Thalassemia Reports doi: 10.3390/thalassrep16020009

Authors: Iqra Javaid Muhammad Ameeq Muhammad Muneeb Hassan

Background: Advances in medical genetics and prenatal diagnosis have improved the detection of fetal abnormalities during pregnancy. The findings may lead some couples to consider termination of pregnancy (TOP). This study aimed to explore parental perspectives on prenatal diagnosis and termination of pregnancy among families in which both parents were β-thalassemia carriers and had at least one previously affected child. Methods: A qualitative study was conducted using semi-structured interviews with 30 participants (15 fathers and 15 mothers) recruited from Bahawal Victoria Hospital, Bahawalpur, Pakistan, between November 2024 and February 2025. Eligible couples were registered for chorionic villus sampling (CVS)-based prenatal diagnosis; both parents had confirmed β-thalassemia carrier status, and each family had at least one previously affected child with β-thalassemia major or intermedia. Interview data were analyzed using thematic analysis. Results: Religious beliefs, financial burden, prior experience with affected children, and partner support emerged as major influences on reproductive decision-making. Many parents viewed prenatal diagnosis as important for preparation and informed decision-making. Mothers more often described emotional conflict, stress, and reliance on support, whereas some fathers expressed greater acceptance of termination in the context of severe disease burden. Conclusions: Religious beliefs, prior disease experience, family dynamics, and socioeconomic pressures were important and interrelated influences on decisions about prenatal diagnosis and termination within this study population. Our findings underscore the importance of culturally sensitive, non-directive genetic counseling in low-resource settings. The study was limited by its small sample, single-center design, the use of joint spousal interviews, and the possibility that pre-interview counseling influenced participants’ responses.

Thalassemia Reports doi: 10.3390/thalassrep16020008

Authors: Loan Do Thi Thanh Anh Nguyen Ngoc Kien Nguyen Trung Ha Nguyen Thi Thu Dung Nguyen Huu Thang Le Viet

Objective: To determine plasma cystatin C concentrations, urine osmolality and their relationship with disease severity in beta-thalassemia patients. Methods: A cross-sectional study was conducted on 234 patients with beta-thalassemia, including equal numbers (78 each) of beta-thalassemia major, intermedia, and minor cases, along with 78 healthy individuals matched for age, sex, and body mass index, who served as the control group. Plasma cystatin C concentrations were quantified in all subjects using the ELISA method, and urine osmolality level was measured automatically on a FISKE 210 machine (USA). Results: The proportion of beta-thalassemia patients with increased plasma cystatin C concentration was 39.3% and the proportion with a decreased urine osmolality level was 67.5% compared with the control group. Plasma ferritin had predictive value for increased plasma cystatin C concentration (cut-off point: 567.5 ng/mL; AUC = 0.803) and decreased urine osmolality level (cut-off point: 488.15 ng/mL; AUC = 0.820), p < 0.001. Plasma cystatin C concentration increased gradually and urine osmolality level decreased gradually from minor beta-thalassemia to intermedia beta-thalassemia to major beta-thalassemia patients, with p < 0.001. Conclusions: Increased plasma cystatin C concentrations and decreased urine osmolality levels are common and are associated with severity in beta-thalassemia patients.

Thalassemia Reports doi: 10.3390/thalassrep16020007

Authors: Mohamed Medhat Abdelwahab Gamaleldin Shaimaa Mahmoud Nashat Sayed Abdelhalim Ivo Abraham

Thalassemia is an inherited hemoglobin disorder characterized by chronic hemolytic anemia and substantial long-term healthcare needs. In β-thalassemia major, patients typically require regular red blood cell transfusions with iron chelation to prevent transfusional iron overload. Although supportive care has markedly improved survival, it is associated with a high treatment burden and does not provide a cure. In recent years, curative and disease-modifying therapies have expanded the treatment landscape. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potentially curative option for selected patients, while autologous gene therapy and gene-editing approaches have shown the capacity to achieve transfusion independence in clinical studies. In parallel, pharmacologic advances—including luspatercept, a transforming growth factor-beta (TGF-β) ligand trap—have been shown to enhance erythropoiesis and reduce transfusion requirements, and emerging agents such as fetal hemoglobin inducers (e.g., thalidomide) and the oral pyruvate kinase activator mitapivat have demonstrated clinically meaningful hemoglobin improvements in selected populations. Adjunctive strategies, including antioxidants, are under investigation to mitigate oxidative stress, and applications of artificial intelligence are increasingly used to support screening, diagnosis, and longitudinal monitoring of iron overload. This review synthesizes recent advances in curative therapies, novel pharmacologic agents, supportive strategies, and AI-enabled tools and highlights priorities for future clinical development and implementation.

Thalassemia Reports doi: 10.3390/thalassrep16020006

Authors: Siddannagoud Dolat Singh Shekhawat Kuldeep Singh Varuna Vyas Pratibha Singh Charu Sharma Navdeep Kaur Ghuman Tanu Gupta

Background: This study investigated the clinical characteristics of consultands and examined their perceived personal control, satisfaction, and decision-making regarding genetic testing, as well as the factors influencing these outcomes, at a tertiary care center in northwestern India. Methods: Detailed clinical and family histories were recorded, and trained genetic professionals provided genetic counseling. Perceived personal control (PPC) was assessed pre- and post-counseling using the PPC (nine-item) questionnaire, while post-counseling satisfaction was measured using the six-item Genetic Counseling Satisfaction Scale (GCSS). Outcomes included awareness of genetic disorders, uptake of genetic testing, and reproductive decision-making. Results: A total of 225 consultands (125 pediatric and 100 antenatal) were enrolled. The most common systemic disorders were: inborn errors of metabolism (21.3%), congenital anomalies (15.2%), neurological disorders (15%), primary immunodeficiencies (12.3%), renal genetic disorders (12.2%), respiratory disorders (12%), thalassemia (9%), endocrine disorders (3.9%), and cardiovascular anomalies (3%). In the pediatric group, socioeconomic status (p = 0.048) and higher education levels (p = 0.02) were significantly associated with higher perceptions of adequate counseling time and overall GCSS. None of the examined factors in the prenatal group showed a statistically significant association with satisfaction scores. Consultands primarily concerned with preventing recurrence in future pregnancies showed significantly higher PPC scores both before (p = 0.026) and after counseling (p = 0.009), with the greatest overall improvement in satisfaction (p = 0.044). In the pediatric group, those with an affected family member showed the greatest post-counseling improvement in PPC. Conclusions: Low education, limited awareness, socioeconomic constraints, delayed presentation and low referral rates were key barriers to effective genetic counseling. Addressing these factors can improve consultand awareness, satisfaction, decision-making, and uptake of genetic testing, thereby enhancing reproductive outcomes in high-risk families.

Thalassemia Reports doi: 10.3390/thalassrep16010005

Authors: Muhammad Hammad Sadaf Fardoos Khadija Shakoor Ali Nasir

Background and Objective: Iron overload remains a significant clinical concern in patients with transfusion-dependent beta-thalassemia (TDT). This study aims to characterize the iron load and endocrine profile of adult transfusion-dependent beta-thalassemia patients and to evaluate their correlation with growth retardation. Methods: A cross-sectional study was conducted at PIMS Hospital, Islamabad, involving 62 adult patients with homozygous or HbE beta-thalassemia receiving regular blood transfusions. Iron overload was assessed using serum ferritin (SF) and transferrin saturation (TS), while endocrine function was evaluated through measurements of thyroid-stimulating hormone-sensitive (TSH), free thyroxine (FT4), and insulin-like growth factor-1 (IGF-1). Data was analyzed using SPSS v26.0 and R v4.3.1, which included Pearson correlation, chi-square testing, and multivariable regression to explore associations between iron indices and endocrine dysfunction. Results: Serum ferritin demonstrated significant negative correlations with FT4 (r = −0.348, p = 0.005) and IGF-1 (r = −0.302, p = 0.015). MRI T2* pancreas values correlated positively with FT4 (r = 0.268, p = 0.037) and IGF-1 (r = 0.312, p = 0.015). Patients with ferritin > 5000 ng/mL exhibited a higher prevalence of low IGF-1 levels (89.2% vs. 64.0%, p = 0.018). No significant gender-based differences were observed in endocrine parameters. Conclusion: Pancreatic iron burden and elevated serum ferritin were significantly associated with impaired thyroid and growth axis function, highlighting the value of integrating MRI T2* and biochemical markers for early endocrine risk stratification in adult TDT patients.

Thalassemia Reports doi: 10.3390/thalassrep16010004

Authors: Duran Canatan Vincenzo De Sanctis Joan Lluis Vives Corrons Giorgio Piacentini Fatih Kara Basak Tezel Aslıhan Ugur Külekci Özlem Zümrüt Zekiye Özdemir Kemal Gürsoy Gamze Kaymak Şirin Aydın Tanju Altunsu İlhan Aydın Mustafa Hambolat Nilgün Keloğlu Elif Durmaz Abdullah Solmaz

Background and aim: Hemoglobinopathies have become an important public health problem due to global migration. The aim of this project was to address the problem of hemoglobinopathy among immigrants living in Türkiye, Spain, and Italy, in addition to training health managers and Syrian family physicians at immigrant health centers in the southeastern provinces of Türkiye. Material and methods: A three-year international project, named EQUALITY PLUS, was supported by the European Union Erasmus Project. We planned transnational meetings (TPM), vocational education meetings (VET), and Practical Implementation Meetings (PIEM) for the education program. Results: Four TPMs were held in Türkiye, Spain, and Italy, involving a total of 49 professionals. Two VETs were held in Spain and Italy. A total of 23 professionals attended both VETs. Six PIEMs were held in the southern and southeastern Turkish provinces, such as Adana Mersin, Hatay, Gaziantep, Kilis, and Sanliurfa. A total of 442 people, including 373 Syrian family physicians and 69 provincial health managers, were educated in six provinces in Türkiye. Discussion: While the immigrants to Italy and Spain come mainly from Central and North West African maritime routes, immigrants to Türkiye predominantly come from Syria. Among a total of 4 million Syrian immigrants to Türkiye, 200.000 were found to be carriers of thalassemia. In the refugee camps where Syrian immigrants live, the fertility rate is high and the number of sick newborns is increasing, and birth control, genetic counseling, and prenatal diagnosis methods are not sufficient. This project was intended to serve as a guide to prevent hemoglobinopathy in Syrian immigrants. Further projects are needed to address the fertility rate and increased number of sick newborns in these refugee camps. Family physicians at migrant health centers received training on the prevention of hemoglobinopathies. This training included providing detailed genetic counseling to families and providing prenatal diagnosis and preimplantation genetic diagnosis opportunities. Because of the major earthquake that occurred in this region after the project, the work could not continue and preliminary data could not be obtained. Public health services will follow the results of project and the registered number of sick newborns with hemoglobinopathies.

Thalassemia Reports doi: 10.3390/thalassrep16010003

Authors: Ankitha K. Puthiyaveettil Harshini K. Musuvathi Deepalakshmi D. Putchen

Background: β-thalassemia is a rare genetic disorder affecting 1–5% of the global population and poses a health burden due to migration of individuals from endemic regions. Identifying asymptomatic β-thalassemia carriers is essential to prevent the birth of thalassemic babies. A simple, sensitive method compatible with self-sampling could enhance the detection of β-thalassemia in the population. Methods: Capillary blood was collected via dried blood spot (DBS) and dried blood matrix (DBM) from 18 members (52.9%, 18/34) of a three-generation family. Hemoglobin was extracted, and globin chains were analyzed on a triple quadrupole mass spectrometer (TQMS). δ/β (%) was utilized as a biomarker to identify β-thalassemia. Venous blood collected from positive and negative individuals (n = 11) was further tested to confirm the findings and validated with complete blood count (CBC) and Capillary Electrophoresis (CE). Results: β-thalassemia was detected in seven individuals: three from generation I, three from generation II, and one from generation III. CBC showed thalassemia indices, while CE demonstrated elevated HbA2 consistent with β-thalassemia. Molecular sequencing of two samples confirmed the heterozygous c.92 + 5 G > C mutation in the β-globin gene. The overall prevalence of β-thalassemia in the family was 20.6% (7/34). High clinical performance was achieved across sample types, with 100% sensitivity for DBS, 100% specificity for DBM, and an overall accuracy of 91% when compared with CE. Conclusions: TQMS in combination with CBC parameters successfully identified asymptomatic heterozygous β-thalassemia carriers using self-sampling techniques. Cascade screening within affected families emerges as a possible strategy for early detection of β-thalassemia pending comprehensive validation.

Thalassemia Reports doi: 10.3390/thalassrep16010002

Authors: Debashis Pal Dipankar Saha Prosanto Kumar Chowdhury Arup Das Anupam Basu

β-thalassemia patients often experience ocular abnormalities such as angioid streaks (ASs), retinal pigmented epithelium degradation, visual field defects, and in rare instances choroidal neovascularization (CNV). Although ASs are common in individuals with hemoglobinopathies, the occurrence of choroidal neovascularization without preceding ASs is exceptionally rare. In this report, we describe a β-thalassemia patient who had developed CNV at the age of 27 years and also had experience of renal stones at the age of 19 years. He had undergone splenectomy and was under conservative therapy of iron supplementation. We conducted whole-exome sequencing (WES) in search of CNV-associated variants. Through variant filtering and Phenolyzer analysis, we have identified a rare heterozygous missense variant in the ABCC6 gene, ABCC6:NM_001171:exon25:c.3524T>C (rs376062004). In silico analysis revealed that this variant is present in the highly conserved region and is likely to decrease the stability of the protein. Mutation in the ABCC6 gene leads to pseudoxanthoma elasticum (PXE). Previously, it was believed that ASs and subsequent CNV-like ocular complication may develop due to the pathophysiological condition of thalassemia. However, our study provides compelling evidence that rare mutations in the ABCC6 gene, in combination with oxygen insufficiency, may contribute to the development of CNV in β-thalassemia patients. This finding highlights the potential genetic basis of PXE-mediated CNV development in β-thalassemia.

Thalassemia Reports doi: 10.3390/thalassrep16010001

Authors: Edi Setiawan Tehuteru Teck Onn Lim Anky Tri Rini Kusumaning Edhy Ludi Dhyani Rahmartani Stephen Diah Iskandar Cresentia Irene Rendi Prawira Gunawan Reganedgary Jonlean Grace Erdiana

Background/Objectives: Thalassemia is highly prevalent in Indonesia, and its treatment imposes a significant financial burden. To date, thalassemia management in Indonesia remains largely limited to supportive therapies. This report aims to present the monitoring of the first Indonesian pediatric thalassemia patient to undergo gene therapy. Methods: Medical summaries were gathered across multiple time points. The gene therapy process consisted of several phases: screening, apheresis and cell manufacturing, conditioning, cell infusion, and post-treatment follow-up. The therapy utilized autologous CD34+ hematopoietic stem and progenitor cells (HSPCs), which were genetically modified using a lentiviral vector carrying the beta-globin gene. The primary outcome of this study was transfusion independence, determined through serial assessments of hematological parameters over a six-month period following gene therapy. Results: A 15-year-old female had been diagnosed with thalassemia major at the age of five. DNA analysis revealed compound heterozygous mutations Hb Malay (codon 19, AACAsn > AGCSer) and IVS1-nt5 (G > C). She had been receiving regular blood transfusions every 3–4 weeks, and hemosiderosis was detected in the liver and pancreas. Given the patient’s age—over 10 years—hematopoietic stem cell transplantation carries increased risks, making gene therapy the most suitable curative option. During the six-month follow-up period after gene therapy, the patient remained transfusion-independent and experienced no complications. Conclusions: In selecting an appropriate curative therapy for thalassemia patients, several factors must be considered. The successful implementation of the first gene therapy in an Indonesian pediatric thalassemia patient should serve as a catalyst for the continued development and expansion of curative treatment options for thalassemia patients across the country.

Thalassemia Reports doi: 10.3390/thalassrep15040012

Authors: Burhan Abdullah Zaman Zuhair Rushdi Mustafa Delshad Abdulah Mohamed Hasan Abdullah Aswad Deldar Morad Abdulah

Background/Objectives: Thalassemia is among the most common hereditary disorders globally, characterized by impaired hemoglobin synthesis and ineffective erythropoiesis. This study analyzed data on hemoglobinopathies, with a particular focus on thalassemia, to support the development of a comprehensive national database and to improve understanding of the disease burden in the Kurdistan Region of Iraq. Methods: In this retrospective cross-sectional study, a total of 910 patients admitted to the region’s sole blood disorder center since its establishment were included. Results: The study analyzed 46.7% male and 53.3% female thalassemia patients in Duhok, with 58.46% reporting parental consanguinity. Hepatitis C virus (HCV) prevalence was 11.87%, while 8.90% underwent bone marrow transplantation (BMT) and 30.11% had splenectomies. Blood group distribution was O+ (36.26%), A+ (30.99%), and B+ (18.46%). Common medications included Deferasirox (34.62%), Hydroxyurea (26.70%), and Deferoxamine (5.82%), with 8.24% and 4.40% discontinuing Deferasirox and Hydroxyurea, respectively. Geographically, 29% of the patients originated from Duhok City, which exhibited a consanguinity rate of 18.65% (p = 0.020). The most prevalent conditions were β-thalassemia major (32.53%) and sickle cell anemia (24.73%). HCV-positive patients were predominantly diagnosed with β-thalassemia major (43.40%) and sickle cell anemia (33.96%). BMT recipients were mostly β-thalassemia major patients (80.25%), while splenectomy was common in β-thalassemia major (43.40%) and sickle cell β-thalassemia (22.64%). Vaccination rates included Pneumococcal (50.78%), Influenza (47.76%), and Hepatitis (39.08%, first dose). Six patients (0.66%) died, with 30.18% diagnosed before age 1 and 43.89% between 1 and 2 years. In conclusion, this study underscores the high prevalence of β-thalassemia major and sickle cell anemia in Duhok, with strong associations to parental consanguinity and low socioeconomic status. Gaps in early diagnosis and vaccination coverage remain significant challenges.

Thalassemia Reports doi: 10.3390/thalassrep15040011

Authors: Nikos Rikos Marilena Tzagkaraki Antigoni Linardaki Maria Moloudaki Manolis Linardakis

Background/Objectives: Thalassemia significantly affects the mental well-being and lifestyle of patients and their families. This study evaluated the temporal changes in quality of life (QoL) and psychological burden among thalassemia patients in 2025 and in relation to 2018. Methods: Two cross-sectional samples of patients (n = 236) were recruited during 2025 (n1 = 117) and 2018 (n2 = 119) at the Thalassemia Units on Crete/Greece. The EQ-5D-3L Quality of Life Scale, the EQ VAS Index, and the Hospital Anxiety and Depression Scale (HADS) were used through multiple logistic regression analysis to assess relative parameters. Results: High mean Health Status (EQ VAS Index) and QoL scores remained consistent from 2018 to 2025, anxiety mean levels were low and remained consistent from 2018 to 2025, depression levels were low but higher in 2025 in relation to 2018 (p = 0.041), anxiety significantly exceeded depression in both 2018 and 2025, better QoL was associated with improved health status and reduced anxiety and depression, and individuals with children exhibited significantly lower odds of experiencing low or moderate QoL. Conversely, each unit increase in the Anxiety score significantly increased the odds of low or moderate QoL (OR = 1.26, p = 0.002). Similarly, each unit improvement in health status significantly reduced the odds of low or moderate QoL (OR = 0.97, p = 0.009). Conclusions: Health status and QoL remained consistent from 2018 to 2025, while depression levels increased. Anxiety significantly exceeded depression, and better QoL was associated with improved health status and reduced anxiety and depression.

Thalassemia Reports doi: 10.3390/thalassrep15040010

Authors: Didar Hossain Mohammad Jakir Hosen

β-thalassemia is a chronic genetic blood disorder characterized by defective β-globin synthesis, requiring frequent transfusions and resulting in iron overload, immune dysfunction, and increased susceptibility to infections. In these immunocompromised patients, altered immune responses lead to significant changes in the human virome, promoting viral persistence, reactivation, and expansion of pathogenic viral communities. This review explores the intricate relationship between β-thalassemia and the human virome, focusing on how clinical interventions and immune abnormalities reshape viral dynamics, persistence, and pathogenicity. Patients with β-thalassemia exhibit profound innate and adaptive immune dysregulation, including neutrophil dysfunction, T cell senescence, impaired B cell and NK cell activity, and expansion of myeloid-derived suppressor cells. These alterations create an immunological niche that favors viral reactivation and virome expansion. Iron overload enhances viral replication, while chronic transfusions introduce transfusion-transmitted viruses. Splenectomy and allo-HSCT further compromise viral surveillance. Additionally, disruptions in the gut virome, particularly bacteriophage-driven dysbiosis, may exacerbate inflammation and impair host–virus homeostasis. The human virome is not a passive bystander but a dynamic player in the pathophysiology of β-thalassemia. Understanding virome–immune interactions may offer novel insights for infection monitoring, risk stratification, and precision therapies in thalassemic patients.

Thalassemia Reports doi: 10.3390/thalassrep15030009

Authors: Khaled Yassen Nawal Omar Abdulaziz Bushehab Renad AlSubaie Lina AlMudayris Sara A. Albunyan Shaima AlAkroush Sherif Saleh Dur I. Shahwar Ossama Zakaria

Background/Objectives: Thalassemias, a hereditary condition commonly linked to chronic anemia, require regular blood transfusions and repeated blood draws for assessments of hemoglobin (Hb) content, which can be uncomfortable. A promising substitute for laboratory hemoglobin testing is non-invasive spectrophotometric hemoglobin (SpHb) monitoring; however, its applicability particularly among blood transfusion-dependent thalassaemic patients needs to be investigated. This study’s primary goal was to investigate the relationships and agreements between SpHb, g/dL, and an automated hematology analyzer (Hb, g/dL) in this particular patient population. The secondary goal was to track how blood transfusions affect SpHb, g/dL, laboratory Hb, and pleth variability index (PVI, %). Methods: In this study, sixty patients were included. A Masimo Radical-7 pulse CO-oximeter was used to measure the SpHb, and a Sysmex XN-1000 hematological analyzer measured the laboratory Hb. Results: The results revealed a significant correlation between SpHb and laboratory Hb (n = 108, r = 0.587, p < 0.001) but also demonstrated that SpHb consistently overestimated laboratory Hb levels, with a mean bias of −1.18 g/dL (95% CI: −1.4344 to −0.9267). The Bland–Altman analysis showed a good degree of reliability between this bias (SpHb–Hb) and laboratory Hb (g/dL), with an Intra Class Correlation (ICC) of 0.613 but with a wide 95% CI ranging from 0.557 to 0.736 (t = 3.817, p < 0.001). The 95% limits of agreement ranged from −3.7893 to +1.4228 g/dL. Conclusions: This significant bias restricted the application of SpHb as a trustworthy method for assessing hemoglobin levels in patients with blood transfusion-dependent thalassemia. Nonetheless, the capability to monitor SpHb and PVI variations during blood transfusions offered a real-time assessment of the impact of transfusions on patients’ hemoglobin levels and volume status.

Thalassemia Reports doi: 10.3390/thalassrep15030008

Authors: Yasin Yilmaz Zeynep Karakas Ayse Erol Bozkurt Demet Kivanc Mediha Suleymanoglu Hayriye Senturk Ciftci Cigdem Kekik Cinar Fatma Savran Oguz

Background: It has been shown that human leucocyte antigen (HLA) alleles are related to certain diseases. Some alleles were associated with alloimmunization in individuals with thalassemia. In this study, we studied the distribution of HLA alleles among beta thalassemia (BT) patients compared to healthy controls. Material and Methods: The HLA results of 100 patients with BT and 100 healthy controls were obtained for the study. The HLA-A, -B and -DRB1 tissue typing were performed at the laboratory. The low-resolution sequence-specific primer (SSP)–polymerase chain reaction (PCR-SSP) (Olerup HLA-A,B,DR typing kit, USA) and sequence-specific oligonucleotide (SSO)–PCR (LABType HLA-A,B,DR kit, ABD) methods were performed using the Luminex genotyping kits. All related data were retrospectively analyzed. Results: One in five patients (21%) underwent hematopoietic stem cell transplantation (HSCT). Patients with HSCT had significantly lower frequency of HLA-B *14, HLA-DRB1 *11 and HLA-DRB1 *16 alleles and had a higher frequency of HLA-A *66, HLA-B *41, HLA-B *55, HLA-DRB1 *3 alleles compared to patients without HSCT (p < 0.05). The HLA-A *3, HLA-B *41 and HLA-B *55 alleles were more commonly seen in HSCT patients compared to the healthy group (p = 0.04). Female patients showed a higher frequency of HLA-B *58 and HLA-DRB1 *4 alleles (p = 0.04). Conclusions: This study demonstrated that HLA-B *41 and -B *55 alleles were closely related to HSCT among BT patients. It might be considered that the variance in certain HLA-B alleles in BT patients might cause difficulty in finding a matched donor in this limited population.

Thalassemia Reports doi: 10.3390/thalassrep15030007

Authors: Kabelo Mokgalaboni Wendy N. Phoswa Perpetua Modjadji Sogolo L. Lebelo

The risk of anemia and iron overload is a global concern in beta (β)-thalassemia. The β-thalassemia primary treatment includes blood transfusion and iron chelation therapy; however, both are associated with risks such as anemia, iron depletion, overload, and oxidative stress if not adequately monitored. Therefore, this study investigates the effects of curcumin on anemia, iron overload, and oxidative stress in β-thalassemia. In this meta-analysis, search terms including “curcumin,” “Curcuma longa,” “curcuminoids,” “turmeric,” and “thalassemia” were used in Scopus and PubMed to identify studies published from inception to 15 February 2025. The quantitative analysis was performed using a meta-analysis web tool, and the effect estimates were reported as the mean difference (MD) or standardized mean difference (SMD), along with 95% confidence intervals (CI). Our analysis showed no significant effect on hemoglobin (p = 0.1788) and red blood cell count (p = 0.9534). In contrast, there was a significant decrease in serum ferritin [SMD = −0.24 (−0.46, −0.02), p = 0.0335], non–transferrin bound iron (NTBI), [SMD = −0.59 (−0.98, −0.19), p = 0.0039] and serum iron, [SMD = −0.30 (−0.60, −0.01), p = 0.0425]. Furthermore, there was a reduction in reactive oxygen species; [SMD = −0.83 (−1.23, −0.44), p < 0.0001] and malonaldehydes, [MD = −343.85 nmol/g Hb (−465.94, −221.76), p < 0.0001]. A dose of 500 mg of curcumin was found to be more effective in reducing the NTBI. The findings suggest that curcumin may help reduce iron overload and oxidative stress in β-thalassemia; however, its effect on improving anemia appears to be limited. Given the small sample size of the included studies, we recommend that future research involve larger cohorts and employ rigorous methodologies to evaluate the therapeutic potential of curcumin in β-thalassemia thoroughly. Additionally, we recommend using curcumin-enhancing strategies to improve its bioavailability and administer an optimal yet effective dose.

Thalassemia Reports doi: 10.3390/thalassrep15020006

Authors: Nathasha Brigitta Selene Ayudra Fitrananda Natasha Yemima Situmorang Kamilia Rifani Ufairah Stephen Diah Iskandar Pustika Amalia Wahidiyat

Background/Objectives: Chronic anemia and iron overload in thalassemia lead to organ failures, including the heart, liver, endocrine glands, and spleen. Comprehensive multidisciplinary management is pivotal in improving patients’ clinical outcomes and well-being. The report aims to present a rare case of improved clinical condition in a transfusion-dependent thalassemia patient. Methods: Medical summaries were collected to compare patients’ conditions at various time frames. Furthermore, the report was composed in chronological order. Results: A 31-year-old male diagnosed with beta-thalassemia major and multiple comorbidities, including diabetes with a history of diabetic ketoacidosis, heart failure with a history of cardiac arrest, hepatomegaly, severe thoracolumbar scoliosis, and depression, exhibited a high physical endurance. The patient managed to maintain a strong treatment adherence and undergo intensive regular multidisciplinary follow-ups. The patient gained cardiac function improvement and metabolic stabilization, leading to completing a 5 k marathon without complication. Conclusions: Intensive management of iron overload through double oral chelation allows organ function improvement. Better mental health attenuates the patient’s overall well-being and is attributed to the ability to gain high physical endurance.

Thalassemia Reports doi: 10.3390/thalassrep15020005

Authors: Radovan Dinić Nevenka Bujandrić Jasmina Grujić

Background/Objectives: Red blood cell (RBC) alloimmunization is a significant challenge in transfusion medicine, particularly among transfusion-dependent patients, such as those with thalassemia. It arises from the production of antibodies against non-self RBC antigens and can lead to complications like hemolytic transfusion reactions. This study aimed to evaluate the prevalence, specificity, and clinical implications of RBC alloimmunization at the University Clinical Center of Serbia (UCCS), emphasizing transfusion-dependent populations. Methods: This retrospective study analyzed 27,530 transfusion records at UCCS between January 2023 and January 2024. Pre-transfusion testing included ABO and RhD typing, irregular antibody screening, and crossmatching. Data from 630 patients with positive antibody screening were reviewed. Alloantibody specificity was determined using indirect antiglobulin tests and advanced phenotyping methods. Results: Among 27,530 patients, 630 (2.29%) tested positive for irregular antibodies, predominantly males (57.14%) with a mean age of 49.6 years. Alloantibodies were detected in 70.47% of cases, most commonly targeting Rh (53.35%) and Kell (17.15%) systems. Anti-E (27.93%) and anti-D (18.02%) were the most frequent antibodies. Multiple alloantibodies were identified in 18.41% of patients, posing challenges for blood compatibility. In a total of 495 patients with thalassemia, antibodies were found in 9.69%. Alloimmunization was significantly associated with higher numbers of transfusions and pregnancies (p < 0.05). Conclusions: Our findings indicate that alloimmunization is predominantly associated with Rh and Kell antigens, suggesting that implementing targeted antigen matching may reduce the frequency of alloimmunization. While our study does not directly assess the impact of genotypic matching, the prior literature supports its role in enhancing transfusion safety, particularly for high-risk populations like thalassemia patients.

Thalassemia Reports doi: 10.3390/thalassrep15020004

Authors: Sreenithi Santhakumar Leo Stephen Aruna Barade Uday Kulkarni Biju George Eunice S. Edison

Background/Objective: Patients with beta-thalassemia are more susceptible to iron overload and have altered neutrophil function. This study investigated the connections between iron metabolism in neutrophils, neutrophil functionality, and overall iron status in individuals with β-thalassemia and sickle cell anemia. Methods: We recruited 18 patients with β-thalassemia, 5 patients with sickle cell anemia, and 15 healthy controls. Our evaluation included measurements of iron and hepcidin concentrations in the serum, along with an analysis of neutrophil function, specifically their phagocytic and oxidative burst capabilities. In addition, we examined the expression of iron transport proteins in neutrophils. Results: Patients with β-thalassemia showed significant iron overload, reduced neutrophil counts, and decreased oxidative burst activity and phagocytosis. Systemic iron status is inversely correlated with the phagocytic capacity of β-thalassemia neutrophils. Regression analysis indicated a significant association between serum iron level, transferrin iron binding capacity, transferrin saturation, and neutrophil percentage. These findings elucidate the essential role of systemic iron levels in neutrophil efficacy against infections. Furthermore, FPN1B and DMT1A mRNA levels were upregulated, and IRP2 was downregulated in the neutrophils of patients with β-thalassemia major and intermedia compared to controls. Conclusions: Elevated systemic iron levels were associated with reduced neutrophil counts and impaired neutrophil function in patients with β-thalassemia. These findings highlight a critical role of systemic iron overload in neutrophil dysfunction.

Thalassemia Reports doi: 10.3390/thalassrep15010003

Authors: Lawrence Faulkner

Thalassemia and sickle cell disease remain the most common life-threatening non-communicable diseases in children worldwide and an increasing burden on affected families and health services. Significant progress has been made in terms of technologies to improve access to a cure by both allogeneic and autologous gene-modified hematopoietic stem cell transplantation (HSCT). However, the high cost of cutting-edge treatments often places them beyond the reach of individual families or even national healthcare systems. Advances in frugal innovation and simplified HSCT procedures for low-risk transplants have significantly reduced the costs and complexities associated with HSCT without compromising on quality and outcomes. Because of the geographical distribution of hemoglobinopathies, i.e., largely in low- and middle-income countries (LMICs), HSCT cost optimization has the potential to impact a huge number of patients, increasing hope for a cure and health-related quality of life normalization, which in turn may affect supportive care compliance. Furthermore, because of the high burden of disease, LMIC transplant centers are rapidly increasing in number and developing unique expertise for the cure of thalassemia and sickle cell disease, particularly in India, where the Sankalp India Foundation with the support of DKMS and Cure2Children has implemented several cost-conscious transplant services. In fact, the very high success rate, increasing cost-effectiveness of transplantation, as well as the chronic nature of these conditions make them ideal initial candidates for start-up transplant centers, so it is likely that the global capacity for a cure for severe hemoglobinopathies will substantially increase in the years to come.

Thalassemia Reports doi: 10.3390/thalassrep15010002

Authors: Sara Deumić Neira Crnčević Mirsada Hukić Muamer Dizdar Monia Avdić

Thalassemia, a genetic condition characterized by defective hemoglobin synthesis, is often managed with transfusion therapy, which can lead to iron overload—a significant contributor to morbidity and mortality due to organ damage and pathogenic infections. Iron chelation therapy, the cornerstone of managing iron toxicity, may inadvertently influence the gut microbiome, a critical modulator of immunity and metabolism. This review provides new insights into the interplay between iron chelation therapy and gut microbiome dynamics in thalassemia patients. It synthesizes findings on how chelators such as deferoxamine, deferasirox, and deferiprone influence microbial composition, iron availability, and systemic inflammation. Emerging evidence highlights alterations in gut microbial diversity, with reduced beneficial taxa and increased pathogenic populations, driven by changes in luminal iron levels. This imbalance contributes to immune dysregulation, systemic inflammation, and susceptibility to infections. The review advocates for tailored treatment strategies that integrate microbiome-targeted interventions alongside traditional chelation therapy to improve patient outcomes. By combining genetic profiling, dietary adjustments, and microbiome modulation, this approach offers a promising avenue for personalized medicine in thalassemia care.

Thalassemia Reports doi: 10.3390/thalassrep15010001

Authors: Sophia Delicou Aspasia Argyrou Sophia Mellou Aikaterini Xydaki Anthippi Gafou Constantina Politis

It is important to recognize the significance of acute painful transfusion reactions (APTRs) as a complication of blood transfusions. These adverse reactions are characterized by the onset of acute pain after the administration of blood components. Despite their potential to cause significant discomfort and distress to patients, these reactions are frequently disregarded and under-reported in clinical practice. This review aims to provide a comprehensive analysis of the clinical features, pathophysiology, diagnosis, incidence, and management of APTRs, emphasizing the necessity for heightened awareness and further research in this field.

Thalassemia Reports doi: 10.3390/thalassrep14040012

Authors: Domenico Dell’Edera Carmela Centoducati Arianna Allegretti Francesco La Rocca Brunilde Persia

Introduction: Generally, microcytic anaemia is caused by sideropenia or a genetic gap. The suspicion that microcytic anaemia is caused by a genetic gap must always be considered in the face of an inadequate response to martial therapy. The aim of this paper is to highlight how biochemical diagnosis alone is sometimes not sufficient to understand the cause of microcytic anaemia. For this reason, for a correct genotype–phenotype correlation, it is essential to identify the defective gene underlying the microcytic anaemia. Detailed Case Description: This case concerns a married couple who both have microcytic anaemia. They came to our attention because the lady, pregnant at 12 weeks, underwent screening for chromosomal abnormalities using combined tests in the first trimester of pregnancy. A biochemical screening performed ten years earlier showed that both spouses were healthy carriers of the beta-thalassemia trait. A careful analysis of the biochemical data and an in-depth molecular diagnosis of the alpha and beta globin genes showed that the woman was a healthy carrier of the beta-thalassemia trait while the husband was a healthy carrier of a mutation in the ALAS2 gene. Analysis of the biochemical data of her husband and family members revealed that she had X-linked microcytic sideroblastic anaemia caused by an alteration in the function of the ALAS2 (5′-Aminolevulinate Synthase 2) gene located on the short arm of the X chromosome (Xp11.21). Discussion and Conclusions: This result is very relevant as, during genetic counselling, we explained to the couple that invasive prenatal diagnosis was not necessary as there is no risk of procreating a transfusion-dependent individual.

Thalassemia Reports doi: 10.3390/thalassrep14040011

Authors: Jannatul Ferdous Marzia Tasnim Firdausi Qadri Md. Ismail Hosen Emran Kabir Chowdhury Hossain Uddin Shekhar

Background: Thalassemias are a group of autosomal recessive disorders and the most common inherited disease worldwide. Fetal hemoglobin (HbF) is the main oxygen carrier protein in the human fetus. Elevated HbF level is known to ameliorate the severity of HbE/β and β-thalassemia. This study aimed to investigate whether two commonly known HbF-associated SNPs (rs28384513 and rs4895441) in the HBS1L-MYB region are associated with HbF level and disease severity in Bangladeshi HbE/β-thalassemia patients. Methods: Blood samples were collected from 160 participants (120 HbE/β-thalassemia patients and 40 healthy controls). Hematological analysis was performed using complete blood count (CBC) and capillary Hb electrophoresis. After genomic DNA extraction, real-time PCR-based high-resolution melting (HRM) for SNP detection, targeting the HBS1L-MYB intergenic region, was done. Results: Patients carrying rs28384513 and rs4895441 SNPs had significantly higher HbF (1.29 ± 1.63 and 1.49 ± 1.7 g/dL, respectively) compared to major allele ‘TT’ and ‘AA’ (0.87 ± 1.1 and 1.19 ± 1.65 g/dL, respectively) with a p-value of 0.01 and 0.03, respectively. It has been detected that HbF levels in SNP-carrying patients significantly correlated with the higher transfusion interval (60 days, r = 0.38, p < 0.0001) and age of first transfusion (65 months, r = 0.26, p < 0.0028) in these patients. Further, non-transfusion-dependent patients had the highest HbF level (2.03 ± 2.05 g/dL) compared to transfusion-dependent moderate (0.58 ± 0.78 g/dL) and severe (0.84 ± 1.27 g/dL) patients generating a significant p-value < 0.0001 in One-Way ANOVA test. The minor allele frequencies of rs28384513 (G) and rs4895441 (G) were found to be 0.43 and 0.11 respectively. Conclusion: These findings suggest that SNPs of HBS1L-MYB may have a role in elevated HbF levels and ameliorating disease severity in terms of transfusion in HbE/β-thalassemia patients.

Thalassemia Reports doi: 10.3390/thalassrep14040010

Authors: Idris Zubairu Sadiq Fatima Sadiq Abubakar Hauwa Salisu Usman Aliyu Dantani Abdullahi Bashiru Ibrahim Babangida Sanusi Kastayal Maryam Ibrahim Hassan Aliyu Hassan

Thalassemia represents a diverse group of inherited hematological disorders characterized by defective globin chain synthesis, leading to chronic anemia and associated complications. The complicated pathophysiology of beta-thalassemia involves genetic mutations or rarely deletions of the beta-globin gene on chromosome 11 whereas alpha-thalassemia involves deletions in the HBA1 and HBA2 genes or occasionally alterations to the DNA sequence in or around these genes. These mutation and deletion effects disrupt the balance of α/β-globin chain production, resulting in ineffective erythropoiesis, hemolysis, and a cascade of clinical manifestations including anemia, bone deformities, and iron overload. Advances in diagnostic techniques have enhanced our ability to detect and characterize these mutations, facilitating early and accurate diagnoses. Current management strategies encompass regular blood transfusions, the use of hydroxyurea to improve hemoglobin levels, and iron chelation therapy to prevent iron-related organ damage. Moreover, other therapeutics such as thalidomide for those not responding to hydroxyurea, Sirolimus for patients with immunodeficiencies, and use of vitamin E as an antioxidant have proven to be effective. Innovative therapies such as gene therapy and bone marrow transplantation offer promising curative potential, opening a new era in the treatment of thalassemia. This review focuses on pathophysiological mechanisms underlying thalassemia, explores the diagnostic methodologies, and highlights recent advancements in therapeutic approaches.

Thalassemia Reports doi: 10.3390/thalassrep14030009

Authors: Hossein Jalali Mohammad Reza Mahdavi Mehrnoush Kosaryan Ahmad Najafi Aily Aliasgharian Ebrahim Salehifar

HbF induction is an appropriate strategy to ameliorate the severity of β-thalassemia symptoms. Hydroxyurea (HU) is the most common chemical agent introduced as an HbF inducer but responsiveness to HU is variable and the introduction of HbF inducers alternative to HU with low cytotoxicity has been a crucial challenge. Resveratrol is an HbF inducer agent that may have favorable effects on the differentiation of hematopoietic erythroid progenitors (HEPs). The present study aimed to investigate the effect of resveratrol on γ-globin, stress response, and anti-apoptotic gene expression among hydroxyurea (HU)-responders and HU-nonresponders (HU-NR). Four cases of HU-R and four cases of HU-NR were studied. HEPs of the patients were cultured, and the expression of γ-globin, Foxo3, and Bclxl was assessed. Moreover, the differentiation and apoptotic rate of the cells were investigated using flow cytometry analysis. In three cases, the γ-globin gene expression increased after resveratrol treatment. All of the HU-NR patients were also non-responders to resveratrol (Res-NR). The expression of Foxo3 and Bclxl genes was higher in responders to resveratrol (Res-R) compared to non-responders (Res-NR). The rate of apoptosis in Res-R patients was also lower than in Res-NR. Responders to resveratrol also had a higher rate of HEP maturation. The cells of both HU–NR and Res-NR patients could not adapt to stress conditions and proceed to the erythroid differentiation. In conclusion, resveratrol increased the γ-globin expression in HEPs of β-thalassemia patients. The response was observed only in R-HU patients with similar cellular pathways.

Thalassemia Reports doi: 10.3390/thalassrep14030008

Authors: Atousa Babamohammadi QiYuee Wang Elham Mohajeri Saeid Esmaeilian

Background: The effective management of iron overload in transfusion-dependent thalassemia (TDT) requires adherence to iron chelation therapy (ICT). However, adherence rates among pediatric thalassemia patients remain suboptimal. This study aimed to evaluate adherence levels and identify sociodemographic and clinical factors impacting ICT adherence in pediatric TDT patients from Sarbaz-Rask, Iran. Methods: This cross-sectional study assessed 58 pediatric TDT patients aged 2–18 years at a thalassemia clinic from April 2021 to March 2022. Adherence was evaluated using the medication possession ratio. Logistic regression and correlation analyses identified predictors of adherence and treatment efficacy based on serum ferritin levels. Results: Adherence was satisfactory in 58.6% of patients and associated with younger maternal age (93.8% for 18–30 years, p = 0.008) and urban residency (p = 0.02). Logistic regression identified urban residency (OR = 20.265, p = 0.073) and a maternal age of 18–30 years (OR = 39.236, p = 0.005) as key predictors of adherence. Adherence was not significantly influenced by having a sibling with thalassemia or the maternal educational level. Treatment efficacy was observed in 27.6% of patients. Maternal age impacted adherence in poorly controlled patients (p = 0.007). Urban residents showed higher adherence rates, particularly with poor control (p = 0.017). Conclusions: Younger maternal age and urban residency emerged as positive predictors of adherence and treatment efficacy in pediatric thalassemia patients from Sarbaz-Rask. Targeted interventions supporting rural families and those with older maternal caregivers may improve adherence and outcomes in this population.

Thalassemia Reports doi: 10.3390/thalassrep14030007

Authors: Arnob Mitro Didar Hossain Md Muhibur Rahman Beauty Dam Mohammad Jakir Hosen

β-thalassemia, a life-threatening inheritable hemoglobin disorder caused by mutations in the HBB gene, poses a significant public health challenge in the world. Although no comprehensive work has been carried out in Bangladesh, the world prevalence and small-scale works indicated the possibility of a high prevalence of this disease in the country. Therefore, this review aims to explore the present situation of β-thalassemia in Bangladesh and propose approaches to mitigate its impact in the future. Limited awareness, a high incidence of consanguineous marriage, and inadequate access to healthcare are possible factors responsible for the high prevalence of thalassemia in Bangladesh, while the absence of public health policy and a national health insurance system further exacerbate the situation. The understanding of the genetic landscape and modern treatment strategies for β-thalassemia is hindered by the lack of comprehensive data on the mutation spectrum. In addition to conventional therapy such as blood transfusion, advanced practices such as splenectomy, hematopoietic stem cell transplantation, and emerging therapies such as gene therapy show promise for future cures but have yet to be widely implemented in this country. To effectively address the challenges of β-thalassemia, it is crucial to adopt comprehensive strategies, including a public awareness campaign, public health intervention, mandatory premarital screening, genetic counselling, and a national thalassemia prevention program. Additionally, understanding the spectrum of mutations and new therapeutic interventions is crucial for advanced healthcare strategies.

Thalassemia Reports doi: 10.3390/thalassrep14020006

Authors: Latifa Alderei Nouf Alshkeili Dana Alnaqbi Omar Abdulla Shehab Ranjit Vijayan Abdul-Kader Souid

The mutation HBA2:c.*94A>G (AATAAA>AATAAG; rs63751269) is a 3′-UTR (3 prime untranslated region) single-nucleotide substitution in the polyadenylation (PA) signal of HBA2 (αPA:A→G). This pathogenic (CADD score, 14.92) variant is sporadic in the Arabian Peninsula. It results in inefficient mRNA processing, transcription termination, and possibly using an alternate cryptic downstream polyadenylation signal. As a result, the allele αT (or αT-Saudi) poses challenges in premarital counseling with respect to fetal risk of hemoglobin H disease. Homozygous HBA2:c.*94A>G (αTα/αTα) results in moderate-to-severe microcytosis (mean red cell volume, MCV, 55 to 65 fL), reflecting markedly impaired hemoglobin synthesis (hemoglobin H disease). Homozygous rightward −α3.7 (a 3804-neocleotide deletion allele, NM_000517.4:c.[-2_-3delAC; −α3.7]), on the other hand, results in mild microcytosis (MCV, 70 to 75 fL, alpha-thalassemia trait). Thus, HBA2:c.*94A>G is more damaging than −α3.7. Consistently, the value of MCV in compound heterozygosity, HBA2:c.*94A>G and −α3.7, is 65 to 70 fL. We report here a healthy couple who presented for premarital counseling on their hemoglobinopathy. The man has homozygous HBA2:c.*94A>G (αTα/αTα), and the woman has compound heterozygous (−α3.7/αTα, also annotated as: −3.7α/αTα). As a result, the genotype of their offspring would be that of the father (αTα/αTα) or the mother (−α3.7/αTα). The counseling was mainly based on the benign phenotypes of the parents. As both were asymptomatic and their anemia was clinically insignificant, they proceeded with the marriage.

Thalassemia Reports doi: 10.3390/thalassrep14020005

Authors: Teny Tjitra Sari Ludi Dhyani Rahmartani Angga Wirahmadi Nathasha Brigitta Selene Stephen Diah Iskandar Pustika Amalia Wahidiyat

Thalassemia a common hereditary blood disorder resulting in anemia. It is an important public health problem, with a high prevalence in Southeast Asia and Mediterranean countries, and preventable through screening programs. However, due to its chronic nature, permanent physical changes, troublesome complications, and lifelong treatment, pediatric patients with thalassemia major are more prone to mental disorders and cognitive impairment. Internalizing and externalizing problems are higher in pediatric patients with thalassemia. Children with β-thalassemia major exhibit lower IQ scores than healthy children. Neurophysiology and neuroimaging examinations have shown abnormal results in children with thalassemia. Co-morbidity with mental disorders increases the mortality, morbidity, and total healthcare costs of patients with thalassemia. Therefore, routine evaluation of mental health problems is recommended to accommodate the early detection and prompt treatment of mental disorders. A multidisciplinary approach for thalassemia patients and families should be delivered by providing appropriate medical care, psychosocial support, and good transition care to improve survival and well-being, assist good social integration and daily functioning, and cope with the stress of chronic disease.

Thalassemia Reports doi: 10.3390/thalassrep14020004

Authors: Konstantinos Manganas Aikaterini Xydaki Angeliki Kotsiafti Olympia Papakonstantinou Sophia Delicou

Extramedullary hematopoiesis (EMH) serves as a compensatory mechanism in chronic hemolytic anemias, such as thalassemia, and can result in spinal cord compression. This case report highlights a 36-year-old woman with transfusion-dependent β-thalassemia (TDT) who presented with lower extremity motor deficiency, pelvic paresthesia, and bladder dysfunction. The patient had a history of lower back pain, bilateral lower limb weakness, and demonstrated poor compliance with iron chelation therapy. MRI findings indicated spinal cord compression attributable to extramedullary hematopoiesis. Due to the infeasibility of surgical intervention, the patient underwent hypertransfusion and iron chelation therapy. While neurological symptoms improved, urinary retention persisted. The patient continues to receive iron chelation treatment and undergo transfusions. Managing extramedullary hematopoiesis in thalassemia necessitates an individualized treatment approach.

Thalassemia Reports doi: 10.3390/thalassrep14010003

Authors: Omar Obajed Al-Ali György Pfliegler Ferenc Magyari Fanni Borics László Imre Pinczés Árpád Illés Boglárka Brúgós

In patients with sickle cell disease (SCD), transfusions pose risks like delayed hemolytic transfusion reaction (DHTR) and hyperhemolytic syndrome (HHS). We present the case of a 61-year-old Nigerian male patient with SCD, developing hyperhemolytic syndrome (HHS) post-orthopedic surgery due to alloimmunization from blood transfusions. Surgery induced massive hemorrhage, requiring RBC transfusions. Postoperatively, he developed HHS with jaundice, hemoglobinuria, and fever. Despite additional transfusions, his condition worsened, leading to hematological consultation on postoperative day +9. Laboratory findings showed positive DAT and multiple alloantibodies. The diagnosis of HHS was established and treatment involved high-dose methylprednisolone, intravenous immunoglobulin (IVIG), and erythropoietin. The patient was discharged on postoperative day +24 with stable hemoglobin levels, tapering doses of methylprednisolone, and continuous administration of hydroxyurea prescribed. HHS pathogenesis involves extensive intravascular hemolysis, exacerbated by alloimmunization. Diagnostic challenges and therapy selection complexity underscore the need for cautious transfusion strategies in HHS, reserving them for hemodynamic instability or hypoxia. This case highlights promptly recognizing and managing HHS in SCD for improved outcomes and avoiding unnecessary transfusions.

Thalassemia Reports doi: 10.3390/thalassrep14010002

Authors: Pimlak Charoenkwan Patcharee Komvilaisak Kaewjai Thepsuthummarat Panya Seksarn Kitti Torcharus

Thalassemia is a hereditary hemolytic anemia that is prevalent in Southeast Asia. The primary treatment for severe thalassemia involves red cell transfusion, iron chelation, and the treatment of long-term complications, leading to frequent hospital visits and admissions. This study aims to delineate the causes and characteristics of hospital admissions among thalassemia patients under the National Health Coverage (NHC) scheme in Thailand. This cross-sectional analysis (2015–2019), conducted using the National Health Security Office database, identified 336,054 admissions among 41,237 patients, with alpha-thalassemia at 12.5%, beta-thalassemia at 61.5%, other thalassemia at 0.5%, and unclassified thalassemia at 25.5%. The overall admission rate was 3.74 per 100 NHC admissions in the pediatric age group. Infections predominated in younger patients, whereas cardiac complications, diabetes mellitus, and cholecystitis/cholelithiasis were more common in older patients. Hospital admissions for cardiac complications and diabetes mellitus in pediatric patients with thalassemia decreased over the study period. The annual hospital admission cost ranged from 8.19 to 12.01 million US dollars, with one-third attributed to iron chelation. In summary, thalassemia poses a significant healthcare challenge in Thai children, characterized by high admission rates and costs. While infections predominate in younger patients, cardiac complications and diabetes mellitus are more common in older individuals. The diminishing admissions for these complications suggest the successful implementation of iron chelation medications.

Thalassemia Reports doi: 10.3390/thalassrep14010001

Authors: Alkistis Adramerina Marina Economou

Thalassemia treatment still relies on supportive care, mainly including blood transfusion and iron chelation therapy. Iron chelation is considered the main factor responsible for the marked improvement in survival rates of thalassemic patients. Hemosiderosis may be prevented if appropriate chelation therapy is offered from early childhood, with timely dose adjustments according to changing body weight and close monitoring of organ iron load. With three iron chelators currently available, the choice of appropriate chelation, either as monotherapy or combined therapy, should be individualized depending on the iron overload of target organs, patient’s age, presence of adverse events and compliance issues, given known limitations related to each agent’s administration.

Thalassemia Reports doi: 10.3390/thalassrep13040022

Authors: Lantip Rujito Ziske Maritska Abdul Salam Sofro

Indonesia is a large island country with a wide variety of ethnic groups. As part of the thalassemia country belt, Indonesia has alleles that are as distinctive as those found in other parts of Southeast Asia. The journey of ancestors in the prehistoric period and the massive increase in human exchange in the last decade have formed the current population of Indonesia. The mutants of the beta-thalassemia allele brought by those predecessors can be seen from the traces of their journey. This paperdescribes the flow gene according to the type of mutations of beta-thalassemia in the country.

Thalassemia Reports doi: 10.3390/thalassrep13040021

Authors: Aily Aliasgharian Hossein Karami Mohammad Zahedi Reza Jahanshahi Hossein Bakhtiari-Dovvombaygi Amirreza Nasirzadeh Mohammad Naderisorki Mehrnoush Kosaryan Ebrahim Salehifar Mobin Ghazaiean Saeid Bitaraf Hadi Darvishi-Khezri

Background and aim: We conducted a review to determine the efficacy of amlodipine alongside iron chelators on serum ferritin levels and liver T2-weighted magnetic resonance imaging (MRI T2*) in β-thalassemia patients. Methods: Systematic search was conducted in multiple databases, including Web of Science, PubMed, Scopus, Embase, Cochrane Library, ClinicalTrials.gov, the Iranian Registry of Clinical Trials (IRCT), ProQuest, OpenGrey, and Web of Science Conference Proceedings Citation Index. The search was closed in January 2023. Primary outcomes were comprised of liver MRI T2* (millisecond (msec)) and serum ferritin levels (ng/mL). Results: Seven studies (n = 227) were included in the study. The pooled Cohen’s d for serum ferritin was estimated at −0.46, 95% confidence interval (CI) −1.11 to 0.19 and p = 0.16 (I2 86.23%, p < 0.0001). The pooled mean difference for serum ferritin was −366.44 ng/mL, 95% CI −844.94 to 112.05, and p = 0.13 (I2 81.63%, p < 0.0001). After a meta-regression based on the length of using amlodipine, a coefficient for the mean difference was also −23.23 ng/mL and 95% CI −155.21 to 108.75. The coefficient obtained from a meta-regression as per the amlodipine dose at 5 mg/day than 2.5 to 5 mg/day anchored at −323.49 ng/mL and 95% CI −826.14 to 1473.12. A meta-regression according to the baseline values of serum ferritin discovered a coefficient of 1.25 ng/mL and 95% CI 0.15 to 2.35. Based on two included studies (n = 96), the overall Cohen’s d for liver MRI T2* was 2.069, 95% CI −0.896 to 5.035, and p = 0.17 (I2 96.31%, p< 0.0001). The synthesized mean difference for liver MRI T2* was 8.76 msec, 95% CI −4.16 to 21.67, and p = 0.18 (I2 98.38%, p < 0.000). Conclusion: At a very low level of evidence, probably using amlodipine at a dose of 2.5 to 5 mg a day, up to a year, alongside iron chelators slightly decreases serum ferritin levels in iron-overloaded thalassemia cases by nearly 366 ng/mL (23 ng/mL per month). The liver MRI T2* might also rise to 8.76 msec upon co-therapy with amlodipine.

Thalassemia Reports doi: 10.3390/thalassrep13040020

Authors: Ahmed M. Abdel Hamied Heba Mostafa Ahmed Dina H. Eldahshan Dalia S. Morgan Abdel Meged A. Abdel Meged Marwa O. Elgendy Mohamed S. Imam Turki A. H. Alotaibi Majed M. S. Alotaibi Manal T. N. Alotaibi Sarah S. S. Alshalan Sara O. Elgendy

β-thalassemia is a genetic disorder affecting chromosome 16, inherited from one or both parents. In spite of the improved treatment of the hematological disorder and its complications, β-thalassemic patients still exhibit an imbalance in bone mineral turnover, resulting in diminished bone mineral density (BMD), more evident in the lumbar spine. The purpose of this study was to investigate the association between genetic polymorphism of the PPAR-γ gene and the presence of osteopenia or osteoporosis in children with β-thalassemia. This case–control study was conducted on 50 children with β-thalassemia from the pediatric hematology unit of Beni-Suef University Hospital, including 50 healthy children as the control group. The age range was 8 to 18 years. Samples of patients and control subjects were analyzed for the presence of polymorphisms of the PPAR-γ gene and other blood labs. An assay of BMD measure using dual-energy X-ray absorptiometry (DXA) was performed to investigate osteopenia or osteoporosis. Statistical analysis was used to investigate the relationship between the risk of osteopenia or osteoporosis and the presence of PPAR-γ Pro12Ala gene polymorphism. Eighteen (eleven males and seven females) of fifty patients (representing 36% of the patients group) have osteopenia with low bone mineral density (Z-score is −1 or less than 1). There was no statistically significant difference between BMD measurements in males and females. By comparing the frequency of 12 Ala gene polymorphisms between the patient group and the control group, we found that no statistically significant difference was detected. The BMD values were not significantly different between the groups of PPAR-γ Pro12Ala gene polymorphism. In conclusion, decreased BMD levels are frequent in β-thalassemia patients. PPAR-γ Pro12Ala gene polymorphism is not common in Egyptian patients with β-thalassemia. No significant relationship was found between the PPAR-γ Pro12Ala gene polymorphism and low BMD levels or osteopenia in Egyptian β-thalassemia patients. However, further studies on a larger population of Egyptian patients are needed to confirm this finding.

Thalassemia Reports doi: 10.3390/thalassrep13030019

Authors: Tarun Sahu Babita Pande Henu Kumar Verma L V K S Bhaskar Meenakshi Sinha Ramanjan Sinha Pasupuleti Visweswara Rao

Sickle cell disease (SCD) is a complex genetic disorder associated with multiple clinical manifestations, including increased susceptibility to bacterial and viral infections. This review article presents a comprehensive analysis of the current literature obtained from various online databases focusing on the relationship between SCD and infections caused by specific pathogens, such as pneumonia- and influenza-causing pathogens, Escherichia coli, Staphylococcus aureus, parvovirus, and hepatitis viruses. We discuss the underlying mechanisms that contribute to the increased susceptibility of individuals with SCD to these infections, primarily related to the pathophysiology of variant hemoglobin (HbSS) and its impact on vascular occlusion, hemolysis, functional asplenia, and immune deficiency. Moreover, we highlight the significant burden of infections on SCD patients, particularly children under five years of age, where they are the leading cause of morbidity and mortality. Additionally, we address the challenges faced in attempts for reducing the global mortality rate associated with SCD, particularly in low-income countries, where factors such as increased pathogen exposure, co-morbidities like malnutrition, lower vaccination rates, and limited healthcare facilities contribute to the high disease burden. This review emphasizes the need for targeted interventions, improved healthcare access, vaccination programs, and infection prevention strategies to alleviate the impact of infections on individuals with SCD and reduce the global mortality rates associated with the disease.

Thalassemia Reports doi: 10.3390/thalassrep13030018

Authors: Shahad Saif Khandker Nurani Jannat Deepannita Sarkar Alif Hasan Pranto Ismoth Ara Hoque Jemema Zaman Md. Nizam Uddin Ehsan Suez

Thalassemia is one of the most prevalent genetic disorders worldwide and has previously been found to have an association with several physiological and organ complications. Several studies have found both its positive and inverse correlation with the glomerular filtration rate (GFR). Therefore, in this meta-analysis, we tried to assess the accurate correlation of β-thalassemia major (β-TM) with GFR. We searched in Google Scholar, PubMed, and ScienceDirect, and from the initial 96 articles, we finally included 12 studies. The quality and publication bias assessment confirmed that all the studies were of high to moderate quality with no publication bias. The main outcome of the mean difference (MD) was −6.94, 95%CI: −20.69, 6.80 (p < 0.00001), which indicated a negative correlation of the GFR with β-TM. The sensitivity analyses found one study to be a slight outlier, and reanalyzing the data excluding that study, an MD was achieved of −16.46, 95%CI: −26.81, −6.11 (p < 0.00001), which provides even stronger support for our main outcome. Our result determined that the GFR is generally higher in healthy people as compared to β-TM patients.

Thalassemia Reports doi: 10.3390/thalassrep13030017

Authors: Subhangi Basu Motiur Rahaman Tuphan Kanti Dolai Praphulla Chandra Shukla Nishant Chakravorty

β-thalassemia, a congenital genetic hematological disorder characterized by the decrease or absence of β-globin chains, leads to a decrease in levels of Hemoglobin A. The affected individuals can be categorized into two cohorts based on transfusion dependency: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). Remarkably, despite the primary pathology lying in β-globin chain depletion, β-thalassemia also exhibits an intriguing association with iron overload. Iron metabolism, a tightly regulated physiological process, reveals a complex interplay in these patients. Over time, both cohorts of β-thalassemic individuals develop iron overload, albeit through distinct mechanisms. Addressing the diverse complications that arise due to iron overload in β-thalassemic patients, the utilization of iron chelators has gained a lot of significance. With varying efficacies, routes of administration, and modes of action, different iron chelators offer unique benefits to patients. In the Indian context, three commercialized iron chelators have emerged, showcasing a high adherence rate to iron chelator-based treatment regimens among β-thalassemic individuals. In this review, we explore the intriguing connection between β-thalassemia and iron overload, shedding light on the intricate mechanisms at play. We delve into the intricacies of iron metabolism, unveiling the distinct pathways leading to iron accumulation in these patients. Additionally, the therapeutic efficacy of different iron chelators in managing iron overload complications is mentioned briefly, along with the guidelines for their usage in India. Through this comprehensive analysis, we aim to deepen our understanding of β-thalassemia and iron overload, paving the way for optimized treatment strategies. Ultimately, our findings provide valuable insights into improving the care and outcomes of individuals affected by β-thalassemia.

Thalassemia Reports doi: 10.3390/thalassrep13030016

Authors: Supradip Dutta Aritra Biswas Sagnik Bakshi Promisree Choudhury Raina Das Shreyasi Nath Prosanto Chowdhury Maitreyee Bhattacharyya Sharmistha Chakraborty Shanta Dutta Provash Chandra Sadhukhan

Background: HCV infection is very common in multi-transfused β-thalassemia patients who need regular blood transfusions. Aim: The study was conducted to determine the epidemiology of HCV in multi-transfused β-thalassemia patients in West Bengal, India. Methods: Over a span of six years, blood samples were collected from HCV sero-reactive β-thalassemia patients and processed for viral RNA isolation followed by nested RT-PCR for qualitative viremia detection. The HCV genotype was determined by amplifying the partial HCV core gene by nested RT-PCR followed by DNA sequencing and NCBI genotyping tools. Phylogenetic and phylogeographic studies were performed with MEGA-X and BEAST software, respectively. Results: Out of 917 multi-transfused HCV sero-reactive β-thalassemia patients, 598 (65.21%) were HCV RNA positive while 250 (41.80%) had spontaneously cleared the virus. A significant percentage of male patients from rural areas (p = 0.042) and economically backward class (p = 0.002) were at higher risk of HCV infection. Female thalassemia patients and individuals belonging to ages 11–15 years had higher chances of spontaneous clearance. The most prevalent circulatory HCV genotype was 3a (78.26%) followed by 1b (12.04%). Phylogeographic analyses revealed that the 3a strains share genomic similarities with strains from Pakistan, Sri Lanka, and Thailand, whereas the 1b strains share similarities with strains from Thailand, Vietnam, Russia, and China. Uncommon HCV subtypes 3g and 3i were also detected. Conclusion: The high prevalence of HCV infection among β-thalassemia patients of West Bengal, India indicates NAT-based assays should be implemented for HCV screening in donor blood to eliminate HCV by 2030.

Thalassemia Reports doi: 10.3390/thalassrep13020015

Authors: Shaun R. McCann Andrea Piccin

Severe Aplastic Anaemia (SAA) is a rare benign disease but carries a high-mortality rate unless treated in a specialised centre. Overwhelming laboratory and clinical evidence points to an autoimmune pathogenesis; although, the aetiology remains obscure in the majority of cases. The differential diagnosis in older patients is problematical and a diagnosis of hypoplastic myelodysplasia remains difficult. This review points out the difficulty in diagnosis without a specific test. Future research needs to define a specific diagnostic test and refine therapeutic interventions.

Thalassemia Reports doi: 10.3390/thalassrep13020014

Authors: Hossein Jalali Hossein Karami Mahan Mahdavi Mohammad Reza Mahdavi

Background: Alpha thalassemia is one of the most common human genetic abnormalities. More than 400 different variations of the α-globin protein have been introduced, most of which are not associated with noticeable clinical manifestations. The identification of all variants of Hb in different regions helps in acquiring comprehensive knowledge concerning thalassemia disease, and it can be used in preventive programs as well as prenatal diagnosis (PND). Aims: In the present study, we describe a new α1 gene mutation that leads to a frameshift after codon 83. Methods: As a plan for a national screening program of thalassemia, routine cell blood count (CBC) and Hb capillary electrophoresis tests were applied. After taking written informed consent, genomic DNA was extracted, and, for identifying common Mediterranean α-Globin gene deletion, multiplex Gap-PCR was performed; for detecting other mutations on α- and β-Globin genes, a DNA sequencing method was used. Results: The results of CBC and capillary electrophoresis tests showed microcytosis in a female subject. The sequencing of the α-Globin gene showed that the case is heterozygote for a single-nucleotide deletion at codon 83 of the α1-Globin Gene. We named this mutation Hb Adrian (α1: c.251–T), which is a novel mutation. The mentioned mutation was also detected in the subject’s mother. Conclusions: The introduced mutation (Hb Adrian) leads to a frameshift change that produces a protein with 100 amino acids, which in comparison to a normal α-chain is shorter, and its amino acids are altered after codon 83. This hemoglobin is undetectable via the use of electrophoresis. Although no major hematological abnormalities were observed in the carriers, Hb Adrian should be considered in screening programs to help prevent Hb H disease in high-risk couples.

Thalassemia Reports doi: 10.3390/thalassrep13020013

Authors: Kelath Murali Manoj

Murburn concept is a novel perspective for understanding cellular function, deeming cells as simple chemical engines (SCE) that are powered by redox reactions initiated by effective charge separation (ECS). The 1-electron active diffusible reactive (oxygen) species, or DR(O)S, equilibriums involved in these processes are also crucial for homeostasis, coherently networking cells, and rendering electromechanical functions of sensing and responding to stimuli. This perspective presents the true physiological function of oxygen, which is to enable ECS and the generation of DR(O)S. Therefore, DR(O)S must now to be seen as the quintessential elixir of life, although they might have undesired effects (i.e., the traditionally perceived oxidative stress) when present in the wrong amounts, places and times. We also elaborated that tetrameric hemoglobin (Hb) is actually an ATP-synthesizing murzyme (an enzyme working via murburn concept) and postulated that several post-translational modifications (such as glycation) on Hb could result from murburn activity. Murburn perspective has also enabled the establishment of a facile rationale explaining the sustenance of erythrocytes for 3–4 months, despite their lacking nucleus or mitochondria (to coordinate their various functions and mass-produce ATP, respectively). Although thalassemia has its roots in genetic causation, the new awareness of the mechanistic roles of oxygen-hemoglobin-erythrocyte trio significantly impacts our approaches to interpreting research data and devising therapies for this malady. These insights are also relevant in other clinical manifestations that involve respiratory distress (such as asthma, lung cancer, COVID-19 and pneumonia) and mitochondrial diseases. Herein, these contexts and developments are briefly discussed.

Thalassemia Reports doi: 10.3390/thalassrep13020012

Authors: Anamul Hasan Jigishu Ahmed Bikash Chandra Chanda Maisha Aniqua Raisa Akther Palash Kanti Dhar Kazi Afrin Binta Hasan Abdur Rouf Siddique Md. Zahidul Islam Sharmine Zaman Urmee Dinesh Mondal

Background: Although the global thalassemia zone covers Bangladesh, there are very limited studies conducted in this region. Therefore, the focus of our study is to understand the prevalence and burden of thalassemia and hemoglobinopathy in Bangladesh. Methods: The analysis was based on a retrospective evaluation of laboratory diagnoses between 2007 January and 2021 October. A total of 8503 specimens were sampled and analyzed which were either referred by corresponding physicians or self-referred. This was neither any epidemiological nationwide survey nor was the study population chosen randomly. Hematological data were obtained through capillary zone electrophoresis and corresponding complete blood count. Results: 1971 samples (~23.18% of the total) were found with at least one inherited hemoglobin disorder. The most common hemoglobin disorder observed was the hemoglobin E (Hb E) trait (10.67%), followed by the β-thalassemia trait (8.4%), homozygotic Hb E (1.59%), and Hb E/β-thalassemia (1.58%). Other variants found in this study with minimal percentages were Hb N-Seattle, Hb S, Hb D-Punjab, Hb Lepore, Hb C, Hb Hope, Hb H, and hereditary persistence of fetal hemoglobin. Discussion: The pattern of thalassemia and hemoglobinopathy in our study is diverse and heterogeneous. A broad and detailed spectrum of such inherited hemoglobin disorders will ultimately be helpful in implementing nationwide thalassemia management and strategy policy in Bangladesh.

Thalassemia Reports doi: 10.3390/thalassrep13020011

Authors: Luca Castagna Stefania Tringali Giuseppe Sapienza Roberto Bono Rosario Di Maggio Aurelio Maggio

Allogeneic stem cell transplantation remains the only therapy for congenital, severe haemoglobinopathies that is able to reverse the pathological phenotype. In the severe form of thalassemia, regular transfusions are needed early in life. This population of patients could benefit from allo-SCT. However, the great efficacy of transplantation must be counterbalanced by the mortality and morbidity related to the procedure. In this short review, we reviewed the most recent data in the field of transplantation in transfusion-dependent thalassemia (TDT), highlighting the factors that have a major impact on outcomes.

Thalassemia Reports doi: 10.3390/thalassrep13010010

Authors: María E. Mónaco Natalia S. Alvarez Asensio Cecilia Haro Magdalena M. Terán Miryam E. Ledesma Achem Blanca A. Issé Sandra S. Lazarte

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.

Thalassemia Reports doi: 10.3390/thalassrep13010009

Authors: Poonam Tripathi Sarita Agarwal Kausik Mandal Anshul Gupta Aditya Narayan Sarangi

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.

Thalassemia Reports doi: 10.3390/thalassrep13010008

Authors: Yesim Aydinok

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.

Thalassemia Reports doi: 10.3390/thalassrep13010007

Authors: Elena Krishnevskaya Marta Molero Águeda Ancochea Ines Hernández Joan-Lluis Vives-Corrons

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.

Thalassemia Reports doi: 10.3390/thalassrep13010006

Authors: Udani Gamage Kesari Warnakulasuriya Sonali Hansika Gayathri N. Silva

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.

Thalassemia Reports doi: 10.3390/thalassrep13010005

Authors: Nathalie Akiki Mohammad H. Hodroj Rayan Bou-Fakhredin Kamal Matli Ali T. Taher

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.

Thalassemia Reports doi: 10.3390/thalassrep13010004

Authors: Androulla Eleftheriou Dimitrios Farmakis Panos Englezos Shobha Tuli Elena Mylona George Constantinou Riyad Elbard Saeed Jafaar Al-Awadhi Sheikha Sheikha Bint Seif Al-Nahyan Robert Ficarra Michelle Abi Saad Anton Skafi Loris Angelo Brunetta Fatemeh Hashemi Eleni Michalaki Abdul Baset Mohd Merdas Michael Angastiniotis

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.

Thalassemia Reports doi: 10.3390/thalassrep13010003

Authors: Edouard Lansiaux Emmanuel Drouin Carsten Bolm

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.

Thalassemia Reports doi: 10.3390/thalassrep13010002

Authors: Michael Angastiniotis Androulla Eleftheriou Mohammed Naveed Ali Al Assaf Andreas Polynikis Elpidoforos S. Soteriades Dimitrios Farmakis

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.

Thalassemia Reports doi: 10.3390/thalassrep13010001

Authors: Ludi Dhyani Rahmartani Micheylla Kusumaning Dewi Stephen Diah Iskandar Anastasia Michelle Pratanata Ganda Ilmana Teny Tjitra Sari Anna Mira Lubis Pustika Amalia Wahidiyat

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.

Thalassemia Reports doi: 10.3390/thalassrep12040020

Authors: Duantida Songdej Suthat Fucharoen

One of the more common single-gene disorders worldwide is α-thalassemia, carriers of which are found at variable frequencies (>1%) across all tropical and subtropical countries. Two linked α-globin genes on each allele of chromosome 16 regulate α-globin chain production. Deletion of one or more α-globin genes is the most frequent molecular defect found in α-thalassemia, whereas non-deletional mutations also occur, leading to unstable α-globin chains. HbH is the most common clinically important α-thalassemia disease and occurs when three α-globin genes are deleted/mutated, leaving only one copy of the gene intact. HbH can be divided into deletional (--/-α) and non-deletional genotypes (--/αTα). Whereas clinical phenotypes of the former are usually homogenously mild to moderate, those of the latter can be diverse. As HbH disease is particularly prevalent in Southeast Asia and some parts of the Mediterranean region, where β-thalassemia is also prevalent, affected patients are sometimes left undertreated. Therefore, hematologists and general physicians need to be educated to provide optimal disease monitoring and early identification of those with more severe phenotypes. Some issues regarding transfusion and iron chelation management differ from those of β-thalassemia, and these need to be recognized. Hb Bart’s hydrops fetalis syndrome (BHFS) is the most severe form of α-thalassemia; affected patients lack production of α-globin chains. Recent advances in fetal medicine and neonatal intensive care have made it possible for BHFS to no longer constitute a universally fatal disorder. Transfusion and chelation strategies for rare survivors are distinct and require updating.

Thalassemia Reports doi: 10.3390/thalassrep12040019

Authors: Michael Angastiniotis Soteroula Christou Annita Kolnakou Evangelia Pangalou Irene Savvidou Dimitrios Farmakis Androulla Eleftheriou

Haemoglobinopathies, including thalassaemias and sickle-cell syndromes, are demanding, lifelong conditions that pose a significant burden to patients, families, and healthcare systems. Despite the therapeutic advances and the resulting improvements in prognosis accomplished in past decades, these patients still face important challenges, including suboptimal access to quality care in areas with developing economies, changing epidemiology due to massive migration flows, an evolving clinical spectrum due to ageing in well-treated patients, and limited access to novel high-cost therapies. We herein describe the organization of healthcare services for haemoglobinopathies in Cyprus—with particular focus on beta-thalassaemia, the most prevalent condition in this region—along with selected patient outcomes. This report aims at underscoring the fact that nationally funded and well-coordinated prevention and care programmes for chronic and complex conditions, such as haemoglobinopathies, with active involvement from patient organizations lead to effective disease control and excellent outcomes in survival, quality of life, social adaptation, and public health savings, and allow timely and effective responses to emerging crises, such as the COVID-19 pandemic. The Cyprus paradigm could therefore serve as a blueprint for the organization or adaptation of haemoglobinopathy programs in other countries since these disorders are still widely occurring.

Thalassemia Reports doi: 10.3390/thalassrep12040018

Authors: Nadeeja Amarasinghe Amila Amarasena Anoj Thabrew Prabhath Werawatte Anuja Premawardhena Farnaz Malik Mohamed Abusayeed Champika Wickramasinghe

Sri Lanka, a country with 22 million people, has nearly 2000 thalassemia patients with severe thalassemia, two-thirds of whom have beta thalassemia major (TM). The current prevention program based on promoting “safe marriages”, which has been in existence for over 15 years, has failed to reduce thalassemia major births. We set about to examine the cost-effectiveness of novel policy options for thalassemia prevention in Sri Lanka. Methods: The current cost for treatment of a thalassemia major patient (USD 2602/yr) was compared against the cost per reduction of single birth with three novel strategies, namely intensifying the screening in the current five districts combined with an education program (policy option 1), a nationwide screening program (policy option 2), and antenatal screening combined with the termination of pregnancy (policy option 3). The incremental cost-effectiveness ratio (ICER) of the different strategies was calculated. Results: The status quo was considered to reduce one TM birth whilst the new policy options were able to reduce births by 14, 35, and 48, respectively. The costs incurred for the program for a year for status quo and the three novel programs were USD 104,788, 173,884, 781,372, and 904,186 respectively. Cost per prevention of a thalassemia major birth was USD 87,324, 12,420, 22,324, and 20,084, respectively. The lifetime cost per treatment of a thalassemia major patient was USD 34,653. Conclusions: Given the current legal restriction on termination of pregnancy for fetal indications, policy option 2, an island-wide screening with mass education, is the most cost-effective and will be expected to deliver a substantial reduction in new births.

Thalassemia Reports doi: 10.3390/thalassrep12030017

Authors: Tsz Yuen Au Shamiram Benjamin Oskar Wojciech Wiśniewski

Thalassemia is a disease of erythrocytes that varies largely on its genetic composition and associated clinical presentation. Though some patients may remain asymptomatic, those with a complicated course may experience severe anemia early in childhood, carrying into adulthood and requiring recurrent blood transfusions as a pillar of symptom management. Due to the consequences of ineffective erythropoiesis and frequent transfusions, patients with severe beta thalassemia may be subsequently susceptible to hemochromatosis. In light of the established role of hepcidin and erythroferrone in the pathogenesis of beta thalassemia, this review aims to discuss current clinical trials and studies in the field while presenting clinical implications of the HAMP gene polymorphisms and novel treatments. Research suggested incorporating erythroferrone and serum hepcidin testing as a part of routine workups for beta thalassemia, as they could be a predictive tool for early iron accumulation. Furthermore, ameliorating low hepcidin and high erythroferrone appeared to be crucial in treating beta thalassemia and its complications due to iron overload. Currently, hepcidin-like compounds, such as minihepcidins, LJPC-401, PTG-300, VIT-2763, and agents that promote hepcidin production by inhibiting TMPRSS6 expression or erythroferrone, were shown to be effective in restoring iron homeostasis in preliminary studies. Moreover, the natural bioactives astragalus polysaccharide and icariin have been recently recognized as hepcidin expression inductors.

Thalassemia Reports doi: 10.3390/thalassrep12030016

Authors: Sehjeong Kim Hamda AlDhaheri So-Yeun Kim

We investigated the impact of three marriageable actions: normal-to-carrier, carrier-to-normal, and carrier-to-carrier marriages on thalassemia and carrier populations. The well-known strategy is limiting the carrier-to-carrier marriage to reduce the thalassemia population. Thus, the other two marriageable actions were often ignored. Other than a simple explanation of their genetic consequences, their important aspect in the thalassemia inheritance mechanism has never been studied at the population level. Moreover, there is no mathematical model investigating problem of interest for blood disorders at the population level. Hence, we developed a mathematical model to examine the possibility of eradication/reduction of thalassemia and carrier populations through each of the three marriageable actions in the long-term. We conducted computer simulations with the demographic data of the United Arab Emirates in which high thalassemia carrier prevalence is identified. We found that promoting more carrier-to-normal marriage will eventually have the same effects on marriage reconsideration for carrier-carrier couples, contributing to the reduction of the carrier population in the long-term. Interestingly, the normal-to-carrier marriage does not necessarily have a similar effect on thalassemia and carrier populations as that of the carrier-to-normal marriage. Thus, the two marriageable actions should be distinguished and also seriously considered in education and public awareness campaigns for thalassemia.

Thalassemia Reports doi: 10.3390/thalassrep12030015

Authors: Hossein Jalali Hossein Karami Mohammad Reza Mahdavi Mehrad Mahdavi

This is a report of a couple with abnormal hematological indices who were investigated for α & β-thalassemia mutations. Based on CBC and capillary hemoglobin electrophoresis results, the male and female subjects were β & α-thalassemia carriers, respectively. Multiplex-Gap-PCR and Sanger sequencing techniques were used for the identification of mutations on α and β-globin genes. The DNA test showed the presence of c.315 + 1 G > A mutation on β-globin gene of male subject while the female case had – MED double gene deletion and c.427T > C mutation on α-globin and, interestingly, she was also a carrier for c.315 + 1 G > A mutation on β-globin gene. Cases with the coinheritance of heterozygous β0-thalassemia with one functional α-globin gene have normal HbA2 levels that may lead to their being misdiagnosed as β-thalassemia carriers, especially in premarital screening programs for thalassemia. Therefore, β-globin gene sequencing is recommended in cases with normal Hb electrophoresis and reduced hematological indices in premarital screening programs for thalassemia, especially in regions with a high frequency of β-globin mutations, in order to identify all the β-thalassemia carriers.

Thalassemia Reports doi: 10.3390/thalassrep12030014

Authors: Ellen B. Fung Elijah K. Goldberg Sakina Bambot Raquel Manzo Ashutosh Lal

Patients with thalassemia (Thal) engage in less physical activity than non-Thal populations, which may contribute to pain and osteoporosis. The purpose of this study was to assess relationships between physical activity, pain, and low bone mass in a contemporary sample of patients with Thal. Seventy-one patients with Thal (50 adults ≥18 years, 61% male, 82% transfusion-dependent) completed the Brief Pain Inventory Short Form and validated physical activity questionnaires for youth and adults. Nearly half of the patients reported daily somatic pain. Using multiple regression, after controlling for age and gender, sedentary behavior was positively associated with pain severity (p = 0.017, r2 = 0.28). Only 37% of adult participants met CDC recommendations for physical activity. Spine BMD Z-score was higher (−2.1 ± 0.7) in those who met activity guidelines compared to those who did not (−2.8 ± 1.2, p = 0.048). A positive relationship was observed between self-reported physical activity (hours/week) and hip BMD Z-score in adults with Thal after controlling for transfusion status and sedentary activity time (p = 0.009, r2 = 0.25). These results suggest that decreased physical activity and increased sedentary behavior contribute to low bone mass, which may be related to pain severity in some patients with Thal. Studies focused on increasing physical activity may contribute to improved bone health and reduced pain in patients with Thal.

Thalassemia Reports doi: 10.3390/thalassrep12030013

Authors: Rosario Di Maggio Alessandra Giuliano Disma Renda Giuseppina Calvaruso Simona Raso Lorella Pitrolo Antonio Carroccio Aurelio Maggio

Venous thromboembolism (VTE) is a life-threatening complication, especially in case of recurrence. The appropriate duration of anticoagulant treatment following the first event is crucial. Risk factors that increase the risk of recurrence of VTE are many, and include medications, kidney disease, renal transplantation (RT), and a diagnosis of sickle cell disease (SCD). There are currently no guidelines that define the duration of anticoagulant therapy after the first event in a patient with RT. We report a case of recurring episodes of VTE after RT in a SCD patient. Our case suggests that the use of a long-term anticoagulant treatment may be recommended in patients with SCD and RT after the first event of VTE.

Thalassemia Reports doi: 10.3390/thalassrep12030012

Authors: Pallavi Thaker Namrata Mahajan Malay B. Mukherjee Roshan B. Colah

Alpha thalassemia is an autosomal recessive disorder caused by large deletions and/or point mutations in the α- globin genes. Hemoglobin H (Hb H) disease is most frequently due to deletion of three of the four α globin genes associated with variable clinical severity depending on the genotype. There are few reports on Hb H disease in Indians where genotyping has been done and we have reviewed the molecular and clinical heterogeneity of these cases. An electronic search for relevant articles was conducted using two journal databases, i.e., PubMed and Science Direct using the key words “Hb H Disease”, “Hemoglobin H”, “α-thalassemia”, “mutations”, “molecular heterogeneity”, “case reports” and “India”. This review was performed based on preferred reporting items for the systematic review and meta-analysis protocols (PRISMA-P) guidelines. The molecular spectrum of Hb H disease in Indians includes the most common [-α3.7, -α4.2, --SA, Poly A (AATAAA→AATA--), Hb Sallanches], rare [--SEA, --MED, IVS 1nt 1 (G→A), Hb Koya Dora, Hb Sun Prairie], very rare [Hb Iberia, Hb Seal Rock, Hb Zürich-Albisrieden] and novel [Codon 76 (+T) and --Kol] α-globin gene mutations inherited largely as compound heterozygotes with considerable clinical variability. The molecular diagnosis of Hb H disease is important for genetic counseling and management.

Thalassemia Reports doi: 10.3390/thalassrep12030011

Authors: Stefania Byrou George Christopoulos Agathoklis Christofides Christiana Makariou Christiana Ioannou Marina Kleanthous Thessalia Papasavva

The assignment of alleles to haplotypes in prenatal diagnostic assays has traditionally depended on family study analyses. However, this prevents the wide application of prenatal diagnosis based on haplotype analysis, especially in countries with dispersed populations. Here, we present an easy and fast approach using Droplet Digital PCR for the direct determination of haplotype blocks, overcoming the necessity for acquiring other family members’ genetic samples. We demonstrate this approach on nine families that were referred to our center for a prenatal diagnosis of β-thalassaemia using four highly polymorphic single nucleotide variations and the most common pathogenic β-thalassaemia variation in our population. Our approach resulted in the successful direct chromosomal phasing and haplotyping for all nine of the families analyzed, demonstrating a complete agreement with the haplotypes that are ascertained based on family trios. The clinical utility of this approach is envisaged to open the application of prenatal diagnosis for β-thalassaemia to all cases, while simultaneously providing a model for extending the prenatal diagnostic application of other monogenic diseases as well.

Thalassemia Reports doi: 10.3390/thalassrep12030010

Authors: Hossein Jalali Mohammad Reza Mahdavi Mahan Mahdavi Adeleh Abbasi

This is a report of a novel variant of the α1-globin gene—(α1) α51 Gly > Cys (CE9), c.154 GGC > TGC, named Hb Mazandaran, which was observed in an Iranian family. This variant gives rise to a previously undescribed haemoglobin variant that was undetectable by capillary haemoglobin electrophoresis (CE). This variant was detected in two cases in combination with β-globin mutation, and it does not seem to be associated with severe haematological abnormalities in the carriers.

Thalassemia Reports doi: 10.3390/thalassrep12020009

Authors: Giuseppina Calvaruso Marta Chiavetta Disma Renda Simona Raso Francesco Dieli Vincenzo Luca Lentini Massimo Gentile Antonio Carroccio Aurelio Maggio

Background: Haemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening systemic hyperinflammatory disease, which can have several aetiologies. Clinical case: a 48-year-old woman affected by a transfusion-dependent β-thalassemia was hospitalized in our haematology unit presenting with intermittent fever, haepatosplenomegaly and pancytopenia, which developed a few days after the booster dose of anti-SARS-CoV-2 mRNA vaccine. The investigations performed during hospitalization led to a diagnosis of HLH and steroid therapy where IV dexamethasone was initiated and provided benefits. Conclusions: the severity of HLH mandates early treatment, but the management of patients with post-vaccine HLH is still challenging and requires further study. No cases of HLH in patients with thalassemia were previously described.

Thalassemia Reports doi: 10.3390/thalassrep12020008

Authors: Sophia Delicou Aikaterini Xydaki Konstantinos Manganas Emmanouil Koullias Loukia Evliati Chryssoula Kalkana Michael D. Diamantidis Achilles Manafas Marianna Katsatou Leonidas Roumpatis Theodoros Aforozis

During a pandemic, people are fearful of becoming infected with the virus, which causes anxiety, loss of purpose, and depression. This study aimed to evaluate the social and psychological impact, as well as the impact on homecare, of patients with hemoglobinopathies during the pandemic. Material and Methods: In total, 130 patients from four Thalassemia and Sickle Cell Disease Units of the National Health System of Greece Hospitals were examined via an anonymous questionnaire developed and distributed through stratified sampling. Results: Transfusion-dependent thalassemia, transfused sickle cell disease, and other hemoglobinopathies were represented by 130 patients. During the pandemic, the main concern of patients was the affordability of blood for transfusion. During the lockdown, patients’ moods varied, and their daily lives were disrupted by a lack of access to basic goods and communication with friends and family. Their eating habits, access to exercise, and, to a lesser extent, their financial situation have all been affected in their daily lives. It is crucial to highlight that while access to health services did not suffer in terms of medication and regular visits for their actual disease, it did suffer in terms of the systematic monitoring of complications.

Thalassemia Reports doi: 10.3390/thalassrep12020007

Authors: Deniz Aslan Şeyda Değermenci

Changes in erythrocyte parameters are well known in both β-thalassemia minor (BTM) and iron deficiency (ID) when either is present alone; however, to our knowledge, there has been no study showing the changes when the two conditions coexist. We herein assessed erythrocyte parameters in BTM with coexistent ID. The BTM cases were divided into two groups based on ferritin levels as ID+ and ID−; the ID+ group was then further divided based on hemoglobin (Hb) levels as iron-deficient carriers with (IDA+) and without (IDA−) anemia. When compared to the ID− group, all parameters were significantly different in the IDA+ group except mean corpuscular volume (MCV) and red blood cells (RBC). All parameters except RBC were significantly different between the IDA+ and IDA− groups. Hb, hematocrit (Hct), MCV, and mean corpuscular hemoglobin (MCH) levels in the IDA− group were found to be lower than in the ID− group. Changes in erythrocyte parameters in iron-deficient carriers are critical in screening for BT, particularly for correct formulation of mathematical algorithms utilized by artificial intelligence programs.

Thalassemia Reports doi: 10.3390/thalassrep12020006

Authors: Annamaria Petrungaro Eugenia Quartarone Paolo Sciarrone Luciana Rigoli

Transfusion-dependent thalassemia patients undergo transfusion immunomodulating effects, which result in a general immune response depression and, consequently, an increase in the frequency of infectious episodes and neoplastic events due to a reduction in phagocytic function. Altered natural killer functions and IL-2-mediated lymphocytic response, defects in antigen presentation due to monocyte–macrophage cells, and decreases in bone marrow precursors and HLA II+ cells all play key roles in immunodepression in thalassemia major. SARS-CoV-2 infection presents marked lymphopenia, occurring in 96.1% of severe cases. COVID-19-related lymphopenia is due to various mechanisms, which lead to an increase in lymphocytic apoptosis. Post-COVID-19 lymphocytic quantitative and functional disorders may compromise immune response and promote the onset of infections via opportunistic pathogens. Herein, we report a case of a thalassemia major patient who developed severe post-COVID-19 lymphocytopenia, which may have facilitated the onset of a severe Klebsiella Pneumoniae infection.

Thalassemia Reports doi: 10.3390/thalassrep12010005

Authors: Thalassemia Reports Editorial Office Thalassemia Reports Editorial Office

From Volume 1 (2011) to Volume 11 (2021), Thalassemia Reports [...]

Thalassemia Reports doi: 10.3390/thalassrep12010004

Authors: Angela Vitrano Khaled M. Musallam Antonella Meloni Sebastiano Addario Pollina Mehran Karimi Amal El-Beshlawy Mahmoud Hajipour Vito Di Marco Saqib Hussain Ansari Aldo Filosa Paolo Ricchi Adriana Ceci Shahina Daar Efthymia Vlachaki Sylvia Titi Singer Zaki A. Naserullah Alessia Pepe Salvatore Scondotto Gabriella Dardanoni Fedele Bonifazi Vijay G. Sankaran Elliott Vichinsky Ali T. Taher Aurelio Maggio International Working Group on Thalassemia (IWG-THAL) International Working Group on Thalassemia (IWG-THAL)

In this work, we aimed to establish subgroups of clinical severity in a global cohort of β-thalassemia through unsupervised random forest (RF) clustering. We used a large global dataset of 7910 β-thalassemia patients and evaluated 19 indicators of phenotype severity (IPhS) to determine their contribution and relatedness in grouping β-thalassemia patients into clusters using RF analysis. RF clustering suggested that three clusters with minimal overlapping exist (classification error rate: 4.3%), and six important IPhS were identified: the current age of the patient, the mean serum ferritin level, the age at diagnosis, the age at first transfusion, the age at first iron chelation, and the number of complications. Cluster 3 represented patients with early initiation of transfusion and iron chelation, considerable iron overload, and early mortality from heart failure. Patients in Cluster 2 had lower serum ferritin levels, although they had a higher number of complications manifesting overtime. Patients in Cluster 1 represented a subgroup with delayed or absent transfusion and iron chelation, but with a high morbidity rate. Hepatic disease and cancer were dominant causes of death in patients in Cluster 1 and 2. Our findings established that patients with β-thalassemia can be clustered into three groups based on six parameters of phenotype severity.

Thalassemia Reports doi: 10.3390/thalassrep12010003

Authors: Aurelio Maggio

The recent transfer of Thalassemia Reports, the only journal fully dedicated on Thalassemia, from PagePress to MDPI was great news for those who contributed to the spread of the journal [...]

Thalassemia Reports doi: 10.3390/thalassrep12010002

Authors: Burhan A. Zaman Suzan O. Rasool Nashwan M. R. Ibrahim Deldar M. Abdulah

Background: The progressive renal function inadequacy results in altered hepcidin metabolism due to a shifting of its renal elimination, which consequently affects enteric iron absorption and iron stores’ availability. This study aimed to investigate and correlate renal function, iron status, and hepcidin in patients with β-thalassemia major through a novel index. Methods: In this 1:1 case–control study, serum hepcidin, serum ferritin, iron study, hematological and renal function parameters were compared between 60 β-thalassemia major patients with iron overload and 61 healthy individuals (2–30 years old). Results: The concentrations of serum hepcidin (21.898 vs. 9.941 ng/mL; p < 0.001) and eGFR (179.71 vs. 132.95; p < 0.001) were significantly higher in β-thalassemia major patients compared to the controls. The serum hepcidin levels decreased with increasing levels of total iron-binding capacity (TIBC; β = −0.442; p = 0.024), transferrin saturation (β = −0.343; p = 0.023), serum creatinine (β = −0.625; p = 0.0030), and eGFR (β = −0.496; p = 0.011). The mean hepcidin/ferritin ratio was significantly lower in the β-thalassemia major cases (0.0069 vs. 0.3970; p < 0.001). The novel hepcidin/eGFR ratio index (HeGRI) was significantly higher in the patient group compared to controls (0.12 vs. 0.09; p = 0.031), respectively. Conclusions: These results suggest that HeGRI could be a potential index of the appropriateness of serum hepcidin suppression associated with the degree of renal dysfunction among β-thalassemia major patients.

Thalassemia Reports doi: 10.3390/thalassrep12010001

Authors: Enric Sayas

Thalassemia Reports (ISSN: 2039-4365) was launched in 2011 and has become the premier peer-reviewed international medical journal devoted entirely to the study, diagnosis, and treatment of thalassemia [...]

Thalassemia Reports doi: 10.4081/thal.2021.9779

Authors: Wasim Muhammad Muhammad Ishaq Muhammad J. Khan Umair Ahmad Muhammad Waseem

The main objective of the current study is to evaluate the level and overload of serum ferritin in multi-transfused beta Thalassemia major patients. There is an earnest need to defend the chelation treatment and to make mindfulness about the results of serum ferritin in the patients beta Thalassemia major. This is a Cross sectional analytical study performed in Fatimid foundation Hayatabad, Peshawar, Khyber Pakhtunkhwa province of Pakistan. Those patients who has beta thalassemia major are included in this study. In this study there are total 108 patients in which 54 males and 54 females. The highest mean of serum ferritin level in the category of male was in the age of 12 years were finds 8160.5 ng/mL. Among the female the highest mean of ferritin level was in the age of 17 years were finds 13,349.5 ng/mL. In this study majority of patient’s revealed much high levels of serum ferritin. These levels reveal insufficient chelation. Appropriate chelation of iron load can improve the quality of the life of these patients. The low level of education, Poverty problems, and insufficient health care facility of are the main obstacle in the effective management of ferritin overload in thalassemia patients.

Thalassemia Reports doi: 10.4081/thal.2021.9803

Authors: Michael Angastiniotis Lily Cannon Eleni Antoniou Angelo Loris Brunetta George Constantinou Eva Maria Knoll Dimitris Loukopoulos Anton Skafi Androulla Eleftheriou

Hemoglobin disorders (thalassemia and sickle cell disease) are a group of hereditary anemias that today occur across the world. The recent population movement has led to a steady increase of carriers and patients in all countries of the European Union. Requiring complex monitoring and treatment and, as a consequence, well-organized and nationally coordinated, supported and funded services, these lifelong conditions are now visible to healthcare services in the EU. The purpose of this study is to provide an overview of the current situation pertaining to these disorders, as perceived by the patient/parent community that the Thalassemia International Federation (TIF) represents. The aim is to establish a comprehensive understanding of the situation and unmet needs faced by migrants with thalassemia. The implementation of activities by TIF in 2018–2020 to identify and address these challenges, paves the way to increased awareness, education and policy changes building on international expertise and knowledge that will enable the provision of state-of-art clinical management services thus guaranteeing an improved quality of life. A bird’s eye view of the prevalence of these disorders is presented contributing to the further understanding of challenges met by both patients and healthcare professionals in the receipt and provision of quality healthcare respectively.

Thalassemia Reports doi: 10.4081/thal.2021.9514

Authors: Mahmoud Hadipour Dehshal Michael Angastiniotis Sachiko Hosoya Fatemeh Hashemi Bahremani Mehdi Tabrizi Namini Androulla Eleftheriou

Thalassemia is one of the important challenges of the health system in Iran. Recently the medicinal drug of luspatercept and gene therapy have opened new horizons for thalassemia treatment. The present article aims to evaluate the attitude of thalassemics in Iran about the new treatments. In this research, data collection through the virtual space has been practiced. The patients were required to declare their opinion on the aforementioned treatments. Finally, 128 male and 204 female plus 1 who did not specify their gender answered the questions. The results showed that despite patients’ positive attitude towards new treatments, their treatment experiences as well as the expenses of the new treatment practices are cause of concern. Moreover, the social problems like unemployment among thalassemics place impact on their perspective about treatment changes. Based on the findings of the present research, providing patients with more information about new treatment regimen and making the their expenses compatible with the economic status of the developing countries would be effective in making the new treatments accessible to all eligible patients.

Thalassemia Reports doi: 10.4081/thal.2020.8655

Authors: Mustafa Majid Mohammed Tareq Mutar Hashim Talib Hashim

Thalassemia is an autosomal recessive disease that is common in Iraq with a prevalence of 35.7 per 100,000. It is the most common type of hereditary anemia registered in 2015. It is a life-threatening condition with many complications which if not managed could cause death in early age. This study aimed to assess the awareness of Iraqi people about thalassemia transmission and prevention and to find their source of information about the disease, as developing good awareness is the first and the most advantageous road to establish a successful prevention program. This cross-sectional study involved 417 participants who were from medical and non-medical fields. It was conducted as an online survey in addition to participants interview using a self-structured questionnaire which was tested for content and face validity, unidimensionality and test-retest reliability in a pilot study of 40 participants. Each participant who had heard about the disease was given a score (0-5) based on their knowledge: 68.8% of the people had heard about the disease previously, those had a mean score of 3 out of 5; 84% claimed that thalassemia is a noncommunicable disease which resembles the highest awareness aspect. The lowest one was about the preventability of the disease. Significant correlation was found between the score of awareness and the age. People awareness about thalassemia was relatively good. A control strategy should be directed to elevate the awareness level about thalassemia in the community with the application of the national program for thalassemia control.

Thalassemia Reports doi: 10.4081/thal.2020.9138

Authors: Androulla Eleftheriou Lily Cannon Michael Angastiniotis

Patients with haemoglobin disorders, particularly β-thalassaemia or sickle cell disease (SCD) or combined forms, on account of their underlying disease pathology and associated (iron load mainly in the case of thalassaemia) co-morbidities are defined as high-risk individuals prone to develop more severe complications from coronavirus disease-2019 (COVID-19). Despite the fact that epidemiological evidence concerning severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection in these patients is currently limited across the world, it is expected that COVID-19 pandemic will have a very serious, negative impact on national economies, healthcare and social systems and consequently significant respective repercussions on the patients particularly chronic ones, and their families. Although this may be a temporary challenge in some countries of high HDI and robust health, public health and social infrastructures, this can be a long term challenge with serious to tragic consequences in countries particularly devoid of universally covered heath care systems. Thalassaemia International Federation (TIF) in this present paper summarises the key challenges as expressed by the patients, their families and involved health care professionals themselves prior and consequent to COVID-19 pandemic, describes its response during the pandemic and expresses its position in support of its global patient community.

Thalassemia Reports doi: 10.4081/thal.2020.9157

Authors: Mahmoud Hadipour Dehshal Sachiko Hosoya Fatemeh Hashemi Bahremani Mehdi Tabrizi Namini Androulla Eleftheriou

Coronavirus disease 2019 (COVID-19) has had and continues to have a significant medical, public health, social and economic impact on every society around the world. Some groups of chronic patients including thalassaemia and other haemoglobin disorders were considered from the beginning of the pandemic, as vulnerable and high risk ones with regards to a more severe clinical outcome of the infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). This is because patients with thalassaemia can present with many and multiple co-morbidities including diabetes, heart, liver, endocrine and other conditions mainly secondary to iron overload and consequent to ineffective or suboptimal medical care and/or adherence to chelation treatment in particular. Transfusion dependent patients with β-thalassaemia have been greatly affected across the world, including in Iran, a country geographically situated in the so called thalassaemia belt. Iran with about 20,000 patients with β-thalassaemia and quite successful disease specific prevention and management national programmes faced challenges similar to others. Blood shortages for example consequent to COVID-19 precaution measures taken in every country to contain the virus and the difficulties in accessing drugs including lifesaving ones (iron chelation medication) constitute major challenges. In Iran however, and despite the multiple difficulties as described above, SARS-CoV-2 had a rather small impact regarding infection rates as compared to the rest of the countries, albeit a higher mortality rate reaching 26.5% amongst COVID-19 diagnosed patients. More comprehensive data however from a bigger number of patients with thalassaemia across the world infected with SARS-CoV- 2 is necessary to draw any reliable conclusions as to the level of vulnerability to SARS-CoV-2 and importantly the clinical impact of this virus in these patients.

Thalassemia Reports doi: 10.4081/thal.2020.8733

Authors: Beverley M. Pullon Jordyn A. Moore

Hemoglobin (Hb) Ottawa [α15(A13)Gly>Arg], also known as Hb Siam, results from GGT>CGT mutation in codon 15 of either HBA1 or HBA2. Hb Ottawa carriers typically have normal hematology but when the variant is coinherited with either α or β thalassemia, microcytic red cell indices were observed. The percentage of variant detected using routine methodology was variable (14-33%), with a higher percentage found when co-inherited with an abnormal α-globin genotype. The case presented here involved an Indian male with microcytic red cell indices, who was heterozygous for Hb Ottawa (HBA2:c.46G>C) and β+ thalassemia (HBB:c.-138C>T). This case represents the first reported finding of Hb Ottawa in the Indian population, as well as the first time capillary zone electrophoresis (CZE) has been used to identify the variant. The abnormal red cell indices were attributed to co-inheritance of β+ thalassemia mutation (HBB:c.-138C>T), which alters binding of transcriptional factors to the HBB promoter and reduces transcription from the allele. The mild β+ thalassemia mutation has commonly been found in the Indian population.

Thalassemia Reports doi: 10.4081/thal.2020.9007

Authors: Waseem F. Al Tameemi Zainab M. J. Altawry

Chronic transfusions program in β-thalassemia patients will inevitably lead to iron overload with a significant morbidity and mortality. Glomerular filtration rate (GFR) is progressively declined in relation to iron overload as well as chronic anemia. Objective is to define levels of Cystatin C in transfusion dependent β-thalassemia major patients as a sensitive marker for detection of earlier glomerular dysfunction in addition to understand the effect of iron overload, chelating therapy and hepatitis infection. A cross sectional study conducted at Al-Basrah Hemoglobinopathy Centre for the period from September 2017 to January 2018 to enroll 75 β-thalassemia major patients. Data collected included duration of the disease, total transfusion requirement, details of chelation therapy and its therapeutic index. In addition to blood urea, serum creatinine and Cystatin C with estimated GFR (eGFR). The mean Cystatin C was 1.075 mg/L where 66.6% of patients had abnormal renal function which is higher proportion than those with renal (42.6%) detected according to serum creatinine level Cystatin C was significantly higher in patients who received desferrioxamine as compared to those received deferasirox (p = 0.007), in accordance with GFR which is significantly higher in patients receiving the latter chelation therapy (p = 0.009). A significant inverse relationship between Cystatin C, and GFR, while positive relationship between ferritin and Cystatin C (p = 0.0001, 0.001 respectively). Cyctatin C is better for detection and monitoring of glomerular dysfunction in B thalassemia major patient which is already not uncommon complications for the disease and iron chelation therapy.

Thalassemia Reports doi: 10.4081/thal.2020.8388

Authors: Eloísa Urrechaga

The Mindray 6800 Plus analyzer reports red cells (RBC) extended parameters, which represent the subsets of erythrocytes. We aimed to evaluate the reliability of RBC extended parameters in the differential diagnosis of microcytic anemia. The learning set comprised samples from 250 patients with microcytic anemia mean cell volume <80 fL. MH ratio (%microcytic cells/%hypochromic cells) and other discriminant functions were calculated. Optimal cut offs were established using receiver operator curves. This value was used in the validation set of 135 patients 50 carriers and 85 with mild iron deficiency anemia (IDA). Area under the curve 0.945 (95% confidence interval 0.890 to 0.977), cut off >10 rendered the best Youden index (0.798), sensitivity 93.2%, specificity 86.2%. In the validation set using MH ratio >10, 45 in 50 patients were correctly classified as carriers. All of 40 beta carriers were correctly classified, while the 5 false negatives resulted to be alpha carriers. In the IDA group 5 patients had MH ratio >10 and thus considered carriers, but all of them had Hyper <3%. The combination of MH ratio >10 and %Hyper <3% correctly classified 100% of IDA patients. An algorithm derived from RBC extended parameters provided by the Mindray 6800 Plus analyzer could be a useful tool in the differential diagnosis of microcytic anemia.

Thalassemia Reports doi: 10.4081/thal.2020.8396

Authors: Ahmad Shoujaa Yasser Mukhalalaty Hossam Murad Faizeh Al-Quobaili

Beta thalassemia (β-thal) is one of the most common worldwide inherited hemoglobinopathies. Proper identification and diagnosis of hemoglobin (Hb) variants provide a major challenge. In this report, we describe a 1-year-old boy, presented with the diagnosis of β-TM (beta thalassemia major), has received regular blood transfusions. The molecular analysis revealed the presence of rare Hb Castilla [Beta 32(B14) Leu>Arg; HBB: c.98T>G] variant associated with β0 [IVS-I-1 (G>A); AG^GTTGGT- >AGATTGGT beta0] (HBB:c.92+1G>A) Mutation in beta-globin (β-globin) gene. To our knowledge, this is the first report of Hb Castilla [Beta 32(B14) Leu>Arg] in ExonII of β-globin gene which were found in Syrian male proband. However, we should investigate abnormal hemoglobins in patients with beta thalassemia to determine whether they have involvement with β-thalassemia mutations in the clinical case of the patients or not.

Thalassemia Reports doi: 10.4081/thal.2019.8101

Authors: Alice Pecoraro Antonio Troia Aurelio Maggio Rosalba Di Marzo

High levels of HbF may ameliorate the clinical course of β-thalassaemia and SCD. Hydroxyurea (HU) is the only HbF inducer approved for the treatment of patients. However not all patients respond to the treatment, for this reason it is noteworthy to identify new HbF inducers. Ruxolitinib is a JAK inhibitor that decreases the phosphorilation of STAT proteins. In particular STAT3 is a repressor of gamma-globin gene. The decrease of STAT3 phosphorilation could derepress gamma-globin gene and reactivate its trascription. In this study we evaluated the efficacy of ruxolitinib as inducer of HbF production. The analyses were performed in cultured erythroid progenitors from 16 beta-thalassemia intermedia (TI) and 4 sickle cell disease (SCD) patients. The use of quantitative RT-PCR technique allowed us to determine the increase of gamma-globin mRNA expression in human erythroid cultured cells treated with ruxolitinib. The results of our study demonstrated an increase in vitro of gamma-globin mRNA expression in almost all patients. These data suggest that ruxolitinib could be a good candidate to be used in vivo for the treatment of hemoglobinopathies.

Thalassemia Reports doi: 10.4081/thal.2018.7744

Authors: Arif Mustafa Efendiyev Gulnara Ibrahim Azizova Arzu Ramiz Dadashova

The aim of this work was a comparative study of the amount of antimicrobial peptides—human neutrophil peptides—defensins (HNP), hepcidin, bactericidal/permeability-increasing protein (BPI), and endotoxin in β-thalassemia. Blood samples of 135 patients with thalassemia were investigated. All patients were divided into 3 groups. The first group included patients with heterozygous form (n = 45). The second group consisted of patients with homozygous form before splenectomy (n = 45). The third group included patients with homozygous form after splenectomy (n = 45). The age of patients varied from 2 to 18 years. Biochemical [unconjugated and conjugated bilirubin, alkaline phosphatase, hemoglobin, ferritin, aspartate transaminase (AST), alanine transaminase (ALT), mean corpuscular volume (MCV)] and immune (IgA, IgM, IgG, phagocytic activity) parameters were defined. Obtained results suggest that increased levels of endogenous antimicrobial peptides are associated with the development of the infectious process and reflect the dynamics of changes in biochemical parameters and immune status.

Thalassemia Reports doi: 10.4081/thal.2018.7286

Authors: Veysel Sabri Hancer Tunc Fisgin Murat Buyukdogan Ceyhun Bozkurt Sotiraq Lako

The mutation detection of β thalassemia is absolutely necessary for molecular diagnosis, as well as any genetic epidemiological study. The β globin gene has 3 exons and 2 introns, involved in β-thalassemic pathogenesis. The study aim of the study is to characterize the spectrum of β globin gene mutations in 136 Turkish, Northern Iraqi and Albanian pediatric β thalassemia major patients. After genomic DNA extraction from venous blood and amplification of the target DNA regions with PCR, genotyping was achieved by Sanger based DNA sequencing. The IVSI-110 G > A mutation was the most frequent allele in the Turkish and Albanian patients. In Northern Iraqi patients IVSI-1 G > A was is the most frequent. There are two mutations are firstly reported for Albania [c.*111 A > G 3’ UTR (rs63751128) and c.113 G > A (p.Trp38Ter, p.W38*) (rs35887507)] with this study. These findings may be of value for genetic counseling, premarital diagnosis, prenatal diagnosis and prevention programs.

Thalassemia Reports doi: 10.4081/thal.2018.7470

Authors: John Porter

Recent years have seen accelerating advances in the treatment, monitoring and potential cures for haemoglobin disorders, as the interaction between basic science, pharmaceutical research, and practical medicine intensifies [...]

Thalassemia Reports doi: 10.4081/thal.2018.7471

Authors: Stephan Lobitz

Migration is the “movement of people to a new area or country in order to find work or better living conditions” (Oxford dictionary) [...]

Thalassemia Reports doi: 10.4081/thal.2018.7472

Authors: Anubha Taneja Mukherjee

Decision making is an inherently complicated procedure, which by its very nature requires the decision-maker to co-opt all the stakeholders concerned [...]

Thalassemia Reports doi: 10.4081/thal.2018.7473

Authors: Cornelis L. Harteveld

The molecular defects underlying haemoglobinopathies are both deletions and point mutations in the alpha- or beta-globin genes or gene-clusters. To detect point mutations causing alpha- or beta-thalassaemia, direct sequencing is the method of choice to detect the widest spectrum of molecular defects. The most established approach in DNA diagnostics to screen for the most common deletion defects causing alpha-thalassaemia or beta-thalassaemia is gap- PCR, Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger Sequencing technology to detect breakpoint sequences of previously uncharacterized deletions/duplications. We demonstrate the recent advances in the determination of duplications and deletions causing alpha- or beta-thalassemia, using Next Generation Sequencing, array Comparative Genome Hybridization and Target Locus Amplification. We present three cases in which the use of advanced technologies allow the diagnosis of unexpected disease genotypes.

Thalassemia Reports doi: 10.4081/thal.2018.7474

Authors: John Old Adele Timbs Janice McCarthy Alice Gallienne Melanie Proven Michelle Rugless Herminio Lopez Jennifer Eglinton Dariusz Dziedzic Matthew Beardsall Mohamed S.M. Khalila Shirley Henderson

The current influx of economic migrants and asylum seekers from countries with a high prevalence of haemoglobinopathies creates new challenges for health care systems and diagnostic laboratories. The migration of carriers introduces new and novel haemoglobinopathy mutations to the diagnostic repertoire of a laboratory, often creating new pressures to improve and update the carrier screening technology and diagnostic scope. For antenatal screening programmes, the marriage of partners from different ethnic groups can lead to the risk of compound heterozygote children being born novel mutation combinations, creating problems in the provision of accurate advice regarding the expected phenotype of the thalassaemia or haemoglobinopathy disorder. In the UK, the impact of immigration required the National Haemoglobinopathy Reference laboratory to change the strategy and techniques used for the molecular diagnosis of thalassaemia and the haemoglobinopathies. In 2005, due to the increasingly large range of β-thalassaemia mutations that needed to be diagnosed, the laboratory switched from a three-step screening procedure using ARMS-PCR to a simpler but more expensive one-step strategy of DNA sequencing of the beta and alpha globin genes for all referrals. After ten years of employing this strategy, a further 57 novel thalassaemia and haemoglobionpopthy alleles were discovered (11 new β-chain variants, 15 α-chain variants, 19 β-thalassaemia mutations and 12 α+-thalassaemia mutations), increasing further the extremely heterogeneous spectrum of globin gene mutations in the UK population.

Thalassemia Reports doi: 10.4081/thal.2018.7475

Authors: Mary Petrou

Knowledge and autonomy are key aspects of informed choice; it is important to define what is important for participants to understand, when accepting or declining screening and for individuals to understand that screening is optional and their own personal choice [...]

Thalassemia Reports doi: 10.4081/thal.2018.7476

Authors: Jennifer L. Oliveira

Although commonly assessed in the context of microcytosis or sickling syndrome screening, hemoglobin mutations may not be as readily considered as a cause of other symptoms. These include macrocytosis with or without anemia, chronic or episodic hemolysis, neonatal anemia, erythrocytosis, cyanosis/hypoxia and methemoglobinemia/ sulfhemoglobinemia. Hemoglobin disorders commonly interfere with the reliability of Hb A1c measurement. Because the clinical presentation can be varied and the differential diagnosis broad, a systematic evaluation guided by signs and symptoms can be effective. A tertiary care reference laboratory is particularly challenged by the absence of pertinent clinical history and relevant laboratory findings, and appropriate use of resources in a data vacuum can be problematic. To address these issues, our laboratory has constructed testing panels with a tiered strategy utilizing screening assays that detect the most common causes and reflexing additional assays that assess less common etiologies. See Figure 1. Our testing algorithm panels include a rapid hemoglobin fraction monitoring test, a generic diagnostic hemoglobin electrophoresis profile, and more specific diagnostic evaluations for microcytic anemia, hereditary hemolytic anemia, methemoglobinemia and sufhemoglobinemia and erythrocytosis. Use of these testing strategies has facilitated the identification of rare and complex hemoglobin disorders from a wide variety of ethnic groups, including over 500 distinct named alpha, beta and gamma variants (of which 60+ were novel variants at the time of first detection), 99 beta thalassemia mutations and greater than 20 large deletional beta globin cluster deletion subtypes.

Thalassemia Reports doi: 10.4081/thal.2018.7477

Authors: John Porter

For reasons of time, this short talk will be confined to the optimal frequency, timing, indications and dosing of blood transfusion [...]

Thalassemia Reports doi: 10.4081/thal.2018.7478

Authors: Rayan Bou-Fakhredin Joseph Elias Ali T. Taher

Iron overload (IOL) is highly prevalent among patients with hemoglobinopathies; both transfusion dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT). Whether IOL is secondary to regular transfusions like in TDT, or develops from increased intestinal absorption like in NTDT, it can cause significant morbidity and mortality. In TDT patients, iron accumulation in organ tissues is highly evident, and leads to organ toxicity and dysfunction. IOL in NTDT patients is cumulative with advancing age, and concern with secondary morbidity starts beyond the age of 10 years, as shown by the OPTIMAL CARE study. Several modalities are available for the diagnosis and monitoring of IOL. Serum ferritin (SF) assessment is widely available and heavily relied on in resource-poor countries. Non-invasive iron monitoring using MRI has become the gold standard to diagnose IOL. Three iron chelators are currently available for the treatment of IOL: deferoxamine (DFO) in subcutaneous or intravenous injection, oral deferiprone (DFP) in tablet or solution form, and oral deferasirox (DFX) in dispersible tablet (DT) and film-coated tablet (FCT). Today, the goal of ICT is to maintain safe levels of body iron at all times. Appropriate tailoring ICT with chelator choices and dose adjustment must be implemented in a timely manner. Clinical decision to initiate, adjust and stop ICT is based on SF, MRI-LIC and cardiac T2*. In this article, we review the mechanism of IOL in both TDT and NTDT, the pathophysiology behind it, its complications, and the different ways to assess and quantify it. We will also discuss the different ICT modalities available, and the emergence of novel therapies.

Thalassemia Reports doi: 10.4081/thal.2018.7479

Authors: Vincenzo de Sanctis

More than five decades ago, thalassemia major (TM) was fatal in the first decade of life [...]

Thalassemia Reports doi: 10.4081/thal.2018.7480

Authors: Dimitrios Farmakis George Papingiotis

Hereditary hemoglobin disorders, also termed haemoglobinopathies, include mainly beta -thalasszemia and sickle cell disease and represent the most common monogenic disorders in human [...]

Thalassemia Reports doi: 10.4081/thal.2018.7481

Authors: Joseph Sleiman Ali Tarhini Ali T. Taher

Thalassemia is a disease with an extensive morbidity profile affecting almost every organ system. Renal involvement, once considered rare, is an underestimated and poorly studied complication that has been on the rise ever since medical advances granted patients longer life spans. Several studies and reports have emerged recently to shed light on the seriousness of this complication, although data is still lacking in terms of pathophysiology, diagnosis, prevention and treatment. In this review, we evaluate and compare renal involvement in the transfusion-dependent and independent variants of β-Thalassemia, highlighting the pathophysiology of kidney damage that involves iron overload, chronic anemia, and iron chelation therapy. An in-depth and focused review of the types of injuries incurred is also presented along with the diagnostic biomarkers accompanying each type of injury. Most research so far has focused on the transfusion-dependent thalassemia population being the group with most renal involvement, however recent reports have shown evidence of comparable, if not worse, involvement of the non-transfusion dependent population, sometimes leading to end-stage renal disease. As such, we try to shed light on distinct renal involvements in NTDT whenever available.