Β-thalassemia Major Patient Research Articles

Mandibular analysis of Beta thalassemia patients from hematological institutes of Karachi Pakistan.

Objective: To study the mandibular changes in the β-thalassemia major patient. Study Design: Cross sectional study. Setting: Husaini Blood Bank and Institute of Hematological Diseases Karachi, Department of Oral and Maxillofacial Surgery, and Department of Orthodontics, Baqai Dental College Baqai Medical University, Karachi. Period: January 2023-December 2023. Methods: 50 Orthopanthogram (OPG) radiographs of beta-thalassemia major patient were taken, analyzed and compared to check any variation from normal. Fifty diagnosed β-thalassemia major patients were voluntarily selected through convenience sampling. The study was carried out in collaboration of Husaini Institute of Blood Diseases Karachi, National institute of Oral Diseases Karachi Pakistan and, Department of Oral and Maxillofacial Surgery and department of orthodontics Baqai Dental College Baqai Medical University. Results: 18 (36%) patient’s alteration of trabecular pattern are present and in 32 (64%) patient alteration of trabecular pattern absent. Similarly, in 16 (32%) patients have short spiky roots are present and 34 (68%) patients short spiky roots absent. Conclusion: Effect of anemia is not so profound in mandible of thalassemia patients from population of Karachi.

Direct sequencing of β-globin gene reveals a rare combination of two exonic and two intronic variants in a β-thalassemia major patient: a case report

BackgroundDue to indels in the β-globin gene, patients with β-thalassemia major exhibit a range of severity, with genotype β0β0 > β0β+ > β+β+, according to the production level of the β-globin chain. More than 300 mutations have been identified in the β-globin gene.Case presentationIn this case study, we report a compound heterozygous condition with a rare concoction of four different variants (CD 3(T > C), CD41/42 (-CTTT), IVS II-16 (G > C), and IVS II-666 (C > T) in a single β-globin gene. A regular transfusion-dependent 4-year-old male patient from India was included in the study. Augmented direct sequencing of the β-globin gene helped reveal the presence of an unusual combination of different variants in a single gene. This patient clinically presented as β-thalassemia major and was genotypically considered as β0β+, although CD41/42(-CTTT) was the only causative/pathogenic mutation in the disease severity.ConclusionAlthough CD41/42-(CTTT) is the only pathogenic variant among the four variants, the clinical complications of such a combination of variants (pathogenic and benign) is not well understood. Intronic mutations may have the ability to modify clinical characteristics. The variants must therefore be reclassified using additional mRNA splicing and expression-based studies. Additionally, these types of combinations may have significance in studying population migration around the world.

PATTERN DYSTROPHY-LIKE CHANGES ASSOCIATED WITH A VERY HIGH SERUM FERRITIN LEVEL IN β-THALASSEMIA MAJOR

To report a rare case of pattern dystrophy-like retinal changes in a young β-thalassemia major patient with a very high serum ferritin level. Observational case report of a β-thalassemia major patient with bilateral pattern dystrophy-like retinal changes. An 18-year-old man experienced blurring of vision in both eyes. Patient had a very high serum ferritin level and had a history of using various iron-chelating drugs. Funduscopy revealed bilateral widespread retinal pigment epithelium changes with macular involvement, which resembled pattern dystrophy-like changes. Fundus autofluorescence imaging showed extensive area of decreased autofluorescence signal interspersed with increased autofluorescence signals, whereas optical coherence tomography demonstrated macular retinal pigment epithelium thinning and interdigitation zone disruption corresponding to retinal pigment epithelium damage and atrophy. Pattern dystrophy-like changes should be considered as a possible manifestation of retinal changes in patients with β-thalassemia major. Iron overload, which is indicated by a very high serum ferritin level, might have a role in the formation of this rare retinal manifestation in β-thalassemia major.

Extramedullary hematopoiesis in β-thalassemia major patient: a case report and review of the literature

Extramedullary hematopoiesis in β-thalassemia major patient: a case report and review of the literature

Drug utilization study and cost analysis of adult β-thalassemia major patient therapy at Dr. Soetomo General Hospital Surabaya.

The main therapy of β-thalassemia major are blood transfusion and iron chelation drugs. However, those therapies also have some adverse effects and problems such as iron overload, transfusion reactions, nutritional deficiencies, and patient compliance problems. Those arising problems also have an impact on therapy cost. Hence, this study was designed to analyze drug utilization study and cost of therapy in β-thalassemia major adult patients at Dr. Soetomo General Hospital Surabaya. This research was conducted in descriptive observational-retrospective design using secondary data obtained from patient's medical records and billing registrations from January 1-December 31, 2019. There were 18 patients out of 233 patients that were analyzed. Deferasirox was the most administered drug with doses between 500mg/day-1,500mg/day while deferiprone was ranged between 1,500 and 4,500mg/day. Patients also received transfusion reaction drugs with dexamethasone injection 5mg/ml which was administered the most. The most administered supplement was folic acid 1mg. Patients had an increase in serum ferritin due to low compliance. Deferasirox had the most adherence number of patients with decrease of serum ferritin. The two highest costs of direct medical components were top-up medicines and consumable medical supplies. Overall, the hospital gained profit from national health insurance claims. The most administered chelating agent was deferasirox. Deferasirox also had the most adherence number of patients with decreased number of serum ferritin. However, deferasirox also yielded the highest cost. Yet, overall, the hospital gained profit from national health insurance claims.

Fanconi syndrome secondary to deferasirox with severe and prolonged urinary potassium loss in a β-thalassemia major patient

Fanconi syndrome secondary to deferasirox with severe and prolonged urinary potassium loss in a β-thalassemia major patient

Hb Midnapore [β53(D4)Ala→Val; HBB: c.161C>T]: A Novel Hemoglobin Variant with a Structural Abnormality Associated with IVS-I-5 (G>C) (HBB: c.92+5G>C) Found in a Bengali Indian Family

We describe a novel C>T substitution at codon 53 of the HBB gene (HBB: c.161C>T). The proband was a transfusion-dependent β-thalassemia major (β-TM) patient. DNA was extracted and subsequently, DNA sequencing was done to detect the mutations on the HBB gene. Capillary zone electrophoresis (CZE) revealed the presence of an unknown peak. She inherited this mutation from her grandmother through her mother. This mutation exists in cis with the common β0 mutation IVS-I-5 (G>C) (HBB: c.92+5G>C). The proband is homozygous for HBB: c.92+5G>C and needs monthly transfusions. On the other hand, her grandmother, mother and sister all possess this novel mutation cis with the heterozygous HBB: c.92+5G>C. They are carriers not thalassemic. This mutation produces the substitution β53(D4)Ala→Val; HBB: c.161C>T, a new structural hemoglobin (Hb) variant. As this variant was identified in a Bengali family from Paschim Midnapore district of West Bengal, India, it has been designated as Hb Midnapore. This variant has now been reported to the HbVar database.

2,3,7,8-tetrachlorodibenzo-p-dioxin decrease expression of aryl hydrocarbon receptor in peripheral lymphocyte of β-thalassemia major patients.

Background:β-thalassemia major is a hereditary disease with inefficient erythropoiesis. Level of inflammatory cytokine is elevated in these patients. In this study, we investigate the effect of aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), on the expression of inflammatory mediators in β-thalassemia major patient's lymphocytes.Materials and Methods:Peripheral blood mononuclear cells of patients and healthy participants was isolated and cultured in favor of lymphocytes increment. Based on the treatment, we divided the cell into four groups. The orders of group's treatments were no treatment, tumor necrosis factor-α (TNF-α) treatment, TNF-α and TCDD treatment, TCDD treatment in Group 1–4, respectively. After cell culture, we extracted the cells RNA and converted them to cDNA. Real-time polymerase chain reaction was performed to assessment relative expression of caspase-1, NLRP3, and AhR. We compared all patient groups with equal healthy (control) groups.Results:Results showed that expression of caspase-1 in patients (Groups 1 and 2) was significantly lower than healthy individuals (P < 0.05). Although, no significant difference was found (Groups 1, 2, and control) in AhR gene expression (P > 0.05). Expression of AhR in other groups of patients (3 and 4) was significantly lower than control groups (P < 0.05). Expression of caspase-1 in Group 4 was significantly larger than the control group (P < 0.001).Conclusions:We show here that chronic inflammation decrease caspase-1 expression and exposure of human lymphocytes to TCDD promote caspase-1 expression. Furthermore, activation of AhR with TCDD decreases AhR expression in lymphocytes of β-thalassemia major disease.

Antibody screening in multitransfused patients: A prerequisite before each transfusion

Life-long red blood cell (RBC) transfusions remain the main treatment for severe thalassemia. We hereby report a case of anti S and anti Lua in a β-thalassemia major patient detected incidentally on antibody screening. The patient was a known case of β-thalassemia major and was on regular blood transfusion every 3 weeks from the institute from the age of 6 months. Subsequently, on one occasion, patient's crossmatch was compatible despite positive antibody screen using microcolumn gel technique. Autocontrol and direct antiglobulin test were negative on microcolumn gel. Anti S and anti Lua antibodies were identified. Blood unit found compatible was negative for S and Lua antigens. Antibody titers were 1:1 for both anti S and anti Lua in AHG phase using tube technique and antibodies were of IgG type. Blood unit was transfused uneventfully to the patient. Donors were traced back (last three donations) and called for repeat blood sample testing for S and Lua antigen. Two out of three donors were found to be S antigen positive and one out of these two was Lua antigen positive. Anti S and anti Lua antibodies were again identified on patient's subsequent visit for transfusion. The present case re-emphasize the importance of antibody screening at each visit in earlier detection of antibodies in multi transfused patients. Encouraging patients to receive transfusion from one center and dedicating donors could reduce alloimmunization rate but larger studies are required.

A Phase 2a, Open-Label, Dose-Finding Study To Determine The Safety and Tolerability Of Sotatercept (ACE-011) In Adults With Beta (β)-Thalassemia: Interim Results

BackgroundBeta (β)-thalassemia is characterized by ineffective erythropoiesis leading to anemia, bone marrow erythroid hyperplasia, iron overload, and organ failure. Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor (ActRIIA) fusion protein that increases the release of mature erythrocytes into circulation by acting mainly on late-stage erythropoiesis (Carrancio S, et al. Blood. 2012;120:abstract 372). Clinical data in healthy volunteers have shown that treatment with sotatercept results in increased red blood cell (RBC) parameters, including hemoglobin level (Ruckle J, et al. J Bone Miner Res. 2009;24:744-52). RAP-011, a murine ortholog of sotatercept, was efficacious in a mouse model of β-thalassemia intermedia, reducing ineffective erythropoiesis as well as significantly improving anemia and decreasing bilirubin levels, supporting the clinical development of sotatercept (Dussiot M et al. Blood 2012;120:abstract 247). MethodsThis is an ongoing phase 2a, multicenter, open-label, dose-finding study to determine a safe and active dose level of sotatercept in adult patients with RBC-transfusion dependent (TD) β-thalassemia major or patients with β-thalassemia intermedia who are either TD or non-transfusion dependent (NTD). The dose levels of sotatercept studied to date are 0.1, 0.3, and 0.5 mg/kg, given subcutaneously once every 3 weeks. Safety is assessed according to NCI-CTC grading. Efficacy is assessed by hemoglobin increase from baseline and/or reduction in transfusion burden. Secondary endpoints include assessment of biomarkers for erythropoiesis, hemolysis, iron metabolism, and bone metabolism, as well as in vitro dyserythropoiesis. Dose escalation to higher dose levels is planned contingent on data review and favorable safety profile as determined by the Steering Committee. ResultsPatient demographics. A total of 25 patients have been enrolled as of July 26, 2013; 8 in the 0.1 mg/kg cohort, 9 in the 0.3 mg/kg cohort, and 8 in the 0.5 mg/kg cohort. Treatment and analysis for the 0.5 mg/kg cohort is underway and will be updated and presented. In the 0.1 and 0.3 mg/kg cohorts, 3 (18%) patients had β-thalassemia major and 14 (82%) had β-thalassemia intermedia (12 of whom were NTD and 2 of whom were TD). Of the 12 NTD β-thalassemia intermedia patients, 6 were treated at the 0.1 mg/kg dose level and 6 at the 0.3 mg/kg dose level. Median baseline hemoglobin for these NTD patients was 8.6 g/dL (range 5.8 to 10.7 g/dL). Median number of sotatercept doses administered was 4 (range 2 to 7) in the 0.1 mg/kg cohort and 8 (range 3 to 9) in the 0.3 mg/kg cohort; 13/17 (76%) patients remained on treatment.Safety.Sotatercept was generally well tolerated. There were no dose-limiting toxicities reported. Two serious adverse events were reported in the 0.1 mg/kg cohort: a grade 2 phlebitis in an NTD patient with a history of high D-dimer at baseline, and a worsening grade 3 bone pain in a TD β-thalassemia major patient with a history of osteoporosis; both were considered possibly study drug-related.Hemoglobin levels/transfusion requirements. Among NTD patients, preliminary data showed that 1 (17%) patient in the 0.1 mg/kg cohort and all 6 (100%) patients in the 0.3 mg/kg cohort had at least a 1 g/dL increase in hemoglobin level from baseline; among these, 1 patient treated with sotatercept 0.3 mg/kg showed a 2 g/dL hemoglobin level increase from baseline as well as a decrease in total bilirubin level from 2.7 × upper limit of normal (ULN) at baseline to 1.8 × ULN. No other relevant decrease in total bilirubin level was reported at the lower dose levels (0.1 mg/kg or 0.3 mg/kg).Three TD patients were still receiving treatment (2 β-thalassemia intermedia and 1 β-thalassemia major). There had been no appreciable reduction in transfusion burden in the 0.1 and 0.3 mg/kg cohorts to date; however further follow up is warranted and an update will be presented. ConclusionBased on these preliminary data, sotatercept administered subcutaneously every 3 weeks may improve anemia via a novel mechanism of action with a favorable safety profile, thereby addressing a significant unmet medical need for patients with NTD β-thalassemia intermedia. The current data suggest a dose-dependent response that supports further evaluation of the exposure–effect relationship of sotatercept in patients with NTD β-thalassemia intermedia.The first, second, and last authors contributed equally to this abstract. Disclosures:Cappellini:Genzyme: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Off Label Use: Sotatercept is an investigational agent that is being assessed for efficacy and safety in beta-thalassemia. Porter:Novartis: Consultancy, Research Funding; Shire: Consultancy; Celgene: Honoraria. Forni:Celgene: Research Funding; Shire: Research Funding; Novartis Pharma: Research Funding. Laadem:Celgene Corp.: Employment, Equity Ownership. Galacteros:Celgene: Consultancy. Miteva:Celgene Corp.: Employment. Sung:Celgene Corp.: Employment, Equity Ownership. Chopra:Celgene Corp.: Employment, Equity Ownership. Klesczewski:Celgene Corp.: Employment. Attie:Acceleron Pharma: Employment. Hermine:Celgene Corporation: Consultancy, Research Funding.

A rare case of Moyamoya syndrome in a β-thalassemia major patient

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THE ROLE OF Treg CELLS AND FoxP3 EXPRESSION IN IMMUNITY OF β-THALASSEMIA MAJOR AND β-THALASSEMIA TRAIT PATIENTS

There is increased susceptibility to infections in β-thalassemia. Changes in T- and B-lymphocyte subsets and functions, defective chemotaxis, and phagocytosis of neutrophils and macrophages have been described in these patients. Regulatory T cells (Treg cells) play a crucial role in the maintenance of immunological self-tolerance. The FOXP3 gene is specifically expressed on Treg cells. Increased antigenic stimuli due to repeated blood transfusions might change the Treg cells and FOXP3 percentage in β-thalassemia. Immune functions of peripheral blood lymphocytes, percentage of Treg cells (defined as CD4+CD25+FoxP3 +) were evaluated in 30 β-thalassemia major, 30 β-thalassemia trait, and 20 healthy children. Percentage of CD4 +CD45RA + cells were increased in β-thalassemia trait compared to both β-thalassemia major and controls, whereas percentage of CD4 +CD45RO+ cells were higher in β-thalassemia major and trait patient compared to controls. Percentages of CD4+CD25bright and CD4+CD25+FoxP3+ Treg cells were increased only in β-thalassemia major patients compared to controls (P = .001 and P = .0001, respectively). T lymphocytes express activated phenotype both in β-thalassemia major and trait patients. However, only in β-thalassemia major patients who were exposed to chronic antigenic stimulus as a result of repeated blood transfusions was an increase observed in Treg cells, which might suppress immune activation status.

Hepcidin mutation in a β-thalassemia major patient with persistent severe iron overload despite chelation therapy

Hepcidin, a 25 amino acid peptide expressed in the liver, has been shown to have a major role in iron homeostasis controlling iron release from reticuloendothelial and intestinal epithelial cells. Human hepcidin is encoded as a prohormone called pre-prohepcidin (84 amino acid) containing a consensus furin cleavage site preceding the C-terminal 25 amino acid bioactive peptide. It is induced by inflammation and iron and decreased by hypoxia and anemia [1]. b-Thalassemia major (TM) is a hereditary hemolytic anemia resulting from the reduction or complete absence of b-globin chain synthesis. Patients with TM and other refractory anemias receiving regular blood transfusions become iron overloaded at the rate of approximately 0.3– 0.5 mg/kg body weight per day. Indeed, iron overload results from transfusional iron and increased intestinal absorption due to inefficient erythropoiesis. Hepcidin mRNA expression was found to be decreased in the liver of C57Bl/6 Hbb (a murine model of thalassemia major) and in patients with thalassemia major urinary hepcidin was disproportionately suppressed in regard to iron burden [2]. In thalassemia major, low hepcidin levels result in increased iron absorption and greater release of stored iron into the circulation and contribute to iron accumulation in liver, endocrine glands and heart. Iron chelator deferoxamine (DFO) reduces iron burden in TM, but limitations of its infusion have stimulated the design of oral chelators which result in better compliance. Thus, almost all TM patients achieve an acceptable iron status. We report a TM case in which mutations in hepcidin could have interfered with distribution and removal of body iron by chelators. The patient was a 23-year-old woman, homozygous for b39 thalassemia major, regularly transfused since 1 year of age, receiving an average of 4 units of packed red cells monthly (corresponding to 7.5 g/year of iron) and chelated by subcutaneous infusion of DFO (40 mg/kg day, 6 days/ week) since early infancy. In her record, a persistent high iron burden was documented despite chelation treatment. The patient developed hypothyroidism and hypogonadotropic hypogonadism and was on hormonal replacement therapy. The echocardiography evaluation showed a slight cardiac left ventricular hypertrophy and an ejection fraction of 66%. Liver iron concentration was estimated at 20 years by Superconducting Quantum Interference Device biomagnetic liver susceptometry method (SQUID-BLS). Despite chelation treatment, the iron concentration evidenced by SQUID was at very high levels (5,230 lg/g liver dw). At the time of the study, non-transferrin-bound iron (NTBI), detected by high-performance liquid chromatography (HPLC) [3], was 3.66 lM (normal value -0.70 ± 0.50); serum ferritin levels and transferrin saturation, measured by standards method, were 4,323 ng/mL and 110%, respectively (normal values 150 ± 100, 35 ± 15). Genomic DNA was isolated from leukocytes by standard method. Exons 1–3 of hepcidin gene were amplified with different pairs of primers: the first pair amplified exon 1, including the promoter and 50-UTR region, the second L. Duca P. Delbini I. Nava M. D. Cappellini Department of Internal Medicine, Maggiore Policlinico, Mangiagalli and Regina Elena Foundation IRCCS, University of Milan, Milan, Italy

Phenotypic cure 6 years after bone marrow transplantation in a β‐thalassemia patient

A β-thalassemia major (TM) male patient underwent bone marrow transplantation from a fully matched carrier sister at age three. He continued to be transfusion dependent although chimerism evaluation, using analysis of the β-globin gene mutation, showed 90-98% donor cells in peripheral leukocytes after 3 months and 82-90% donor cells in the bone marrow after 26 and 30 months. Clinical improvement occurred gradually, and the patient became transfusion free 6 years posttransplant. We reason that an exceptional slow displacement of host red-blood-cell lineage took place that was not evident from the high level of chimerism found in peripheral leukocytes and bone marrow.

An emergency diagnostic dilemma: a case of Yersinia enterocolitica colitis mimicking acute appendicitis in a β-thalassemia major patient: the role of CT and literature review

The role of computed tomography (CT) scanning in a case of Yersinia enterocolitica (YE) enteritis mimicking acute appendicitis in a 34-year-old female patient with beta-thalassemia major is presented. Although the abdominal CT findings on admittance were indicative of acute appendicitis (enlargement of the appendix and thickening of its wall), making appendectomy a likely treatment option, a second CT scan 3 days later was diagnostic for infectious colitis (bowel wall thickening, ulcerations of the colonic mucosa, and fat stranding), and an unnecessary appendectomy was thus avoided. The diagnosis of YE colitis was later confirmed by serology tests.

A rare mutation [IVS-I-130 (G-A)] in a Turkish β-thalassemia major patient

Here we describe the identification of the rare β-thalassemia mutation IVS-I-130 (G-A) for the first time in Turkey. The hematological evaluation of the patient showed classical signs of β-thalassemia major requiring regular blood transfusions every 30–35 days. DNA analysis was carried out using reverse dot-blot hybridization and restriction endonuclease digestion, as well as genomic sequencing. The patient was found to be heterozygous for the IVS-I-6 (T-C) and IVS-I-130 (G-A) mutations. In order to deduce a possible origin for the IVS-I-130 (G-A) mutation, the sequence polymorphisms in the DNA of the patient and her family were characterized. The method included the analysis of nine polymorphic nucleotides and the hypervariable microsatellite of composite sequence (AT)xTy 5′ to the β-globin gene by DNA sequencing. The sequence haplotype (HT4) carrying the IVS-I-130 (G-A) mutation is also observed in Algeria. This favors a Northeastern African origin for this allele. The observed results agree well with a recent introduction of this mutation to Turkey from Egypt toward the end of the 19th century. Am. J. Hematol. 63:223–225, 2000. © 2000 Wiley-Liss, Inc.

Technetium-99m Sestamibi Scanning Reflects Marrow Activity in a β-Thalassemia Patient Treated with an Allogeneic Bone Marrow Transplant.

β-thalassemia major is a disorder of globin synthesis, resulting in anemia and compensatory bone marrow hyperproliferation. Conventional imaging studies do not measure bone marrow activity reliably. We report on the use of technetium-99m sestamibi (MIBI) in a β-thalassemia major patient treated with an allogeneic bone marrow transplant. Pre-transplant and early post-transplant MIBI scannings demonstrated generalized marrow uptake, reflecting marrow hyperproliferation. After full engraftment, post-transplant MIBI showed disappearance of abnormal uptake in the skeleton, indicating normalization of the marrow activity. MIBI scan may be used as a noninvasive measure of bone marrow proliferation that may guide hypertransfusion therapy in thalassemia patients.