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Transfusion-dependent β-thalassaemia (TDβT) is a genetic disorder characterised by reduced or absent β-globin chain synthesis, resulting in chronic anaemia. Treatment consists of regular blood transfusions and chelation therapy to limit iron overload and its negative effects on organs (e.g. heart, lungs and liver). Despite improved life expectancy with transfusions and chelation therapy, TDβT patients experience poor quality of life and impaired exercise capacity (mainly due to muscle deconditioning and reduced cardiac inotropism). The aims of this review are (i) to discuss the role of organ dysfunction in the impairment of exercise capacity and reduced quality of life of TDβT patients; and (ii) to discuss physical activity as a potential therapeutic strategy to alleviate the multifactorial impact of the disease., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Red blood cell (RBC) antigen matching beyond ABO and RhD is commonly recommended for patients with sickle cell disease (SCD) and thalassaemia. We present an updated systematic literature review to inform evidence-based guidelines on RBC matching. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool was used to develop recommendations. Six new observational studies (4 prospective, 2 retrospective) were identified. The six studies reported on 583 patients in total, including cross-over designs, with sample sizes from 10 to 343. Studies were heterogeneous, utilising varying degrees of RBC matching and different definitions for 'extended' matching. All reported on alloimmunisation. One study reported on molecular matching. The reported prevalence of alloimmunisation using limited matching was 0%-50% and with extended matching was 0%-24%. Eighty-two patients were alloimmunised before study entry. The risk of bias across studies was moderate to critical. The guideline panel recommends that ABO, RhDCcEe, and K-compatible RBCs are selected for individuals with SCD and thalassaemia, even in the absence of alloantibodies, and that RBCs which are antigen-negative to already existing clinically significant antibodies are chosen. There is a need for comparative research to define the benefit, impact, cost-effectiveness, and feasibility of extended RBC matching strategies to prevent alloimmunisation., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Thalassaemia, caused by over 250 mutations in the beta globin gene, changes the haematopoietic stem cell (HSC) differentiation, leading to ineffective erythropoiesis. This Wider Perspective article overlooks its underlying nature as a benign HSC disorder with a significant impact on the erythroid cell lineage. The simplicity of managing symptoms through transfusions and iron chelation therapy has shifted the focus away from the development of cell-based treatments. The identification of the beta039 mutation by Chang and Kan in 1979 marked a turning point, suggesting as main approach the molecular level by correcting the beta globin chain imbalances through gene insertion and editing. However, challenges of technology have delayed the implementation of these strategies for over four decades. In contrast, the past two decades have witnessed significant advances in the treatment of HSC disorders of the myeloid clone which are driven by a 'target cell strategy'. Many current and innovative treatments for thalassaemia are now adopting this approach, highlighting the importance of identifying suitable candidates through risk stratification. This manuscript explores the evolving understanding of thalassaemia syndromes as congenital HSC disorders of the erythroid clone and examines the implications of this perspective for the development of future treatments., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: Accurate epidemiological data are crucial for effective disease prevention and treatment. We conducted a large-scale survey to explore the thalassaemia prevalence and spectrum among the two major ethnic groups in Hainan Province., Methods: A total of 399,053 childbearing-age individuals of Li ( n  = 77,563) and Han( n  = 321,490) ethnic groups were recruited from 18 cities and counties in Hainan, and their thalassemia genotypes were systematically screened and statistically analysed., Results: This study revealed a significantly higher thalassaemia carrier rate in the Li (55.39%) than that in the Han (13.13%). Specifically, the carrier rate of α-thalassaemia was 46.39% in the Li and 10.02% in the Han. The predominant α-thalassaemia mutations were - α 3.7 and - α 42. in Li, whereas the main mutation were - SEA and - α 4.2 in Han. For β-thalassaemia, the carrier rates were 1.68% in Li and 2.38% in Han, with CD41-42(-CTTT) the most prevalent mutation in both groups. The carrier rates of β-/α-compound thalassaemia were 7.32% in Li and 0.73% in Han. Additionally, there were regional differences in the distribution of thalassemia among the Li and Han within Hainan Province., Conclusion: Epidemiological characteristics and molecular spectrum of thalassaemia among the Li and Han ethnic groups in Hainan were revealed in this study. These findings can provide a scientific basis to develop and implement prevention strategies for thalassaemia in Hainan.

Background: Many patients with β-thalassaemia die prematurely due to iron overload. In this study, we aim to evaluate the efficacy and safety of the triple combination of deferoxamine, deferasirox and deferiprone on iron chelation in patients with transfusion-dependent β-thalassaemia with very high iron overload., Methods: This open-label, randomised, controlled clinical trial was conducted at Colombo North Teaching Hospital, Sri Lanka. Transfusion-dependent β-thalassaemia patients with ferritin >3500 ng/mL were randomised 2:1 into intervention (deferoxamine, deferasirox and deferiprone) and control (deferoxamine and deferasirox) arms. Reduction in serum ferritin after six months was the primary outcome measure. Reduction in liver iron content, improvement in cardiac T2∗, and adverse effects were secondary outcome measures., Findings: Twenty-three patients (intervention-15, control-8) were recruited. 92% and 62% in the intervention and control arms showed a reduction in ferritin, respectively. The mean reduction of ferritin was significantly higher in intervention (-1094 ± 907 ng/mL) compared to control (+82 ± 1588 ng/mL) arm (p = 0.042). There was no statistically significant difference in the liver iron content in two arms. In the intervention arm, 67% improved cardiac T2∗ (mean change +6.72 ± 9.63 ms) compared to 20% in the control arm (mean change -3.00 ± 8.24 ms). Five patients discontinued deferiprone due to arthralgia, which resolved completely after stopping the drug., Interpretation: Triple combination therapy with deferoxamine, deferasirox and deferiprone is more efficacious in reducing iron burden measured by serum ferritin and showed a positive trend in reducing myocardial iron content in patients with transfusion-dependent β-thalassaemia with very high iron overload. Deferiprone has the disturbing side effect of reversible but severe arthropathy., Funding: None., Competing Interests: We declare no competing interests., (© 2024 The Author(s).)

Haemoglobin (Hb) Malay is variant haemoglobin with a β ++ thalassemia phenotype. The prevalence of Hb Malay in the Malaysian population was 5.5%. We describe a 58-year-old male who presented with symptomatic anaemia to the Hospital Universiti Sains Malaysia. Further history revealed that the patient had anaemia since the age of 28, and on regular follow-up at other hospital. Physical examination revealed pallor, jaundice and hepatosplenomegaly. The full blood count and peripheral blood smear showed hypochromic microcytic anaemia with anisopoikilocytosis, and many target cells. High-performance liquid chromatography results showed a β thalassemia trait. However, the diagnosis does not alight with the patient's condition. Bone marrow aspirate was completed and showed reactive changes and erythroid hyperplasia. A molecular test was then performed for β globin gene mutation detection using Multiplex Amplification Refractory Mutation System (M-ARMS) PCR method. This revealed the result as homozygous codon 19 mutation or Hb Malay. Therefore, in this case report we would like to highlight the laboratory approaches, the challenges faced by the usual haematological investigations and the importance role of molecular testing in the diagnosis of severe anaemia., (© 2024 R Bahar et al., published by Sciendo.)

Transfusion-dependent thalassemia (TDT) is often accompanied by complications related to iron overload and the development of malignant solid tumors or hematological malignancies. The occurrence of Neuroendocrine carcinoma, specifically in the respiratory tract, is very rare, with a prevalence of approximately 25%. Therefore, this study presented a case of a 42-year-old male with a beta-thalassemia major at 28 years, complaining of shortness of breath. This case was reported due to its rarity in providing information about solid tumors in thalassemia patients. The physical examination revealed several symptoms, including tachycardia, tachypnea, anemia, icteric sclera, elevated jugular venous pressure, coarse wet Ronchi in the medial to basal areas of both lungs, hepatomegaly, and splenomegaly (Schuffner 4). The patient regularly received blood transfusions and iron chelation therapy. A thoracic CT scan showed a lung mass and a biopsy of the mass revealed Pulmonary Neuroendocrine Carcinoma with high-grade proliferation and, large cell type. The patient also passed through cisplatin-etoposide chemotherapy for 6 cycles every 21 days. There is almost no data on pulmonary neuroendocrine carcinoma in thalassemia patients, so it is hoped that this case report can provide information about malignant solid tumors that can occur in thalassemia patients.

Background: Medication burden and complexity have been longstanding problems in chronically ill patients. However, more data are needed on the extent and impact of medication burden and complexity in the transfusion-dependent thalassaemia population., Aim: The aim of this study was to determine the characteristics of medication complexity and polypharmacy and determine their relationship with drug-related problems (DRP) and control of iron overload in transfusion-dependent thalassaemia patients., Method: Data were derived from a cross-sectional observational study on characteristics of DRPs conducted at a Malaysian tertiary hospital. The medication regimen complexity index (MRCI) was determined using a validated tool, and polypharmacy was defined as the chronic use of five or more medications. The receiver operating characteristic curve analysis was used to determine the optimal cut-off value for MRCI, and logistic regression analysis was conducted., Results: The study enrolled 200 adult patients. The MRCI cut-off point was proposed to be 17.5 (Area Under Curve  =  0.722; sensitivity of 73.3% and specificity of 62.0%). Approximately 73% and 64.5% of the patients had polypharmacy and high MRCI, respectively. Findings indicated that DRP was a full mediator in the association between MRCI and iron overload., Conclusion: Transfusion-dependent thalassaemia patients have high MRCI and suboptimal control of iron overload conditions in the presence of DRPs. Thus, future interventions should consider MRCI and DRP as factors in serum iron control., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This comprehensive guideline, developed by a representative group of UK-based medical experts specialising in haemoglobinopathies, addresses the management of conception and pregnancy in patients with thalassaemia. A systematic search of PubMed and EMBASE using specific keywords, formed the basis of the literature review. Key terms included "thalassaemia," "pregnancy," "Cooley's anaemia," "Mediterranean anaemia," and others, covering aspects such as fertility, iron burden and ultrasonography. The guideline underwent rigorous review by prominent organisations, including the Endocrine Society, the Royal College of Obstetricians and Gynaecologists (RCOG), the United Kingdom Thalassaemia Society and the British Society of Haematology (BSH) guideline writing group. Additional feedback was solicited from a sounding board of UK haematologists, ensuring a thorough and collaborative approach. The objective of the guideline is to equip healthcare professionals with precise recommendations for managing conception and pregnancy in patients with thalassaemia., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Graft rejection and Graft-versus-host disease (GVHD) are some of the significant factors resulting in morbidity and mortality following allogeneic hematopoietic cell transplantation. Prophylaxis for GVHD using T-cell depleting agents is helpful in reducing the transplant-related mortality and graft rejection. Both tATG and fATG exhibit varied amounts of antibody specificities and perform distinct immunomodulatory effects, regardless of their capacity to deplete T-lymphocytes. We conducted this single-center, retrospective study at our center to compare both formulations. Twenty-six patients were included in the study, 13 in each cohort. The median age at diagnosis of β-thalassemia was 5 months (range, 3-12 months) in the tATG group and 6 months (range, 3-9 months) in the f-ATG group, respectively. Acute GVHD was observed in 1 (7.7) and 2(15.4) in the tATG and fATG group, respectively. No cases of chronic GVHD were observed in either group. There was no difference in the mixed chimerism observed at 6 months in both groups, tATG ( n  = 5, 38.5%) and fATG ( n  = 6, 46.15). There was 1 (7.6) rejection at day +72 observed in the tATG group, whereas no rejection was observed in the fATG group. At a mean follow-up duration of 288 days since transplant, there were no deaths in either of the groups. In conclusion, both ATG preparations showed equivalent effectiveness in preventing rejections and GVHD. However, further larger studies are required to establish the long-term efficacy and safety of both formulations in ASCT.

Background and Objectives : The effective management of chronic diseases, particularly hereditary and rare diseases and thalassaemia, is an important indicator of the quality of healthcare systems. We aimed to assess healthcare services in different countries for thalassaemia patients by using publicly available health indicators and by surveying thalassaemia patients and their caregivers. Materials and Methods : We reviewed official worldwide databases from the WHO, World Bank, and scientific resources, and we used a structured patient-tailored self-completed questionnaire to survey thalassaemia patients and their caregivers in 2023. Results : A total of 2082 participants were surveyed (mean age, 27 years; males, 42%). About 1 in 4 respondents did not complete high-school education, while 24% had a bachelor's degree. About a third of respondents were married and were in either full- or part-time employment. The vast majority (~80%) had initiated transfusion therapy between 1 and 4 years of age. Only 42% reported no delays in receiving blood transfusion, while 47% reported occasional delays and 8% serious delays. About half of patients reported being very satisfied (11%) or satisfied (38%) with the quality of services provided, while 1 in 3 patients reported being unsatisfied or very unsatisfied, and that their access to treatment was difficult or very difficult due to traveling expenses and the high cost of treatment. Conclusions : Important improvements in the care of thalassaemia patients have been documented during the past few decades. Nevertheless, additional focus is required through national healthcare systems to effectively address the many unmet needs revealed by our recent survey, as well as to achieve satisfactory patient outcomes.

Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically reviewed iron-chelation therapy (ICT) compliance, and the relationship between compliance with health outcome and health-related quality of life (HRQoL) in thalassaemia patients. Several reviewers performed systematic search strategy of literature through PubMed, Scopus, and EBSCOhost. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed. Of 4917 studies, 20 publications were included. The ICT compliance rate ranges from 20.93 to 75.3%. It also varied per agent, ranging from 48.84 to 85.1% for desferioxamine, 87.2-92.2% for deferiprone and 90-100% for deferasirox. Majority of studies (N = 10/11, 90.91%) demonstrated significantly negative correlation between compliance and serum ferritin, while numerous studies revealed poor ICT compliance linked with increased risk of liver disease (N = 4/7, 57.14%) and cardiac disease (N = 6/8, 75%), endocrinologic morbidity (N = 4/5, 90%), and lower HRQoL (N = 4/6, 66.67%). Inadequate compliance to ICT therapy is common. Higher compliance is correlated with lower serum ferritin, lower risk of complications, and higher HRQoL. These findings should be interpreted with caution given the few numbers of evidence., (© 2023. The Author(s).)

Background: In the last few decades, the life expectancy of patients with transfusion-dependent thalassaemia (TDT) and sickle cell disease (SCD) has improved significantly, in part because of improved iron chelation. Fertility challenges and pregnancy complications have historically limited reproductive options in this group; however, improved multi-disciplinary care has made infertility a chronic disease complication requiring attention. Despite this, there are very few reports and no Australian data describing fertility and pregnancy outcomes in this population., Aims: To identify the rate of assisted reproductive technologies (ART) utilisation in our female transfusion-dependent haemoglobinopathy patients and to establish the nature of maternal and neonatal complications in this cohort., Methods: A 20-year retrospective analysis (1997-2017) at an Australian centre captured data on conception rates, use of assisted reproductive techniques (ART), and pregnancy and neonatal outcomes in female transfusion-dependent haemoglobinopathy patients., Results: Conception was attempted in 14 women (11 TDT and three SCD) during the study period. A total of 28 pregnancies resulting in 25 live births were recorded. ART supported 13 conceptions. A positive association was not identified between elevated mean serum ferritin and ART use; however, all patients with an established diagnosis of hypogonadotropic hypogonadism (HH) required ART. Maternal complications included gestational diabetes mellitus and post-partum haemorrhage. There were no cardiac complications. Two-thirds of women underwent lower segment caesarean section, with prematurity complicating 20% of births. There were no neonatal or maternal deaths., Conclusion: Pregnancy is an achievable goal for women with transfusion-dependent haemoglobinopathies, although the support of ART may be required in a subset of patients., (© 2023 Royal Australasian College of Physicians.)

We evaluated the impact of peer reviews in driving improvement in healthcare quality for people with haemoglobinopathy in the United Kingdom. We analysed compliance to four Quality Standards (QS)-based peer reviews from 2010 to 2020 to evaluate its impact in driving healthcare quality. Seventeen paediatric and 29 adult haemoglobinopathy centres were reviewed in 2010/11 and 2012/13 respectively; 33 paediatric and 33 adult centres were reviewed in 2014/16, and 32 paediatric and 32 adult centres were reviewed in 2018/2020. Compliance with QS and participant feedback were analysed to assess the impact of peer review programmes to drive improvement in quality of care. We noted that haemoglobinopathy centres significantly improved their compliance to QS between the first two review programmes, but not in the final review programme. In comparison to other disease-group reviews, the haemoglobinopathy departments were less able to address critical peer review recommendations in their own institutions. The peer review programme was unable to drive sustained improvement in healthcare quality, underscoring the need for sustained development and support for haemoglobinopathy services in the National Health Service. Further work is needed to understand why disparities exist among peer review-driven improvement initiatives within different disease groups., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

The life-threatening genetic blood disorder, thalassaemia, which causes decreased haemoglobin production, is preventable. Sociocultural determinants and the level of public health awareness must be used to adopt control measures of prevention. Identifying information gaps and educating the community about screening should be a priority, especially in areas with high disease burdens. A relevant health education technique, with which the audience can identify, can effectively bring understanding necessary effectively to sensitise the community. We propose the 'Bag and Ball' method, which includes role-play for health education specifically concerning inherited genetic disorders., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

For this paper, cases reported formally and anecdotally to the authors in their screening and diagnostic roles have been selected to demonstrate areas where errors have occurred, and caution should be exercised. The cases demonstrate that it is vital that the performance and limitations of the techniques used, along with the phenotypic presentation of cases where haemoglobin variants and/or thalassaemias are coinherited are understood by those performing result interpretation. Those who deliver the service as well as those who receive reports and give results and counselling should be aware of the complexity of the topic., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

The Danish national haemoglobinopathy screening programme seeks to determine parental haemoglobinopathy carrier state antenatally. In this retrospective register-based study, we evaluated the 16-year trajectory of this programme, utilising the Danish Red Blood Cell Centre's laboratory database, covering approximately 77% of the Danish population. During the study period, we observed a substantial increase in annual diagnostic examinations performed, from 389 in 2007 to 3030 in 2022. Women constituted 88% of these cases, aligning with the emphasis of the screening programme. Of these, 54% of women of reproductive age (15-40 years) and 10% of women >40 years were specified as pregnant. During our study period, 61 children were born with a severe haemoglobinopathy, out of which 23 children were born from mothers not residing in Denmark during their first trimester thus not included in the screening programme. Prenatal invasive testing was performed for 60 fetuses, identifying 12 with homozygous or compound heterozygous haemoglobinopathy. The Danish haemoglobinopathy screening programme has provided screening, information and reproductive choices for numerous families. During the study period, screening for haemoglobinopathies has been steadily increasing and is expected to continue to increase. Awareness of and adherence to the screening programme is subject of further investigation and optimisation., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Haemoglobinopathies, including sickle cell disease and β-thalassaemia, are monogenic disorders with a relatively higher prevalence among malaria-endemic areas in Africa. Despite this prevalence, most African countries lack the necessary resources for diagnosing and managing these debilitating conditions., Aim: This study provides a critical review of newborn screening for detecting haemoglobinopathies in Africa, highlighting challenges and proposing strategies for improved diagnosis and management., Methods: A literature search on haemoglobinopathies in Africa was conducted in PubMed, Google Scholar and ScienceDirect, using specific keywords and Boolean operators, including articles published from January 1981 to December 2022., Results: The data show that sickle cell disease is prevalent among populations in Central and West Africa; however, β-thalassaemia is prevalent among people in the northern parts of Africa. Newborn screening pilot initiatives for haemoglobinopathies were being implemented in Angola, Nigeria, Ghana, the Democratic Republic of Congo and the Republic of Benin. The cost of testing, lack of sufficient and accessible medical records, and inadequacy in healthcare infrastructure pose significant challenges in bridging the gaps in newborn screening. Furthermore, the stigmatisation and lack of awareness of haemoglobinopathies and access to newborn screening programmes pose additional challenges., Conclusion: This review highlights the challenges associated with haemoglobinopathy testing, effective strategies for mitigating these challenges, and future perspectives for expanding efforts toward detecting and managing these disorders across Africa. Providing affordable diagnostic tools, mobile clinics, government subsidies, education campaigns, and the implementation of electronic medical records systems could help bridge the gaps in newborn screening in Africa., What This Study Adds: The study presents a comprehensive view of newborn screening of haemoglobinopathies in Africa, provides a detailed outline of the challenges faced by newborn screening for haemoglobinopathies in Africa, and offers strategies for better diagnosis and care., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2023. The Authors.)

Thalassaemia is a typically monogenic disease caused by mutations or deletions in the globin gene and has a high prevalence in southern China. Prenatal screening for thalassaemia can be effective in reducing the incidence of thalassaemia. Haematologic parameters of pregnant thalassaemia carriers are diverse and potentially valuable for identifying different types of genotypes. By comparing and evaluating haematological parameters, formulas in the literature, we tried to reveal differences between pregnant women carrying different types of thalassaemia genes. The Mentzer formula (MCV/RBC) showed a strong ability to differentiate thalassaemia genotypes in pregnant women. In addition, combined with haemoglobin electrophoresis HbA2 can further distinguish the -α/αα, α T α/αα, -/αα, β + /N and β 0 /N groups. HbA2 divides them into two groups. Based on the Mentzer formula, we can further decide which type of thalassaemia to screen (α/β and the subgroups) for genotyping. Therefore, this simpler and more cost-effective workflow has great potential for application in screening pregnant women for thalassaemia carriers.Impact Statement What is already known on this subject? Currently, it is known that thalassaemia gene carriers have abnormal blood indicators. Many findings describe their important values in distinguishing thalassaemia and other blood diseases. They combined different metrics as an algorithm to distinguish thalassaemia and iron deficiency anaemia. Prenatal screening is an effective method to reduce the incidence of thalassaemia. The current main method is PCR. Due to technical and financial constraints, many backward places cannot use this technology. The necessity for prenatal screening for thalassaemia has been overlooked. What Among these algorithms, Mentzer formula revealed differences in haematological parameters during pregnancy between normal individuals and thalassaemia carriers. Combining the HbA2, thalassaemia carriers can be distinguished from normal individuals, including -α/αα, α the results of this study add? Among these algorithms, Mentzer formula revealed differences in haematological parameters during pregnancy between normal individuals and thalassaemia carriers. Combining the HbA2, thalassaemia carriers can be distinguished from normal individuals, including -α/αα, α T α/αα, -/αα, β 0 /N and β + /N. What are the implications of these findings for clinical practice and/or further research? We provide another tool for these hospitals that donot have Hb electrophoresis test and PCR. Then the clinical doctor can get some evidence and suggest women go to another big hospital for essential tests. It is an excellent suggestion. In the future, we will collect more specific gene types and further investigate their potential relationship using these formulas.

The early eluting peaks in the first minute of cation-exchange high-performance liquid chromatography (CE-HPLC) are often not analysed in haemoglobin pattern studies, except for haemoglobin (Hb) Bart's and Hb H peaks. In this study, we described the presence of a specific α-thalassaemia early eluting peak (αEEP) at the retention time of 0.24 min generated by Variant II CE-HPLC (β-Thalassaemia Short Program; Bio-Rad Laboratories). We have evaluated the utility of αEEP for the screening of α-thalassaemia trait in our local Chinese population in comparison to the Hb H inclusion body test. A total of 303 blood samples presenting with microcytosis were sent for haemoglobin pattern study and were analysed for the presence or absence of αEEP and Hb H inclusions. Twenty cases with a normal mean corpuscular volume were assessed as a control. Discordant results between the αEEP and the Hb H inclusion test were reviewed with the α-globin genotyping test performed. The concordance rate of the αEEP and the Hb H inclusion body test was 96.0% (κ=0.921, p<0.001). Eight of 303 cases (2.6%) were initially negative for the Hb H inclusion test but positive for the αEEP. All eight cases were found to have occasional Hb H inclusion bodies upon review. Four of 303 cases (1.3%) were negative for the αEEP but positive for the Hb H inclusion test. Of these four cases, two (50%) showed heterozygous Southeast Asian (SEA) type deletion, one (25%) showed Hb Quong Sze mutation, and one (25%) showed no mutation detected upon molecular testing. All the Hb E trait cases with no Hb H inclusions and the negative control group showed the absence of the αEEP. The sensitivity and specificity of αEEP for detecting SEA deletion were 93.8% and 100% respectively, which is superior to the Hb H inclusion test (sensitivity 81.3%, specificity 95.2%). The αEEP is found to be a more sensitive method than the Hb H inclusion body test in the screening of α-thalassaemia trait in our Chinese population, in which SEA type deletion is prevalent. Further study is needed to explore the utility of the αEEP in the screening of α-thalassaemia traits in other populations. The exact nature of the αEEP is yet to be defined., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Patients with thalassemia and sickle cell disease (SCD) require blood transfusions as part of their supportive care. However, one of the most serious side effects of this treatment is the risk of red cell alloimmunization. The goal of this study was to assess the prevalence and Specificity of red cell alloimmunization in Egyptian thalassemia and sickle cell anaemia patients. This study included 200 multi transfused Egyptian patients, one hundred and forty patients with transfusion dependent thalassaemia and sixty patients with sickle cell anaemia, who were attending the Paediatric Children Hospital-Cairo University at the period from March 2019 to October 2019. Alloantibody identification was made by Diamed- ID microtyping system. In the studied groups both thalassemia and sickle patients, the prevalence of alloimmunization was 22/200 (11%) patients. The two most often alloantibodies were, antibodies against Kell antigen (37%) and against E antigen (30%). The prevalence of alloimmunization was more in females in comparison to males, but it did not reach statistical significance and patients with thalassemia major had higher alloimmunization rates than other studied groups but was not statistically significant. In the D negative patients in the research group, alloimmunization demonstrated a statistically significant difference ( p  = 0.01). Age, gender, age of transfusion onset and splenectomy were not contributing factors to the antibody presence in the group of patients being investigated. Before receiving blood transfusions, extended red blood cell phenotyping should be thought of as a crucial procedure for hemoglobinopathies patients who would likely have several transfusions. It is advised that haemoglobinopathies patients in Egypt be checked through phenotyping of RBC units for Kell and all Rh antigens to be phenotyped before starting transfusion in these patients which is also standard of care for these patients presently., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© The Author(s) 2023.)

The iron chelating orphan drug deferiprone (L1), discovered over 40 years ago, has been used daily by patients across the world at high doses (75-100 mg/kg) for more than 30 years with no serious toxicity. The level of safety and the simple, inexpensive synthesis are some of the many unique properties of L1, which played a major role in the contribution of the drug in the transition of thalassaemia from a fatal to a chronic disease. Other unique and valuable clinical properties of L1 in relation to pharmacology and metabolism include: oral effectiveness, which improved compliance compared to the prototype therapy with subcutaneous deferoxamine; highly effective iron removal from all iron-loaded organs, particularly the heart, which is the major target organ of iron toxicity and the cause of mortality in thalassaemic patients; an ability to achieve negative iron balance, completely remove all excess iron, and maintain normal iron stores in thalassaemic patients; rapid absorption from the stomach and rapid clearance from the body, allowing a greater frequency of repeated administration and overall increased efficacy of iron excretion, which is dependent on the dose used and also the concentration achieved at the site of drug action; and its ability to cross the blood-brain barrier and treat malignant, neurological, and microbial diseases affecting the brain. Some differential pharmacological activity by L1 among patients has been generally shown in relation to the absorption, distribution, metabolism, elimination, and toxicity (ADMET) of the drug. Unique properties exhibited by L1 in comparison to other drugs include specific protein interactions and antioxidant effects, such as iron removal from transferrin and lactoferrin; inhibition of iron and copper catalytic production of free radicals, ferroptosis, and cuproptosis; and inhibition of iron-containing proteins associated with different pathological conditions. The unique properties of L1 have attracted the interest of many investigators for drug repurposing and use in many pathological conditions, including cancer, neurodegenerative conditions, microbial conditions, renal conditions, free radical pathology, metal intoxication in relation to Fe, Cu, Al, Zn, Ga, In, U, and Pu, and other diseases. Similarly, the properties of L1 increase the prospects of its wider use in optimizing therapeutic efforts in many other fields of medicine, including synergies with other drugs.

Because of successful thalassaemia prevention programmes in resource-rich countries and it's huge population China now has the greatest number of new cases of thalassaemia globally as well as more people with thalassaemia than any other country. 30 million Chinese have thalassaemia-associated mutations and about 300,000 have thalassaemia major or intermedia requiring medical intervention. Over the past 2 decades there has been tremendous economic growth in China including per capita spending on health care. There is now nation-wide availability and partial or full insurance for prenatal genetic testing, RBC-transfusions, iron-chelating drugs and haematopoietic cell transplants. Prenatal screening and educational programmes have reduced the incidence of new cases. However, substantial challenges remain. For example, regional differences in access to medical care and unequal economic development require innovations to reduce the medical, financial and psychological burdens of Chinese with thalassaemia and their families. In this review we discuss success in preventing and treating thalassaemia in China highlighting remaining challenges. Our discussion has important implications for resource-poor geospaces challenged with preventing and treating thalassaemia., Competing Interests: Declaration of Competing Interest RPG is a consultant to NexImmune Inc. and Ananexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd., (Copyright © 2023. Published by Elsevier Ltd.)

Background: In countries with low resources, the health and quality-of-life of people living with thalassaemia can be severely affected., Aims: This study examined the health-related quality-of-life of people living with thalassaemia in the West Bank and Gaza, Palestine., Methods: This was a cross-sectional study of a convenience sample of 104 patients (71 adults and 33 children) who lived with thalassaemia and their families in 2015 in the West Bank and Gaza. Participants were surveyed using the 36-item Short Form Health Survey, version 2 (SF36v2), Pediatric Quality of Life InventoryTM (PedsQL) and PedsQL Family Impact Module to assess their quality-of-life. With the SF36v2, we used normed-based scoring and for the PedsQL and Family Impact Module, we used the 0-100 scoring. Scores are reported as means and standard deviations and P < 0.05 considered statistically significant., Results: Quality-of-life scores were low across all domains, indicating poor quality-of-life. For bodily pain in the SF36v2, a significant difference was observed between the West Bank and Gaza. No significant differences were found between males and females. Data from the PedsQL showed no significant differences between the West Bank and Gaza. With the Family Impact Module, the summary score was higher among adults than among paediatric patients. Compared with other countries, thalassaemia patients in Palestine generally had lower quality-of-life scores in most domains., Conclusion: The lack of access to healthcare and blood transfusions, and the geopolitical challenges may be responsible for the low quality-of-life scores of patients living with thalassaemia in Palestine., (Copyright © Authors 2023; Licensee: World Health Organization. EMHJ is an open access journal. This paper is available under the Creative Commons Attribution Non-Commercial ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo).)

Objective: To develop the methods for an extended reporting of anaemia and to measure the status of the key contextual underlying factors of anaemia., Design: Statistical appraisal of Hb v . key influencers of anaemia in Bangladesh – the intake of animal source food (ASF), concentration of Fe in the drinking groundwater (GWI) and the prevalence of congenital Hb disorder (CH) are conducted. The primary data of the National Micronutrient Survey 2011–2012 and the British Geological Survey 2001 are analysed to assess the intake of ASF and the GWI concentration, respectively. The prevalence of thalassaemia from a national survey is used to appraise the CH. ASF is evaluated relative to the 97·5 th percentile intake and group scores are assigned. Association of the GWI and Hb is examined by the linear fit and the mspline fit and the group scores are allocated. Group score is allocated for the prevalence of thalassaemia. Inflammation-adjusted ferritin is considered to report Hb., Setting: A nationwide survey in Bangladesh., Participants: Preschool children (6–59 months), school-age children (6–14 years) and non-pregnant non-lactating women (NPNLW, 15–49 years)., Results: The extended reporting to the prevalence of anaemia in Bangladeshi preschool children, school children and women is – anaemia 33 % (ASF: 2·08; GWI: 1·75; CH: 2), anaemia 19 % (ASF: 1·98; GWI: 1·56; CH: 2) and anaemia 26 % (ASF: 2·16; GWI: 1·58; CH: 2), respectively., Conclusion: The extended reporting of anaemia is a useful tool to understand the status of the key influencers of anaemia, to design the context-customised intervention and to monitor the intervention.

Antenatal screening/testing of pregnant women should be carried out according to the guidelines of the National Health Service (NHS) Sickle Cell and Thalassaemia Screening Programme. Newborn screening and, when necessary, follow-up testing and referral, should be carried out according to the guidelines of the NHS Sickle Cell and Thalassaemia Screening Programme. All babies under 1 year of age arriving in the United Kingdom should be offered screening for sickle cell disease (SCD). Preoperative screening for SCD should be carried out in patients from ethnic groups in which there is a significant prevalence of the condition. Emergency screening with a sickle solubility test must always be followed by definitive analysis. Laboratories performing antenatal screening should utilise methods that are capable of detecting significant variants and are capable of quantitating haemoglobins A 2 and F at the cut-off points required by the national antenatal screening programme. The laboratory must ensure a provisional report is available for antenatal patients within three working days from sample receipt., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Objective: The development of red blood cell alloimmunization intensifies transfusion complication in thalassaemia patients. The purpose of this paper is to evaluate the existing evidence on the prevalence of erythrocyte alloimmunization in China by meta-analysis. We systematically searched cross-sectional studies regarding the alloimmunization of thalassaemia patients with regular blood transfusion in China from year 2000 to May 2021 in the Cochrane library, PubMed, EMBASE, Web of Science, and Chinese databases including CNKI, Wanfang Data, Vip and CBM. Data extraction and quality evaluation of the included studies were performed. Meta-analysis was performed using the DerSimonian and Laird random-effects models with inverse variance weighting. The presence of publication bias was tested by Egger's test, and the methodological quality of each included article was evaluated by the criteria specific to prevalence studies., Results: A total of 1874 patients and 263 alloantibodies from 11 studies were identified and included in the meta-analysis. The proportion of alloantibodies against antigens belonging to the Rh, MNSs and Kidd systems were as high as 70.3%, 17.9%, and 6.5%, respectively. Meta-analysis showed that the overall prevalence of alloimmunization among transfusion-dependent thalassaemia patients in China is 11.4% (95%CI: 7.2%∼16.3%)., Conclusions: The characteristics of red blood cell alloimmunization among thalassaemia patients with regular transfusion in China differ greatly from those in other countries. Therefore, transfusion strategies shall be actively adapted in line with thalassaemia patients in China to minimize the risk of alloimmunization., (Copyright © 2023 Société française de transfusion sanguine (SFTS). Published by Elsevier Masson SAS. All rights reserved.)

The quantification of haemoglobin A 2 by high-performance liquid chromatography (HPLC) was compared with quantification by capillary electrophoresis for control subjects and patients with sickle cell trait or sickle cell anaemia. Significant differences were found, with estimated values being higher by HPLC for control subjects and higher by capillary electrophoresis for sickle cell trait and sickle cell anaemia patients. There is an ongoing need for improved standardisation and alignment of methods., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

The thalassaemias are a group of genetic disorders of haemoglobin which are endemic in the tropics but are now found worldwide due to migration. Basic standard of care therapy includes regular transfusions to maintain a haemoglobin level of around 10 g/dL, together with iron chelation therapy to prevent iron overload. Novel therapies, bone marrow transplantation, and gene therapy are treatment options that are unavailable in many countries with stressed economies. This Wider Perspectives article presents the strategies for management of an adolescent refugee patient with beta thalassaemia, as it would be performed by expert haematologists in six countries: Italy, Lebanon, Oman, the Sudan, Thailand and the United States. The experienced clinicians in each country have adapted their practice according to the resources available, which vary greatly. Even in the current modern era, providing adequate transfusions and chelation is problematic in many countries. On the other hand, ensuring adherence to therapy, particularly during adolescence, is a similar challenge seen in all countries. The concluding section highlights the disparities in available therapies and puts the role of novel therapies into a societal context., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Thalassaemia affects many families in Northeast Syria, an area devastated by over a decade of conflict which has significantly impacted their health system. People with thalassaemia require holistic multidisciplinary care for the clinical complications of thalassaemia. The risks of thalassaemia treatment include blood-borne viral infections secondary to unsafe transfusion, increased vulnerability to serious bacterial infection following splenectomy, and complications of both iron overload and iron chelation therapy. Médecins Sans Frontières (MSF) provided outpatient thalassaemia care programmes in northeast Syria between April 2017 October 2019 in a complex conflict context challenged by population displacement, the destruction of medical facilities, and periods of insecurity., Methods: We performed a secondary descriptive analysis of the thalassaemia cohort data to describe basic clinical and demographic characteristics of the patient population. A desk review of internal and publicly available documents was supplemented by informal interviews with MSF staff to describe and analyse the programmatic approach., Case Description: MSF delivered programmes with thalassaemia investigations, provision of blood transfusion, iron chelation therapy, and psychosocial support. Thalassemia programmes were novel for the organisation and operational learning took place alongside service implementation. Lessons were identified on equipment procurement and the requirements for the implementation of vital investigations (including ferritin testing), to inform clinical decision making. Lessons included the importance of supply planning for sufficient blood products to meet diverse clinical needs in a conflict area, so those with thalassaemia have continued access to blood products among the competing priorities. Iron chelation therapy met a large need in this cohort. Adapted protocols were implemented to balance social factors, hygiene considerations, toxicity, tolerability, and adherence to therapy. Wider service needs included considerations for family planning advice and services, continuity of care and patient access through decentralised services or laboratory access, psychosocial support, and improved data collection including quality of life measurements to understand the full impact of such programmes., Conclusions: Although this type of programming was not "routine" for the organisation, MSF demonstrated that life-sustaining thalassaemia care can be provided in complex conflict settings. International non-governmental organisations can consider this care possible in similar contexts., (© 2023. The Author(s).)

Haploidentical transplantation strategies for patients with transfusion-dependent thalassaemia (TD-TM) remain to be investigated. In this study, 54 paediatric patients with TD-TM were treated with a novel approach using post-transplant cyclophosphamide (PTCy) and low-dose methotrexate (LD-MTX), following a myeloablative regimen. The incidence of neutrophil and platelet engraftment was 96.3% ± 2.6% and 94.4% ± 3.1% respectively. The cumulative incidence of grades II-III acute graft-versus-host disease (GVHD) was 13.8% ± 4.8% at 100 days. At three years, the cumulative incidence of chronic GVHD was 28.5% ± 8.5%. With a median follow-up of 520 days (132-1325 days), the overall survival (OS) and event-free survival (EFS) were 98.1% ± 1.8% and 90.7% ± 3.9% respectively. Compared with the low-dose cyclophosphamide (CTX) conditioning regimen (120 mg/kg), the high-CTX regimen (200 mg/kg) achieved a higher incidence of stable engraftment (100% vs 66.7% ± 15.7%, p = 0.003), a comparable incidence of grades II-III acute GVHD, a lower incidence of chronic GVHD (20.2% ± 8.3% vs 66.6% ± 19.2%, p = 0.011), and better overall survival (100% vs 88.9% ± 10.5%, p = 0.025) as well as EFS (95.6% ± 3.1% vs 66.7% ± 15.7%, p = 0.008). Our results using unmanipulated haploidentical grafts and PTCy with LD-MTX in TD-TM are encouraging. (chictr.org.cn ChiCTR1800017969)., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Childhood anaemia is one of the most common public health problems worldwide. Here, we aim to describe the knowledge and practices on childhood anaemia, thalassaemia and iron deficiency among mothers of children aged between 6 and 59 months in a suburban district of Sri Lanka., Methods: We performed a cross-sectional survey in the Gampaha District of Sri Lanka from December 2020 to February 2021. One well-baby clinic each from four Medical Officer of Health areas in the district was selected using stratified random sampling. Mothers of all children aged between 6 and 59 months attending well-baby clinics were recruited until the sample size was achieved. Data were collected using a self-administered questionnaire and analysed using logistic regression., Results: A total of 392 mothers were recruited; 53% of their children were males. Only 33% of mothers had an accurate understanding of anaemia, while 71% and 28%, respectively, could name at least one symptom and two causes of anaemia; 12% could not name a single food rich in iron. Only 13% of mothers knew that thalassaemia is a cause of anaemia, and 14% had been screened for thalassaemia. Logistic regression analysis that examined for factors associated with higher knowledge of anaemia revealed that an accurate understanding of anaemia was associated with maternal age over 30 years (p < 0.05) and maternal education level beyond grade ten (p < 0.001). In contrast, higher knowledge of symptoms of anaemia was associated with maternal employment (p < 0.01)., Conclusions: The knowledge of anaemia and awareness of thalassaemia among mothers was poor. Very few mothers were aware of iron-rich food and feed it to their children. Despite being located in a thalassaemia-endemic region, very few knew that thalassaemia is a cause of anaemia and have got themselves screened for thalassaemia., (© 2022. The Author(s).)

Background: Hyperfunctional platelets play important roles in thromboembolism in patients with β-thalassaemia/ haemoglobin E (β-thal/HbE). Our previous study revealed ex vivo inhibitory effects of deferiprone on normal platelets. Herein, we aimed to investigate the in vivo effects on platelets in patients with β-thal/HbE., Methods: A prospective, self-controlled clinical study on 30 patients with β-thal/HbE who had received therapeutic deferiprone (20.8-94.5 mg/kg/day) was conducted. The study included a 4-week washout period followed by 4 and 12 weeks of deferiprone treatment. Platelet aggregation was performed by a turbidimetric method. Levels of deferiprone and soluble platelet (sP)-selectin in serum were measured by high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA) kit, respectively., Results: The washout period significantly enhanced platelet hyperactivity both in patients who had undergone splenectomy and in those who had not. At 2 hours following the administration of a single dose of deferiprone, platelet sensitivity to ADP and arachidonic acid was significantly reduced. The inhibitory effects of deferiprone were gradually increased over the period of 4 and 12 weeks. Deferiprone also depressed sP-selectin levels, but the effect was stable over longer follow-up periods. Correlation analysis demonstrated the relationship between serum levels of deferiprone, sP-selectin, and platelet activities induced by ADP and arachidonic acid., Conclusion: We first demonstrated the in vivo antiplatelet effect and benefit of short-term treatment of deferiprone in patients with β-thal/HbE. The impact on thrombotic outcomes deserves further study., Competing Interests: Disclosure and potential conflicts of interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2022/11/dic.2022-7-6-COI.pdf, (Copyright © 2022 Tran NT, Sutcharitchan P, Janprasit J, Rojnuckarin P, Morales NP, Luechapudiporn R.)

Introduction: Iron chelation therapy (ICT) is essential to prevent complications of iron overload in patients with transfusion-dependent thalassaemia. However, there is currently no standard for how to best measure adherence to ICT, nor what level of adherence necessitates concern for poor outcomes, especially in paediatric patients. The objectives of this review are to identify rates of adherence to ICT, predictors of adherence, methods of measurement, and adherence-related health outcomes in children and adolescents., Methods: This review covers the literature published between 1980 and 2020 on ICT in thalassaemia that assessed adherence or compliance. Included studies reflect original research. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed for reporting results, and the findings were critically appraised with the Oxford Centre for Evidence-based Medicine criteria., Results: Of the 543 articles, 37 met the inclusion criteria. The most common methods of assessing adherence included patient self-report ( n  = 15/36, 41.7%), and pill count ( n  = 15/36, 41.7%), followed by subcutaneous medication monitoring (5/36, 13.8%) and prescription refills ( n  = 4/36, 11.1%). Study sizes ranged from 7 to 1115 participants. Studies reported adherence either in "categories" with different levels of adherence ( n  = 29) or "quantitatively" as a percentage of medication taken out of those prescribed ( n  = 7). Quantitatively, the percentage of adherence varied from 57% to 98.4% with a median of 89.5%. Five studies focussed on interventions, four of which were designed to improve adherence. Studies varied in sample size and methods of assessment, which prohibited performing a meta-analysis., Conclusions: Due to a lack of clinical consensus on how adherence is defined, it is difficult to compare adherence to ICT in different studies. Future studies should be aimed at creating guidelines for assessing adherence and identifying suboptimal adherence. These future efforts will be crucial in informing evidence-based interventions to improve adherence and health outcomes in thalassaemia patients.Key messagesPredictive factors associated with ICT adherence in the paediatric population include age, social perception of ICT, social support, and side effects/discomfort.Increased adherence in the paediatric population is associated with decreased serum ferritin and improved cardiac, hepatic, and endocrine outcomes.Inadequate adherence to ICT is associated with increased lifetime health costs.There are few studies that focussed on interventions to increase adherence in the paediatric population, and the studies that do exist all focussed on different types of interventions; successful interventions focussed on consistent, long-term engagement with patients.

Introduction: Around 5% of the world's population is expected to have some degree and type of thalassaemia. Beta thalassaemia (BT) occurs due to a deficient production of the beta-globin chain of haemoglobin. Extramedullary haematopoiesis (EMH) is one of the complications of BT, mainly observed in minor/intermedia subtypes. EMH is the production of blood cells outside the marrow as a compensatory response to longstanding hypoxia. Due to chronic transfusions, it is not expected in patients with beta-thalassaemia major (BTM). However, there are increasingly reported cases of EMH in BTM. The incidence of EMH in BTM is thought to be <1%. We aim to pool the available data and provide cumulative evidence on the occurrence of EMH in BTM patients., Methods: This is a systematic review of case reports, series, and retrospective studies that presented data on the occurrence of EMH in BTM patients. Data were recorded and analyzed in Microsoft Excel 2016 and SPSS 26. The protocol has been registered in PROSPERO: CRD42021242943., Results: Data from 253 cases of EMH in BTM patients were extracted with a mean age of 35.3 years. Mean haemoglobin at presentation with EMH was 8.2 mg/dL. Lower limb weakness was the most common presenting feature ( N  = 23) (paraspinal EMH). Magnetic resonance imaging (MRI) was the most widely used diagnostic modality (226). Overall, blood transfusion was the commonest reported treatment (30), followed by radiotherapy (20), surgery (15), hydroxyurea (12), steroids (6), and exchange transfusion (2). An outcome was reported in 20% of patients, all recovered, except one who died as a result of nosocomial infection., Conclusion: EMH is rare in BTM and can occur in any organ system with varied clinical features. MRI can effectively diagnose EMH, and conservative management has similar results compared to invasive treatments. Larger studies, focussing on outcomes may enhance guidelines on preventive and therapeutic strategies for managing EMH in BTM.KEY MESSAGESExtramedullary haematopoiesis is a rare complication in beta thalassaemia. Although it is more common in non-transfusion dependent thalassaemia, increasingly reported cases suggest a higher prevalence of EMH in TDT than what is known before.There are no clear guidelines on the management of EMH in TDT, with reported patients showing similar outcomes with conservative invasive treatment modalities.More extensive and preferably prospectively designed studies are required focussing on the management of EMH and its outcomes in patients with TDT to formulate evidence-based guidelines.

Haemoglobinopathies are the commonest monogenic diseases worldwide and are caused by variants in the globin gene clusters. With over 2400 variants detected to date, their interpretation using the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines is challenging and computational evidence can provide valuable input about their functional annotation. While many in silico predictors have already been developed, their performance varies for different genes and diseases. In this study, we evaluate 31 in silico predictors using a dataset of 1627 variants in HBA1 , HBA2, and HBB . By varying the decision threshold for each tool, we analyse their performance (a) as binary classifiers of pathogenicity and (b) by using different non-overlapping pathogenic and benign thresholds for their optimal use in the ACMG/AMP framework. Our results show that CADD, Eigen-PC, and REVEL are the overall top performers, with the former reaching moderate strength level for pathogenic prediction. Eigen-PC and REVEL achieve the highest accuracies for missense variants, while CADD is also a reliable predictor of non-missense variants. Moreover, SpliceAI is the top performing splicing predictor, reaching strong level of evidence, while GERP++ and phyloP are the most accurate conservation tools. This study provides evidence about the optimal use of computational tools in globin gene clusters under the ACMG/AMP framework., Competing Interests: ST, MX, AM, CS, CH, CB, JT, IF, NY, FA, EE, HH, BZ, AK, MK, PK No competing interests declared, (© 2022, Tamana, Xenophontos et al.)

Background: Haemoglobinopathies and G6PD deficiency are inherited disorders found mostly in malaria-endemic areas among different tribal groups of India. However, epidemiological data specific to Particularly Vulnerable Tribal Groups (PVTGs), important for planning and implementing malaria programmes, is limited. Therefore, the present community-based study aimed to assess the prevalence of haemoglobinopathies and G6PD deficiency among the 13 PVTGs found in the state of Odisha, reporting the maximum malaria cases in the country., Methods: This cross-sectional study was conducted from July 2018 to February 2019 in 12 districts, home to all 13 PVTGs, in an estimated sample size of 1461, selected two-stage sampling method. Detection of haemoglobinopathies was done by the variant analyser. Screening of G6PD deficiency was carried out using DPIP method followed by quantification using spectrophotometry. The PCR-RFLP technology was used to determine variant of G6PD deficiency and haplotype analysis of sickle cell, while ARMS-PCR and GAP-PCR was used for detecting the mutation pattern in β-thalassaemia and α-thalassaemia respectively. The diagnosis of malaria was done by Pf-PAN RDT as point of care, followed by nPCR for confirmation and Plasmodium species identification., Results: The prevalence of sickle cell heterozygotes (AS) was 3.4%, sickle cell homozygous (SS) 0.1%, β-thalassaemia heterozygotes 0.3%, HbS/β-thalassaemia compound heterozygote 0.07%, HbS-α-thalassaemia 2.1%, G6PD deficiency 3.2% and malaria 8.1%. Molecular characterization of β S revealed the presence of Arab-Indian haplotype in all HbS cases and IVS 1-5 G → C mutation in all β-thalassaemia cases. In case of α-thal, αα/α-3.7 gene deletion was most frequent (38%), followed by αα/α-4.2 (18%) and α-3.7/α-3.7 (4%). The frequency of G6PD Orissa (131C → G) mutation was found to be 97.9% and G6PD Mediterranean (563C → T) 2.1%. Around 57.4% of G6PD deficient individuals and 16% of the AS were found to be malaria positive., Conclusion: The present study reveals wide spread prevalence of sickle cell anaemia, α-thalassaemia, G6PD deficiency and malaria in the studied population. Moderate to high prevalence of G6PD deficiency and malaria warrants G6PD testing before treating with primaquine (PQ) for radical cure of Plasmodium vivax. Screening and counselling for HbS is required for the PVTGs of Odisha., (© 2022. The Author(s).)

Aim: To explore the experiences of Jordanian nurses regarding the psychosocial care needs of children with thalassaemia and their families., Design: A descriptive phenomenological approach was employed., Methods: A purposive sampling strategy was used to select 10 nurses who had experience in caring for children with thalassaemia. Unstructured, face-to-face interviews were conducted. Coliazzi's data analysis process was applied., Results: The analysis revealed three major themes: (1) valuing psychosocial support; (2) caring for paediatric patients needs certain competencies in nurses and (3) barriers to providing psychosocial care. Nurses expressed the importance of providing psychosocial care. A lack of specialists in psychosocial care as well as a lack of screening tools, and entertainment facilities for children was identified to be impeding effective psychosocial care. Implementing training programmes for nurses concerning providing psychosocial care and making the appropriate changes in nursing curricula at the educational level are recommended., (© 2021 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

The objective of the study was to compare the maternal and foetal outcomes of pregnancies complicated by Hb H-constant spring (HbH-CS) disease/deletional HbH (HbH-del) disease and low-risk pregnancies. A retrospective cohort research was undertaken on singleton pregnancies with Hb H-CS and Hb H-del diseases. The controls were randomly selected with a control-to-case ratio of 10:1. A total of 55 cases of HbH-CS disease, 231 cases of HbH-del disease and 2860 controls were compared. The mean gestational age at delivery and birthweight were significantly lower in the HbH-CS group than in the HbH-del and control groups. The clinical course of Hb H-CS was more severe than that of HbH-del disease. The rates of preterm birth, foetal growth restriction and low birthweight were significantly increased in the HbH-CS and Hb H-del groups. These rates were significantly greater in the HbH-CS group than in the H-del group. The maternal outcomes were not significantly different among the three groups. In conclusion, pregnancy worsens the course of HbH disease, more noticeably in HbH-CS disease. Hb H disease significantly increases the risk of adverse foetal outcomes, more noticeably in the HbH-CS group. Pregnancy is relatively safe for women with HbH disease., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Sickle cell disease and thalassaemia are life-long haematological diseases that can impact the quality of life of patients. This impact on quality of life can require intermittent psychological input throughout the lifespan for management. Managing everyday life during the COVID-19 pandemic could be challenging for people with these health conditions, which could impact their health, their mood and anxiety, their perception of control, and their engagement with their regular healthcare services. This report describes the characteristics of these health conditions and discusses reflections, from a specialist psychology service working with this clinical population, about the impact of COVID-19 on patient engagement with the service. The main aim of this report is to highlight the relevance and usefulness of videoconferencing as a therapy format, suggest implications for further service development and suggest alternate ways of working therapeutically with clients., Competing Interests: The authors declare no conflict of interest.

Thalassaemia is a common hereditary haemolytic anaemia. Mild cases of this disease may be asymptomatic, while patients with severe thalassaemias require high-dose blood transfusions and regular iron removal to maintain life or haematopoietic stem cell transplantation to be cured, imposing an enormous familial and social burden. Therefore, early, timely, and accurate screening of patients is of great importance. In recent years, with the continuous development of thalassaemia screening technologies, the accuracy of thalassaemia screening has also improved significantly. This article reviews the current research on thalassaemia screening., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Red blood cell (RBC) indices, including mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH), have been widely used for primary screening for thalassaemia (thal) syndromes. Recently, a single nucleotide polymorphism (SNP) rs855791 of TMPRSS6 , an iron regulation gene involved in the substitution of a nucleotide between thymine (T) and cytosine (C) in exon 17 resulted in an amino acid change, p.Val736Ala (V736A), has been described to associate with RBC indices. The objective was to study the effects of common SNP V736A on RBC indices in deletional α-thal variations. SNP rs855791 genotypes were identified from 433 Thai volunteers, including 32.6% males and 67.4% females with an average age of 23.0 ± 8.7 years. These populations included individuals (82.4%) who had normal globin genotype (αα/αα, ββ) and α-thal carriers, which were divided into two subgroups, including α + -thal (-α/αα) (14.1%) and α o -thal (--/αα) (3.5%). Among three SNP genotypes, the C allele gradually expressed higher MCV and MCH than those of the T allele in both α + - and α o -thal traits. Importantly, SNP rs855791 of TMPRSS6 responded to α-globin deletions for sustaining RBC sizes and haemoglobinisation in α-thal carriers.

Aims: To develop a drug-disease model describing iron overload and its effect on ferritin response in patients affected by transfusion-dependent haemoglobinopathies and investigate the contribution of interindividual differences in demographic and clinical factors on chelation therapy with deferiprone or deferasirox., Methods: Individual and mean serum ferritin data were retrieved from 13 published studies in patients affected by haemoglobinopathies receiving deferiprone or deferasirox. A nonlinear mixed effects modelling approach was used to characterise iron homeostasis and serum ferritin production taking into account annual blood consumption, baseline demographic and clinical characteristics. The effect of chelation therapy was parameterised as an increase in the iron elimination rate. Internal and external validation procedures were used to assess model performance across different study populations., Results: An indirect response model was identified, including baseline ferritin concentrations and annual blood consumption as covariates. The effect of chelation on iron elimination rate was characterised by a linear function, with different slopes for each drug (0.0109 [90% CI: 0.0079-0.0131] vs. 0.0013 [90% CI: 0.0008-0.0018] L/mg mo). In addition to drug-specific differences in the magnitude of the ferritin response, simulation scenarios indicate that ferritin elimination rates depend on ferritin concentrations at baseline., Conclusion: Modelling of serum ferritin following chronic blood transfusion enabled the evaluation of drug-induced changes in iron elimination rate and ferritin production. The use of a semi-mechanistic parameterisation allowed us to disentangle disease-specific factors from drug-specific properties. Despite comparable chelation mechanisms, deferiprone appears to have a significantly larger effect on the iron elimination rate than deferasirox., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Patients with transfusion-dependent thalassaemia (TDT) are considered an at increased-risk population for severe and/or morbid coronavirus disease 2019 (COVID-19) infection. Timely vaccination is the main preventive method for severe COVID-19. Different adverse events and reactions after vaccination have been reported, with severe ones being extremely rare. Patients with TDT may have altered immunity due to chronic transfusions, iron overload and chelation therapy, and splenic dysfunction. Here, we show that adult patients with TDT following vaccination with the novel messenger RNA vaccines have mild adverse events and can produce protective antibodies comparable to the healthy population., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

In case of heavy and even moderate censoring, a common problem with the Greenwood and Peto variance estimators of the Kaplan-Meier survival function is that they can underestimate the true variance in the left and right tails of the survival distribution. Here, we introduce a variance estimator for the Kaplan-Meier survival function by assigning weight greater than zero to the censored observation. On the basis of this weight, a modification of the Kaplan-Meier survival function and its variance is proposed. An advantage of this approach is that it gives non-parametric estimates at each point whether the event occurred or not. The performance of the variance of this new method is compared with the Greenwood, Peto, regular, and adjusted hybrid variance estimators. Several combinations of these methods with the new method are examined and compared on three datasets, such as leukemia clinical trial data, thalassaemia data as well as cancer data. Thalassaemia is an inherited blood disease, very common in Pakistan, where our data are derived from., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Khan, Zaman, Azmi, Shahzada and Jakovljevic.)

In tropical areas, there are a variety of parasitic and nonparasitic causes of high-grade splenomegaly. An adolescent male patient with haemoglobin E/β-thalassaemia came with high-grade splenomegaly and severe anaemia, requiring blood transfusions on a regular basis. Treatment with folic acid and antioxidant vitamins reduced the requirement for blood transfusions, brought haemoglobin levels back to near normal, and reduced splenic enlargement.  Haemoglobin E/β-thalassaemia is a haematological condition that causes anaemia and high-grade splenomegaly in the tropics. Initially, the disease was only seen in Southeast Asia, but it has since spread around the world due to migration from that region., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Singh et al.)

Aims: To explore the impact of incorporating a faster cardiac magnetic resonance (CMR) imaging protocol in a low-middle-income country (LMIC) and using the result to guide chelation in transfusion-dependent patients., Methods and Results: A prospective UK-India collaborative cohort study was conducted in two cities in India. Two visits 13 months apart included clinical assessment and chelation therapy recommendations based on rapid CMR results. Participants were recruited by the local patient advocate charity, who organized the patient medical camps. The average scanning time was 11.3 ± 2.5 min at the baseline and 9.8 ± 2.4 min (P < 0.001) at follow-up. The baseline visit was attended by 103 patients (mean age 25 years) and 83% attended the second assessment. At baseline, 29% had a cardiac T2* < 20 ms, which represents significant iron loading, and 12% had left ventricular ejection fraction <60%, the accepted lower limit in this population. Only 3% were free of liver iron (T2* ≥ 17 ms). At 13 months, more patients were taking intensified dual chelation therapy (43% vs. 55%, P = 0.002). In those with cardiac siderosis (baseline T2* < 20 ms), there was an improvement in T2*-10.9 ± 5.9 to 13.5 ± 8.7 ms, P = 0.005-and fewer were classified as having clinically important cardiac iron loading (T2* < 20 ms, 24% vs. 16%, P < 0.001). This is the first illustration in an LMIC that incorporating CMR results into patient management plans can improve cardiac iron loading., Conclusion: For thalassaemia patients in an LMIC, a simplified CMR protocol linked to therapeutic recommendation via the patient camp model led to enhanced chelation therapy and a reduction in cardiac iron in 1 year., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)