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Non-transfusion-dependent (NTD) thalassaemia is characterised by ineffective erythropoiesis and haemolytic anaemia, leading to long-term complications, poor quality of life, and early mortality. No oral disease-modifying therapies are approved for β-thalassaemia and no agents are approved for α-thalassaemia. The objective of this study was to evaluate the efficacy and safety of mitapivat, an oral activator of pyruvate kinase, in adults with NTD α-thalassaemia or NTD β-thalassaemia. ENERGIZE is a phase 3, double-blind, randomised, placebo-controlled trial followed by an open-label extension conducted at 70 hospitals in 18 countries globally. Participants had to be aged 18 years or older with NTD α-thalassaemia or NTD β-thalassaemia and haemoglobin concentrations of 10 g/dL or lower. Participants were randomly assigned 2:1 to mitapivat or placebo (100 mg orally twice a day for 24 weeks) via a central interactive response technology system using block randomisation, stratified by baseline haemoglobin concentration and thalassaemia genotype. Everyone was masked to the patients' treatment assignment until the study was unblinded for the analysis of the primary endpoint. The primary endpoint was haemoglobin response (≥1·0 g/dL increase from baseline in mean haemoglobin concentration from week 12 through week 24), analysed in all patients who were randomly assigned. Safety was analysed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT04770753, and is active but not recruiting. Between Nov 8, 2021, and March 31, 2023, 235 patients were screened, of whom 194 were enrolled (123 [63%] were female and 71 [37%] were male). 130 patients were randomly assigned to mitapivat and 64 patients to placebo and formed the full analysis set. One patient in each group was randomly assigned but not given treatment and was therefore excluded from the safety analysis set (mitapivat 129 patients and placebo 63 patients). Seven patients in the mitapivat group and one patient in the placebo group discontinued treatment before the end of the 24-week double-blind period. 55 (42%) of 130 patients in the mitapivat group had a haemoglobin response versus one (2%) of 64 in the placebo group (least-squares mean difference 41% [95% CI 32–50], two-sided p<0·0001). Adverse events were reported in 107 (83%) of 129 patients who received mitapivat and 50 (79%) of 63 patients who received placebo. The most commonly reported adverse events with mitapivat were headache (29 [22%] of 129 patients in the mitapivat group vs six [10%] of 63 in the placebo group), initial insomnia (18 [14%] vs three [5%]), nausea (15 [12%] vs five [8%]), and upper respiratory tract infection (14 [11%] vs four [6%]). No deaths were reported. Mitapivat could be a new oral treatment for adults with NTD α-thalassaemia or NTD β-thalassaemia by increasing haemoglobin concentration and improving fatigue. Agios Pharmaceuticals.

Non-deletional α-thalassemia variants, particularly hemoglobin Constant Spring (Hb CS) and hemoglobin Pakse, are prevalent in northeastern Thailand and neighboring regions. Homozygous Hb CS and compound heterozygous Hb CS/Hb Pakse can present with a wide clinical spectrum. In this study, 49 patients with these α-globin variants—with or without co-inheritance of beta-thalassemia—were evaluated. Genotypes included homozygous Hb CS ( n  = 27), homozygous Hb CS with Hb E ( n  = 8), compound heterozygous Hb CS/Hb Pakse ( n  = 10), compound heterozygous Hb CS/Hb Pakse with Hb E ( n  = 3), and homozygous Hb Pakse ( n  = 1). Fetal anemia with hydrops fetalis occurred in 25 patients; 21 underwent intrauterine transfusions (IUTs), resulting in favorable postnatal outcomes in most cases. Two patients with homozygous Hb CS died from complications of severe anemia and prematurity. Early neonatal jaundice occurred in 27 patients, most requiring phototherapy. Direct hyperbilirubinemia was observed in 10 patients; most recovered with supportive care and transfusion, though one died from progressive cholestasis. Twenty four patients required 1–2 postnatal transfusions, with only two requiring later transfusion. Four patients with childhood anemia were initially misdiagnosed with iron deficiency anemia before confirmation of α-thalassemia variants. After the first few months of life, patients typically exhibit mild hypochromic microcytic anemia, elevated red cell distribution width, and reticulocytosis, with basophilic stippling more prominent in Hb CS. During follow-up (3–160 months, median 66), no patients developed hepatosplenomegaly, iron overload, or gallstones. These α-thalassemia variants may cause severe fetal anemia requiring IUT but generally evolve into transfusion-independent mild anemia. Early detection and targeted intervention can improve outcomes in high-prevalence regions.

This study aims to investigate the adverse effects of different types of α-thalassemia on pregnant women and their differences, so as to provide reference for the prevention and monitoring of perinatal complications in different types of α-thalassemia pregnancy. The observation group comprised 1371 singleton pregnant women with α-thalassemia, control group comprised 680 non-thalassemia singleton pregnancies during the same period. The thalassemia genotypes of the observation group were tallied and categorized based on their respective genotypes within the group. The hemoglobin in the experimental group was lower than control group. The incidences of electrocardiographic abnormality, abnormal liver function, hypertensive disorders, gestational diabetes mellitus and thyroid disorders during pregnancy were higher in the observation group than in the control group. The incidences of preterm labor, caesarean section and postpartum hemorrhage were all higher in the observation group than in the control group. The delivery weight and neonatal hemoglobin in the observation group were lower than those in the control group. Pregnant women with α-thalassemia have more pregnancy and delivery complications than those without α-thalassemia, they should receive more frequent and standardized prenatal examination, so as to find and correct abnormal indicators in time.

Mild to severe anemia is caused by thalassemia, a common genetic disorder affecting over 100 countries worldwide, that results from the abnormality of one or several of the four globin genes. This leads to chronic hemolytic anemia and disrupted synthesis of hemoglobin chains, iron overload, and poor erythropoiesis. Although the diagnosis of thalassemia has improved globally along with the treatment and transfusion support, it is still a major problem in diagnosing in high-prevalence areas like Pakistan. This work aims to assess the performance of numerous combinations of machine learning methods to detect alpha and beta-thalassemia in their minor and major types. These results are obtained from CBC and HPLC analysis. The analyzed models are K-nearest Neighbor (KNN), Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost). The study aims to examine the effectiveness of the developed models in discriminating thalassemia variants, especially in the light of Pakistani patients’ data. The study found that XGBoost achieved the highest performance on both the CBC and HPLC datasets, with training accuracies of roughly 99.5% for CBC and 99.3% for HPLC. The test accuracy across both datasets was consistently high and thus the best model for detecting thalassemia in this research study. The imported SVM model, slightly less accurate than XGBoost, still has strong performance, particularly on the HPLC data where the cumulative testing accuracy of the model stood at 99.4%. As can be seen from the results, XGBoost specifically shows a very high accuracy of above 99% in the detection of thalassemia types using CBC and HPLC data for Pakistani patients. To the author’s knowledge, this research is the first to predict alpha and beta-thalassemia in its major and minor forms using these diagnostic reports. These models indicate that they can offer significant support in detecting thalassemia in resource-constrained settings such as Pakistan. If deep learning is incorporated, even greater accuracy could be achieved.

Alpha-thalassemia is a common inherited hemoglobin disorder caused by deletions or point mutations in the HBA1 and/or HBA2 genes, leading to reduced or absent synthesis of alpha-globin chains. Although deletional mutations are predominant, non-deletional mutations can also contribute to the clinical spectrum of the disease, with varying severity. This study aimed to characterize two novel mutations in the HBA1 gene, a 230 bp microdeletion and a missense mutation (NP_000549.1:p.Ala29Pro), identified in two unrelated Tunisian families. Additionally, we assessed the clinical, hematological, molecular, and in silico structural impact of these mutations. Peripheral blood samples were collected from affected individuals and family members. Hematological parameters were measured using automated cell counters, and hemoglobin fractions were analyzed by high-performance liquid chromatography (HPLC). Genomic DNA was extracted, and common α-thalassemia deletions were screened via gap-PCR. Negative cases underwent sequencing of HBA1 and HBA2 exons. The novel deletion was confirmed by gap-PCR, gel purification, and sequencing. The pathogenicity of the missense mutation was assessed using in silico tools (PolyPhen-2, SIFT, MutationTaster), and structural modeling was performed using Swiss-PdbViewer and DynaMut to evaluate protein stability and flexibility. In Family A, a 4-year-old proband exhibited mild anemia, microcytosis, hypochromia, and low ferritin levels unresponsive to iron supplementation. A novel heterozygous 230 bp deletion (NC_000016.10:g.176695_176925del), named Hemoglobin Ariana, was identified in the HBA1 gene, affecting the 5’UTR, exon 1, and part of intron 1. In Family B, a 4-month-old proband presented with co-inheritance of α-thalassemia and Hemoglobin C. Sequencing revealed a novel missense mutation (NM_000558.5:c.85G > C, NP_000549.1:p.Ala29Pro), designated Hemoglobin Tozeur. In silico analysis predicted the mutation as deleterious, with structural modeling indicating destabilization of the α-globin protein, reduced stability, and altered flexibility near the heme-binding region. This study identifies two novel HBA1 mutations associated with α-thalassemia in Tunisia. The combined clinical, molecular, and structural analyses highlight the importance of comprehensive genetic screening and in silico modeling for accurate diagnosis and improved management of thalassemia cases.

Alpha-thalassemia is a widespread genetic disorder, and accurately distinguishing between alpha-plus (α⁺) and alpha-zero (α⁰) types is critical for effective screening and management. This study developed and evaluated machine learning models to classify α⁺ and α⁰ carriers based on hematological parameters. A dataset of 956 cases was analyzed, including variables such as red blood cell (RBC) count, hemoglobin (Hb) level, and RBC indices. Feature selection identified the most predictive markers, and five machine learning models were trained and compared. The stacking ensemble model demonstrated the best performance, achieving 94% accuracy and a high F1-score. Key predictors included RBC count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Correlation analysis revealed strong interrelationships among RBC indices, while platelet (PLT) and white blood cell (WBC) parameters had moderate associations. These findings suggest that machine learning, particularly ensemble methods, can enhance the detection of alpha-thalassemia carriers. The development of models based on both data-driven and clinical features provides a flexible framework for screening and could support more personalized approaches in future research.

High molecular weight kininogen (HK) deficiency is a rare autosomal recessive disorder caused by mutations in the KNG1 gene. This study reports a 66-year-old male Chinese patient who presented with significantly prolonged activated partial thromboplastin time (aPTT) and microcytic hypochromic anemia. Whole-exome sequencing revealed a homozygous nonsense mutation in exon 6 of the KNG1 gene (c.718 C > T, p.Arg240*) in the proband. This mutation results from a cytosine-to-thymine substitution, generating a premature termination codon that leads to truncated HK protein translation and loss of function. Additionally, genetic testing identified a concurrent heterozygous α-thalassemia -- SEA deletion in the proband, located at 16p13.3 and encompassing the HBA2 and HBA1 genes. Pedigree analysis indicated that both the proband and his sister were homozygous for the KNG1 mutation and exhibited prolonged aPTT, whereas their children and some descendants were heterozygous carriers with normal coagulation function. Within the same family, all heterozygous carriers of the α-thalassemia -- SEA deletion presented with microcytic hypochromic anemia. This study represents the first documented case of co-occurrence of a homozygous KNG1 p.Arg240* mutation and the -- SEA deletion α-thalassemia.

The blood counts of α thalassemia carriers (α-thal) are similar to those of β thalassemia carriers, except for Hemoglobin A2 (Hb A2), which is not elevated. The objective of this study was to determine whether mathematical formulas are effective for detecting suspected α-thal. The data were obtained from the database of the prevention program for detecting couples at risk for having a child with hemoglobinopathy. Red Blood Cells (RBC) indices were analyzed using mathematical formulas, and the sensitivity and negative predictive value (NPV) were calculated. Among 1334 blood counts suspected of α-thal analyzed, only the Shine and Lal and the Support Vector Machine formulas revealed high sensitivity and NPV. Sensitivity was 85.54 and 99.33%, and NPV was 98.93 and 99.93%, respectively. Molecular defects were found in 291, and 81 had normal α genes. Molecular analysis was not performed in 962 of the samples. Based on these results, mathematical formulas incorporating one of these reliable formulas for detecting suspected α or β thalassemia carriers in the program of the automatic analyzers can flag these results, increase the awareness of the primary physicians about the carrier risk, and send an alert with a recommendation for further testing.

To determine the optimal cutoffs of the three indicators (MCV, MCH and HbA2) for alpha-thalassemia screening and to evaluate the validity of these indicators in Fujian Province, China. We conducted a retrospective analysis on the results of specimens received from May 2016 to April 2023. Receiver operating characteristic (ROC) curves were used to confirm the optimal cutoffs of the screening indicators. And the effectiveness of different combined screening methods was evaluated in patients with and without alpha-thalassemia. The optimal cutoffs of MCV, MCH, and HbA2 were 77.85, 27.05 and 2.55, respectively. Among them, the area under the ROC curve of MCH was 0.912, and it was the best of the three parameters used for alpha-thalassemia screening. The results can help clinicians and laboratory technicians perform genetic counseling and prenatal diagnosis for patients. It also provide a reference for alpha-thalassemia genotype distributions in our region and the optimal cutoff values of MCV, MCH and HbA2.

α-thalassemia is a hereditary hemolytic anemia, in which the clinical manifestations vary greatly depending on the degree of α-globin gene deletion. -α3.7/--SEA thalassemia is an intermediate type of α-thalassemia, with three α-globin genes deletion. The clinical symptoms of -α3.7/--SEA thalassemia vary from mild to moderate anemia [ 1 ]. However, little studies had reported the diagnosis and clinical symptoms of -α3.7/--SEA thalassemia. Here we reported two cases of -α3.7/--SEA thalassemia, one inpatient for chronic headache and one outpatient for elevated bilirubin. Two patients were first subjected to blood test, and the laboratory data showed the decreased hemoglobin concentration and mean corpuscular volume. Peripheral blood cells smear displayed that the mature red blood cells were markedly different in size, with enlarged central pale area, occasional oval red blood cells, suggesting the potential microcytic hypochromic anemia. Hemoglobin electrophoresis displayed the low level of HbA2, indicating the α-thalassemia or δ-thalassemia. Reverse dot blot hybridization assay detected the deletion of α-globin genes in the two cases. After ameliorative treatment for anemia, the inpatient’s headache was significantly relieved and stable. Comprehensive judgment of clinical symptoms and laboratory test results is applicative for -α3.7/--SEA thalassemia diagnosis. -α3.7/--SEA thalassemia may lead to individual differences in clinical symptoms and complications, which requires more attention and early treatment.