahmed Ammar
- RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah 11127, United Arab Emirates; (G.S.A.Q.); (A.R.); (G.J.); (M.S.)
| | - Gayatri Janardhan
- RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah 11127, United Arab Emirates; (G.S.A.Q.); (A.R.); (G.J.); (M.S.)
| | - Maryam Safdar
- RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah 11127, United Arab Emirates; (G.S.A.Q.); (A.R.); (G.J.); (M.S.)
| | - Hesham Amin Hamdy Elshamy
- Department of Surgery, RAK Medical and Health Sciences University, Ras Al Khaimah 11127, United Arab Emirates;
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Shash H. Non-Transfusion-Dependent Thalassemia: A Panoramic Review. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58101496. [PMID: 36295656 PMCID: PMC9608723 DOI: 10.3390/medicina58101496] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 10/08/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022]
Abstract
Non-transfusion-dependent thalassemia (NTDT) has been considered less severe than its transfusion-dependent variants. The most common forms of NTDT include β-thalassemia intermedia, hemoglobin E/beta thalassemia, and hemoglobin H disease. Patients with NTDT develop several clinical complications, despite their regular transfusion independence. Ineffective erythropoiesis, iron overload, and hypercoagulability are pathophysiological factors that lead to morbidities in these patients. Therefore, an early and accurate diagnosis of NTDT is essential to ascertaining early interventions. Currently, several conventional management options are available, with guidelines suggested by the Thalassemia International Federation, and novel therapies are being developed in light of the advancement of the understanding of this disease. This review aimed to increase clinicians’ awareness of NTDT, from its basic medical definition and genetics to its pathophysiology. Specific complications to NTDT were reviewed, along with the risk factors for its development. The indications of different therapeutic options were outlined, and recent advancements were reviewed.
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Affiliation(s)
- Hwazen Shash
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia;
- Department of Pediatrics, King Fahad Hospital of the University, Al-Khobar 31952, Saudi Arabia
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Isa Tafreshi R, Radgoodarzi M, Arjmandi Rafsanjani K, Soheilipour F. Subclinical Left Ventricular Dysfunction in Children and Adolescence With Thalassemia Intermedia. Front Pediatr 2022; 10:774528. [PMID: 35783313 PMCID: PMC9249082 DOI: 10.3389/fped.2022.774528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 05/24/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Cardiac complications are important causes of morbidity in patients with thalassemia intermedia (TI). We aimed to assess left ventricular (LV) function, using new tissue Doppler imaging (TDI) indices, in order to diagnose early ventricular impairment in asymptomatic children and adolescence with the TI. MATERIALS AND METHODS We investigated possible differences in echocardiographic systolic and diastolic parameters between a population of 28 asymptomatic patients (mean age, 13.6 ± 5.7 years) and 35 age-matched healthy control members. All of them underwent 2-D, pulsed Doppler, and tissue Doppler echocardiographic studies for the assessment of the LV mass, Trans-mitral velocities, mitral annular systolic and diastolic velocities, myocardial performance index (MPI), and myocardial acceleration during isovolumic contraction (IVA). The cardiac iron load was estimated by magnetic resonance imaging T2*. RESULTS Left ventricular hypertrophy (LVH) was found in 13 (46.4%) patients. We found significantly reduced TDI-derived peak systolic myocardial velocity (s') in patients, whereas no significant difference was identified between the patients and control group members when the IVA was compared. The ratio of peak mitral inflow velocity to annular early diastolic velocity (E/e') of the mitral valve as an index of the diastolic function was significantly higher in patients (9 ± 1 vs. 6 ± 1, p < 0.05). Choosing a TDI-derived MPI > 0.33 as a cutoff point, the global LV dysfunction was detected with a sensitivity of 78% and a specificity of 80%. The patients with LVH significantly exhibited higher values of TDI-MPI and lower values of s' velocity and IVA when compared against the subjects with normal LV mass. CONCLUSION Subtle LV systolic and diastolic dysfunction develops early in young patients with the TI who have normal cardiac iron concentration. Moreover, LV remodeling as a main cardiac adaptive response plays a principal role in developing myocardial impairment.
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Affiliation(s)
- Roya Isa Tafreshi
- Department of Pediatric Cardiology, Ali Asghar Children's Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Radgoodarzi
- Department of Pediatrics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Kadijeh Arjmandi Rafsanjani
- Department of Pediatric Hematology and Oncology, Ali Asghar Children's Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Soheilipour
- Department of Pediatric Endocrinology, Minimally Invasive Surgery Research Center, Aliasghar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Hamed EM, Meabed MH, Aly UF, Hussein RRS. Recent Progress in Gene Therapy and Other Targeted Therapeutic Approaches for Beta Thalassemia. Curr Drug Targets 2020; 20:1603-1623. [PMID: 31362654 DOI: 10.2174/1389450120666190726155733] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 06/17/2019] [Accepted: 07/05/2019] [Indexed: 01/19/2023]
Abstract
Beta-thalassemia is a genetic disorder characterized by the impaired synthesis of the betaglobin chain of adult hemoglobin. The disorder has a complex pathophysiology that affects multiple organ systems. The main complications of beta thalassemia are ineffective erythropoiesis, chronic hemolytic anemia and hemosiderosis-induced organ dysfunction. Regular blood transfusions are the main therapy for beta thalassemia major; however, this treatment can cause cardiac and hepatic hemosiderosis - the most common cause of death in these patients. This review focuses on unique future therapeutic interventions for thalassemia that reverse splenomegaly, reduce transfusion frequency, decrease iron toxicity in organs, and correct chronic anemia. The targeted effective protocols include hemoglobin fetal inducers, ineffective erythropoiesis correctors, antioxidants, vitamins, and natural products. Resveratrol is a new herbal therapeutic approach which serves as fetal Hb inducer in beta thalassemia. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for beta thalassemia major and is preferred over iron chelation and blood transfusion for ensuring long life in these patients. Meanwhile, several molecular therapies, such as ActRIIB/IgG1 Fc recombinant protein, have emerged to address complications of beta thalassemia or the adverse effects of current drugs. Regarding gene correction strategies, a phase III trial called HGB-207 (Northstar-2; NCT02906202) is evaluating the efficacy and safety of autologous cell transplantation with LentiGlobin. Advanced gene-editing approaches aim to cut DNA at a targeted site and convert HbF to HbA during infancy, such as the suppression of BCL11A (B cell lymphoma 11A), HPFH (hereditary persistence of fetal hemoglobin) and zinc-finger nucleases. Gene therapy is progressing rapidly, with multiple clinical trials being conducted in many countries and the promise of commercial products to be available in the near future.
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Affiliation(s)
- Eman M Hamed
- Department of Pharmaceutics and Clinical Pharmacy; Faculty of Pharmacy; Nahda University, Nahda, Egypt
| | | | - Usama Farghaly Aly
- Asso. Professor of Pharmaceutics; Faculty of Pharmacy; Minia University, Minya, Egypt
| | - Raghda R S Hussein
- Lecturer of Clinical Pharmacy; Faculty of Pharmacy; Beni- Suef University, Egypt
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Faraon R, Daraghmah M, Samarah F, Srour MA. Molecular characterization of β-thalassemia intermedia in the West Bank, Palestine. BMC HEMATOLOGY 2019; 19:4. [PMID: 30820323 PMCID: PMC6380065 DOI: 10.1186/s12878-019-0135-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 02/07/2019] [Indexed: 12/23/2022]
Abstract
BACKGROUND We aimed to investigate the molecular basis of β-Thalassemia intermedia (TI) in the West Bank region and its management practices. METHODS This was a case series multi-center study and included 51 cases of TI. DNA sequencing was used to analyze β-globin gene mutations. Common α-globin gene mutations were screened by Gap-PCR (-α3.7, -α4.2, --MED, αααanti3.7) or DNA sequencing (α2-IVS II 5 nt del). XmnI -158 C > T polymorphisms of Gγ-globin gene was determined by RFLP-PCR. RESULTS Seven β-globin gene mutations were observed, namely IVS-I -6 C > T, IVS-I-110 G > A, IVS-II-1 G > A, IVS-I-1 G > A, Codon 37 Trp > Stop, beta - 101 and IVS-II-848 C > A. Ten genotypes were observed. Homozygosity for IVS-I-6 accounted for the majority of TI cases with a frequency of 74.5%. The second common β-globin gene genotype was homozygote IVS-I-110 G > A (5.8%) and homozygote IVS-II-1 G > A (5.8%). The remaining seven genotypes were each detected in about 2% of patients. α-Thalassemia mutations were seen in five patients (9.8%), and included (-α3.7, αααanti3.7 and α2-IVSII-5 nt del). XmnI polymorphism was observed in four patients (7.8%), three homozygotes and one heterozygote. CONCLUSIONS Homozygosity for the mild β-globin gene IVS-I-6 allele was the major contributing factor for the TI phenotype among the study subjects. The role of XmnI SNP and α-thalassemia mutations in ameliorating the TI phenotype was observed in few patients for each factor. The beta - 101 C > T mutation was diagnosed in one patient in homozygote state for the first time in Palestine.
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Affiliation(s)
- Rashail Faraon
- Department of Medical Laboratory Sciences, Al-Quds University, East Jerusalem, Palestine
| | - Mahmoud Daraghmah
- Palestine Thalassemia Patients’ Friends Society, Al-Bireh, Palestine
| | - Fekri Samarah
- Department of Medical Laboratory Sciences, Arab-American University, Jenin, Palestine
| | - Mahmoud A. Srour
- Department of Medical Laboratory Sciences, Al-Quds University, East Jerusalem, Palestine
- Department of Biology & Biochemistry, Birzeit University, P.O. Box 14, Birzeit, Palestine
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Efficacy of Oral Acetaminophen and Intravenous Chlorpheniramine Maleate versus Placebo to Prevent Red Cell Transfusion Reactions in Children and Adolescent with Thalassemia: A Prospective, Randomized, Double-Blind Controlled Trial. Anemia 2018; 2018:9492303. [PMID: 30364108 PMCID: PMC6188761 DOI: 10.1155/2018/9492303] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 09/16/2018] [Indexed: 01/25/2023] Open
Abstract
Background Thalassemia is a common congenital hemolytic disorder. In severe cases, regular blood transfusion is essentially required. The role of premedications to prevent transfusion reactions is varied among institutions with no standard guideline. Objective To prospectively compare the risk of transfusion reactions in thalassemia patients premedicated with acetaminophen and chlorpheniramine maleate (CPM) versus placebo prior to blood transfusion. Material and Method A randomized, double-blinded, placebo-controlled transfusion reaction study of 147 eligible patients was analyzed. All administered red blood cell (RBC) products were leukoreduced blood products. Patients were monitored and followed for the development of transfusion reactions for 24 hours after RBC transfusion. Results A total of 73 patients randomized to receive active drugs consisting of acetaminophen and CPM were compared to 74 patients receiving placebo. The overall incidences of febrile reaction and urticarial rash were 6.9% and 22% in the patients randomized to receive active drugs comparing with 9.5% and 35.2% in the patients receiving placebo with no significant differences between two groups. However, delayed development of urticarial rash at 4-24 hours after RBC transfusion was significantly higher in female and patients receiving placebo. Conclusion Administration of premedications in thalassemia patients receiving RBC transfusion without a history of transfusion reactions does not decrease the overall risk of transfusion reactions. However, the use of CPM might be beneficial to prevent delayed urticarial rash in those patients especially in females (Thai Clinical Trial Registry (TCTR) study ID: 20140526001).
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