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Background and Objectives: With increasing life expectancy and prevalence of thalassaemia, it has led to a greater need for safe blood, yet the current supply from voluntary donors is insufficient to meet this demand. Thalassaemia recipients face a significant risk of alloimmunization because of repeated exposure to foreign red cell antigens. Study aims to determine high prevalent Rh antigen negative donors in western India donor population along with what percentage of these donors are willing to become dedicated voluntary donors for thalassaemia patients. Study also aims to examine factors influencing their willingness and challenges faced in mobilizing dedicated donors., Method: 700 whole blood donors from western India, following screening for inclusion & exclusion criteria as per Drugs and Cosmetic Act (DCA) 2020 amendment guidelines & were sero-negative for transfusion transmitted infections were enrolled for the study. Red cell phenotyping was performed using Conventional Tube Technique (CTT) for "D", "C", "E", "c", "e" and "K" antigen using known antisera. Donors that were "C" AND/OR "e" antigen negative were contacted telephonically and were counseled and motivated for becoming voluntary blood donors. Statistical analysis assessed correlation between donation frequency, donor's occupation and education., Result: Among 700 donors, 96.6% (n = 676) were males and 3.4% (n = 24) were females. The most predominant blood group was B > O > A > AB. Rh(D) antigen was present in 91.44% (n = 640) and absent in 8.6% (n = 60). Prevalence of other Rh antigens is as follows: "e" (99%) > "C" (85.4%) > "c" (59.1%) > "E" (18.0%). Only 1.15% had "K" antigen positive. The commonest Rh phenotype R 1 R 1 (DCe/DCe) was expressed by 40.57% (n = 283), and the least common r″r (cE/ce), r″r″ (cE/cE) and r'r' (Ce/Ce) was found in 0.14% (n = 1), respectively. 'C' negative, 'e' negative, 'C' and 'e' antigen negative donors constituted 14.8% (n = 104) with 93.2% (n = 97) C-antigen negative, 1.92% (n = 2) e-antigen negative and 4.8% (n = 5) both "C" and "e" antigen negative donors. The commonest phenotypes among C-antigen and e-antigen negative donors were rr (50%) and R z R 2 (1.94%) respectively. Likewise, the most common phenotype amongst both C- and e-antigens negative donors was R 2 R 2 (3.84%). 61.5% of the donors agreed to enroll for voluntary blood donation following telephonic invitation, while 6.8% of them refused permanently. Approximately, 3.9% of the blood donors were willing to donate blood only when needed and 27.8% of them could not be contacted., Conclusion: Creating a database of voluntary donors with known phenotype, especially who lack very common antigens like "C" and "e" and are willing to become dedicated, regular voluntary donors for thalassemic patients can ensure timely administration of safe blood. One of the major challenges for this noble initiative was lack of awareness which can be circumvent effectively with proper counseling efforts., (Copyright © 2024 Socit francophone de transfusion sanguine (SFTS). Published by Elsevier Masson SAS. All rights reserved.)

Iron overload causes cognitive impairment in thalassemia patients. The gut-brain axis plays an important role in cognitive function. However, the association between gut/blood microbiome, cognition, and iron burden in thalassemia patients has not been thoroughly investigated. We aimed to determine those associations in thalassemia patients with different blood-transfusion regimens. Sixty participants: healthy controls, transfusion-dependent thalassemia (TDT) patients, and non-transfusion-dependent (NTDT) patients, were recruited to evaluate iron overload, cognition, and gut/blood microbiome. TDT patients exhibited greater iron overload than NTDT patients. Most thalassemia patients developed gut dysbiosis, and approximately 25% of the patients developed minor cognitive impairment. Increased Fusobacteriota and Verrucomicrobiota with decreased Fibrobacterota were observed in both TDT and NTDT groups. TDT patients showed more abundant beneficial bacteria: Verrucomicrobia. Iron overload was correlated with cognitive impairment. Increased Butyricimonas and decreased Paraclostridium were associated with higher cognitive function. No trace of blood microbiota was observed. Differences in blood bacterial profiles of thalassemia patients and controls were insignificant. These findings suggest iron overload plays a role in the imbalance of gut microbiota and impaired cognitive function in thalassemia patients. Harnessing probiotic potential from those microbes could prevent the gut-brain disturbance in thalassemia patients., (© 2024. The Author(s).)

Most of the thalassemic children of Bangladesh are receiving repeated blood transfusion. But they do not receive chelation therapy due to financial constraints. As a result, iron overload occurs in various organs of these children. Extra iron that is loaded in thyroid gland causes thyroid dysfunction. This study was undertaken to evaluate thyroid status in children with transfusion dependent Thalassemia patient. This cross-sectional analytical study was conducted in the Department of Pediatrics, Mymensingh Medical College Hospital, Bangladesh from September 2016 to April 2018. Children having thalassemia diagnosed by Hb electrophoresis, aged 3-12 years of both sexes were included as study group. Children of same age and sex admitted in indoor of Mymensingh Medical College Hospital with minor illness and without thalassemia were taken as comparison group. Purposive Sampling technique was applied. Serum FT₄, TSH and ferritin level were estimated in all children. Data analysis was done with Statistical Package for Social Science (SPSS) version 21.0. A total of 60 patients were enrolled as study group and another 60 patients were compared as comparison group. Mean ages of study group was 7.88±2.55 years and comparison group were 7.22±2.48 years. The mean pre-transfusion hemoglobin, serum ferritin, serum FT₄ and serum TSH level were found 6.23±0.60 gm/dl, 2658.33±879.39 ng/ml, 15.14±4.40 fmol/mL, 4.29±4.60 μIU/mL respectively in study group. The mean serum FT₄ was found significantly lower and mean serum TSH was significantly higher in thalassemic children in comparison to non-thalassemic children (p= <0.05). Frequency of subclinical hypothyroidism was found significantly higher in study group (25.0%) compared to comparison group (3.3%) (p=0.001). Mean serum ferritin level was found significantly higher in hypothyroid cases. Mean FT₄ level was significantly lower and mean TSH level was significantly higher in hypothyroid thalassemic patients (p= <0.001). Significant positive correlation between serum ferritin level and serum TSH level was found. Higher serum ferritin level was found significantly associated with the development of hypothyroidism in thalassemic patients.

Background: The current investigation aims to analyze the occurrence of thalassemia in patients who participated in hemoglobin A1c (HbA1c) testing in clinical laboratory showing high hemoglobin F (HbF) level (≥ 1.5%) or abnormal Hb peak and predict the main influence factors by using different statistical models., Methods: The current investigation is a single-center retrospective cohort study. HbA1c concentration was detected by using TOSOH HLC-723G8 glycated hemoglobin analyzer. SNaPshot SNP (Single Nucleotide Polymorphism) typing and AccuCopy technology were employed to detect mutations in thalassemia-related pathogenic genes., Results: A total of 126 patients endured high HbF levels or abnormal Hb peak during HbA1c detection, and 66.7% of subjects (n = 84) showed thalassemia mutations. Three heterozygosity mutations, including c.52A>T (p.K18*), c.-78A>G, and c.126&#95;129delCTTT(p.F42Lfs*19) present in HBB gene, were also identified. -- SEA /αα mutation demonstrated the youngest ages (p < 0.001). 17 M (p < 0.001) and 41/42 M (p < 0.01) mutations with β-thalassemia showed higher HbF levels compared with patients without thalassemia mutations. Except for -α 3.7 , mutations in thalassemia showed lower levels of mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) compared with patients without thalassemia mutations. Patients with thalassemia mutations showed younger age (p < 0.001), lower Hb (p < 0.001), MCV and MCH levels (p < 0.001), higher red blood cell (RBC) count (p < 0.001), and platelet distribution width (PDW) level (p = 0.007) than patients without thalassemia mutations. Three statistical models indicate MCV is the most valuable independent factor for predicting thalassemia and ROC (receiver operating characteristic) curves analysis of AUC (Area Under the Curve) of 0.855 (95% CI [0.787-0.923], p < 0.001) with MCV., Conclusion: High HbF level (≥ 1.5%) or abnormal Hb peak present in HbA1c testing indicated high incident rate of thalassemia. MCV is the most valuable independent predicting factor for subjects having thalassemia., (© 2024 The Author(s). Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Adipocyte fatty acid-binding protein (A-FABP; FABP4) plays a significant role in the pathogenesis and progression of metabolically driven low-grade inflammation and organ damage. This study aimed to evaluate the performance of circulating FABP4 as a predictive and diagnostic biomarker for thalassemia-associated cardiometabolic events. This case-control study enrolled 50 adults with β-thalassemia and 30 age-, sex-, and body mass index-matched controls. Participants underwent a comprehensive evaluation, including complete blood count, liver and kidney function tests, serum blood glucose, lipid profile, and ferritin levels, pelviabdominal ultrasound, ECG, and echocardiography after taking a full medical history and conducting a clinical examination. Serum levels of FABP4 were measured using an Enzyme-Linked-Immunosorbent-Assay. The diagnostic performance of FABP4 was assessed using receiver operator characteristic (ROC) curve analysis to determine optimal values for excluding and confirming cardiometabolic metflammation. The thalassemia cohort exhibited a statistically significant higher concentration of FABP4 compared to the control group (p-value < 0.001). Positive correlations were found between FABP4 and ferritin serum levels above 800 or 1000 ug/L, as well as with ALT, TGS, and LDL (p-value < 0.05). Circulating FABP4 was identified as a statistically significant risk factor for thalassemia-associated cardiometabolic comorbidities (OR = 84.00, 95%CI:18.6-378.6, p-value < 0.001). ROC analysis determined that the FABP4 exclusionary cut-off value > 2.30 ng/ml could effectively discriminate between thalassemia-associated adverse metaflammation and controls, while the FABP4 confirmatory cut-off value was > 2.58 ng/ml. In conclusion, circulating FABP4 appears to be a potential risk factor for predicting progression to cardiometabolic events in thalassemia-associated adverse metaflammation. FABP4 holds promise as a diagnostic and prognostic biomarker for disease monitoring and risk stratification. Further validation through large-scale, multicenter, prospective studies is warranted., (© 2024. The Author(s).)

Objectives: In this study, we aim to evaluate the long-term impact of thalassaemia on bone mineral density (BMD) through sequential analysis, compare changes in BMD values between male and female patients and find any correlation between BMD and biochemical markers in the adult thalassaemia group. BMD is a bone mineral density test using dual-energy X-ray to measure calcium hydroxyapatite per unit of bone, reflecting bone strength., Methods: We conducted a longitudinal retrospective observational cohort study to determine the changes in BMD values and biochemical parameters in adult thalassaemia patients. BMD was assessed at the lumbar spine (L1-L4) and proximal femora using Hologic's bone dual-energy X-ray absorptiometry. Five serial BMD values were retrieved from electronic records. Biochemical parameters, including serum calcium, phosphorus and 25-hydroxyvitamin D levels, were also assessed., Results: A total of 108 patients (47 males and 61 females; median age: 44 years) with thalassaemia major 71 patients, intermedia 20 patients, haemoglobin E disease 14 patients and thalassaemia-alpha three patients were included. The incidence of low BMD in patients with thalassaemia increased from 64 to 74% over three decades of analysis. Females and thalassaemia major patients had lower hip BMD values and corresponding Z -scores., Conclusion: There is a progressive decline in BMD values in adult thalassaemia, which was apparent in female thalassaemia major patients. No changes in biochemical parameters, however, were observed over long-term assessments., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Transfusion-dependent thalassemia (TDT) is a severe form of beta-thalassemia, characterized by defective-globin production, resulting in a buildup of unpaired alpha globin chains. Patients with TDT can only survive if they receive safe blood transfusions regularly, which causes iron overload in their blood, which causes a variety of disorders. Cations and trace elements in TDT patients as a drug target deserve more studies., Objectives: In the present study, the cations and some trace elements were studied in TDT patients as a tool to adjust their level in the case of any disturbances., Methods: Serum calcium, magnesium, zinc, copper, and iron were measured spectrophotometrically while manganese and cobalt were measured by flameless atomic absorption spectroscopy in 100 TDT patients and compared with 35 healthy control children., Results: Patients with TDT exhibit a notable elevation in blood levels of iron, copper, copper/zinc ratio, and manganese, with a substantial reduction in serum levels of zinc, magnesium, calcium, and cobalt, as compared to the control group. These minerals have diverse associations with clinical data and transfusion frequencies. The receiver operating characteristic (ROC) analysis revealed that the elevated levels of iron, manganese, and calcium exhibit the greatest diagnostic capability, with a sensitivity and specificity of over 80 %, and a Youdin's J value of more than 0.6., Conclusion: The levels of cations and trace elements are disturbed in TDT patients. Hence, the monitoring and adjustment of the level of these minerals are important to prevent further consequences., Competing Interests: Conflict of interest The authors declare no conflicts of interest with any commercial or other affiliation on the submitted paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Hemoglobin (Hb) is an important protein in red blood cells and a crucial diagnostic indicator of diseases, e.g., diabetes, thalassemia, and anemia. However, there is a rare report on methods for the simultaneous screening of diabetes, anemia, and thalassemia. Isoelectric focusing (IEF) is a common separative tool for the separation and analysis of Hb. However, the current analysis of IEF images is time-consuming and cannot be used for simultaneous screening. Therefore, an artificial intelligence (AI) of IEF image recognition is desirable for accurate, sensitive, and low-cost screening., Results: Herein, we proposed a novel comprehensive method based on microstrip isoelectric focusing (mIEF) for detecting the relative content of Hb species. There was a good coincidence between the quantitation of Hb via a conventional automated hematology analyzer and the one via mIEF with R 2  = 0.9898. Nevertheless, our results showed that the accuracy of disease diagnosis based on the quantification of Hb species alone is as low as 69.33 %, especially for the simultaneous screening of multiple diseases of diabetes, anemia, alpha-thalassemia, and beta-thalassemia. Therefore, we introduced a ResNet1D-based diagnosis model for the improvement of screening accuracy of multiple diseases. The results showed that the proposed model could achieve a high accuracy of more than 90 % and a good sensitivity of more than 96 % for each disease, indicating the overwhelming advantage of the mIEF method combined with deep learning in contrast to the pure mIEF method., Significance: Overall, the presented method of mIEF with deep learning enabled, for the first time, the absolute quantitative detection of Hb, relative quantitation of Hb species, and simultaneous screening of diabetes, anemia, alpha-thalassemia, and beta-thalassemia. The AI-based diagnosis assistant system combined with mIEF, we believe, will help doctors and specialists perform fast and precise disease screening in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Transfusion-dependent thalassemia (TDT) is an autosomal recessive disorder characterized by defective hemoglobin synthesis, leading to severe complications such as iron overload and multi-organ dysfunction. This study aims to elucidate the distinctive clinical and biochemical profiles of TDT patients compared to healthy controls, with an emphasis on cardiovascular risk assessment using novel markers such as the Plasma Atherogenic Index (PAI) and Triglyceride-Glucose (TyG) index., Methods: This cross-sectional study included 32 TDT patients and 36 healthy controls, matched for age and gender. Comprehensive demographic, laboratory, and imaging data were collected and analyzed. TDT patients were further stratified based on cardiac involvement and ferritin levels. Key assessments included hemoglobin levels, liver enzymes, lipid profiles, and cardiac imaging. The PAI and TyG index were calculated to evaluate cardiovascular risks. Statistical analyses were performed using SPSS 27.0, employing Student's t -test, Mann-Whitney U test, and Pearson chi-square test as appropriate., Results: No significant differences in basic demographic parameters were observed between groups; however, TDT patients exhibited significant clinical and laboratory differences. Notably, these patients had lower hemoglobin levels, higher platelet counts, elevated liver enzymes (ALT and AST), and markedly increased ferritin levels. Lipid profiles were significantly altered, with lower levels of total cholesterol, HDL, and LDL but elevated triglycerides. Importantly, the PAI was significantly higher in TDT patients, suggesting an increased atherosclerotic risk. Subgroup analysis revealed that patients with cardiac involvement had worse metabolic profiles, higher TyG indices, and prolonged QT intervals, indicating heightened cardiovascular risk. As the iron burden increases, the TyG index and PAI may lose their sensitivity in distinguishing between varying levels of iron overload, suggesting that their effectiveness plateaus beyond a certain threshold of iron accumulation., Conclusion: TDT patients show significant hematological and metabolic deviations, including elevated cardiovascular risk markers like PAI and TyG index. As iron burden increases, these markers lose discriminative power, and cardiac involvement escalates rapidly once a critical iron threshold is surpassed, as supported by studies showing a non-linear relationship between iron load and cardiac complications. Comprehensive cardiovascular risk assessment and tailored management are essential for these patients. Future studies should focus on tracking cardiovascular risk progression and the effects of targeted interventions.

Background: A common complication of thalassemia is secondary osteoporosis. This study aimed to assess the prevalence and factors associated with low BMD in thalassemic patients., Method: This is a cross-sectional study. Eligible patients were males aged within 18-49 years or premenopausal women diagnosed with thalassemia in Chiang Mai University Hospital between July 2021 and July 2022. The diagnosis of low BMD by dual-energy x-ray absorptiometry (DXA) was defined as a Z-score of -2.0 SD or lower in either the lumbar spine or femoral neck. Clinical factors associated with low BMD were analyzed using a logistic regression model., Results: Prevalence of low BMD was 62.4% from 210 patients with a mean age of 29.7 ± 7.6 years. The predominant clinical characteristics of low BMD thalassemia patients were being female, transfusion-dependent (TDT) and a history of splenectomy. From multivariable analysis, the independent variables associated with low BMD were transfusion dependency (odds ratio, OR 2.36; 95%CI 1.28 to 4.38; p=0.006) and body mass index (BMI) (OR 0.71; 95%CI 0.61 to 0.82; p<0.001). Among patients with low BMD, we observed a correlation between a Z-score with low IGF-1 levels (β=-0.42; 95% CI -0.83 to -0.01; p=0.040), serum phosphate levels (β=0.40; 95% CI 0.07 to 0.73; p=0.016) and hypogonadism (β=-0.48, 95% CI -0.91 to -0.04, p=0.031)., Conclusion: This study found a prevalence of low BMD in 62.4% of subjects. Factors associated with low BMD were TDT and BMI. Within the low BMD subgroup, hypogonadism, serum phosphate and low serum IGF-1 levels were associated with a lower Z-score., 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 © 2024 Ananvutisombat, Tantiworawit, Punnachet, Hantrakun, Piriyakhuntorn, Rattanathammethee, Hantrakool, Chai-Adisaksopha, Rattarittamrong, Norasetthada, Fanhchaksai and Charoenkwan.)

Objective: To explore the distribution and hematological characteristics of rare thalassemia-associated mutations in Chenzhou region of Hunan Province with an aim to provide a basis for genetic counseling and effective prevention., Methods: A total of 37 370 individuals enrolled from January 2015 to December 2021 were screened by routine blood test and hemoglobin electrophoresis. The genotypes were determined with high-throughput sequencing., Results: A total of 8 455 thalassemia mutations (including 185 rare ones) were detected, which had involved 27 mutational types. Rare type α-Thalassemia --THAI and CD31 (AGG>AAG) have the typical microcytic hypochromic hematological features, whilst SEA-HPFH, CD14 (CTG>-TG), CD37 (TGG>TAG), -90(C>T), Codon 15 (G>A), IVS-I-128 (T>G), CD86 (GCC>GC-) and Chinese Gγ+(Aγδβ)0 had typical microcytic hypochromic and β-thalassemia-associated hematological features of elevated HbA2 or HbF. In addition, the -50（G>A）heterozygotes of β-thalassemia had normal or slightly decreased MCV and MCH without an increase in HbA2., Conclusion: Various forms of thalassemia-associated mutations have been identified in the Chenzhou region of Hunan Province. Above finding has facilitated development of preventive and control strategies for thalassemia as well as birth health programs.

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 paper aims to propose an approach leveraging Artificial Intelligence (AI) to diagnose thalassemia through medical imaging. The idea is to employ a U-net neural network architecture for precise erythrocyte morphology detection and classification in thalassemia diagnosis. This accomplishment was realized by developing and assessing a supervised semantic segmentation model of blood smear images, coupled with the deployment of various data engineering techniques. This methodology enables new applications in tailored medical interventions and contributes to the evolution of AI within precision healthcare, establishing new benchmarks in personalized treatment planning and disease management.

Objective: To explore the plasma metabolomic characteristics of children with transfusion-dependent thalassemia (TDT), and reveal the changes of metabolic pattern in children with TDT., Methods: 23 children with TDT who received regular blood transfusion in Ganzhou Women and Children's Health Care Hospital in 2021 were selected, and 11 healthy children who underwent physical examination during the same period were selected as the control group. The routine indexes between children with TDT and the control group were compared, and then the metabolic composition of plasma samples from children with TDT and the control group was detected by liquid chromatography-mass spectrometry. An OPLS-DA model was established to perform differential analysis on the detected metabolites, and the differential metabolic pathways between the two groups were analyzed based on the differential metabolites., Results: The results of routine testing showed that the indexes of ferritin, bilirubin, total bile acid, glucose and triglycerides in children with TDT were significantly higher than those in healthy controls, while hemoglobin and total cholesterol were significantly lower (all P <0.05). However there was no significant difference in lactate dehydrogenase between the two groups ( P >0.05). Compared with the control group, 190 differential metabolites (VIP>1) were identified in TDT children. Among them, 168 compounds such as arginine, proline and glycocholic acid were significantly increased, while the other 22 compounds such as myristic acid, eleostearic acid, palmitic acid and linoleic acid were significantly decreased. The metabolic pathway analysis showed that the metabolic impact of TDT on children mainly focused on the upregulation of amino acid metabolism and downregulation of lipid metabolism., Conclusion: The amino acid and lipid metabolism in children with TDT were significantly changed compared with the healthy control group. This finding is helpful to optimize the treatment choice for children with TDT, and provides a new idea for clinical treatment.

Background: Deletions in the β-globin cluster are uncommon and cause thalassemia (thal) with hereditary persistence of fetal hemoglobin. They constitute a heterogenous group of disorders characterized by absent or reduced synthesis of adult hemoglobin (Hb A) and increased synthesis of fetal hemoglobin (Hb F). Although the clinical severity of these disorders are asymptomatic owing to the increased Hb F levels, the molecular basis is very heterogenous due to the large deletions in the β-globin cluster spanning both HBD and HBB genes. Here, we describe a Tunisian family carrying a novel deletion mutation causing (δβ)°-thalassemia., Methods: The amounts of hemoglobin fractions were measured by capillary electrophoresis of hemoglobin. Amplification and sequencing of different regions on the β-gene cluster were performed by Sanger method., Results: Family study and genetic analysis revealed a large deletion mutation in the β-globin cluster of 14.5 kb (NG&#95;000,007.3:g. 58,253 to g.72837del14584) at the homozygous state in the patient and at heterozygous state at the other members of the family. This deletion removes the HBD and HBB genes., Conclusions: In our knowledge, this new large deletion is described for the first time in the Tunisian population and in the world, designed Tunisian(δβ) 0 in Ithanet database (IthaID: 3971). Therefore, it is important to identify the deletion leading to δβ-thalassemia carriers at the molecular level, to highlight the importance of recognizing the clinical features and implementing appropriate testing to clarify the diagnosis and manage the condition.

Introduction: Newborn screening is an important supplement to thalassemia control and prevention. Capillary electrophoresis (CE) technology has several advantages for thalassemia screening but with low sensitivity, especially for thalassemia carriers. This study aims to illustrate the application of an optimized interpretation model in newborn thalassemia screening by capillary hemoglobin electrophoresis., Methods: Two thousand, two hundred fifty-eight neonates selected from four regions in China were enrolled and were screened for α-thalassemia and β-thalassemia by capillary electrophoresis. Results were interpreted based on an optimized model integrated with multiple parameters. Molecular analysis was carried out in synchrony and used as the gold standard for the screening performance assessment. The consistency among different regions and thalassemia genotypes were also investigated., Results: Among the 2258 neonates, 485 were identified to have a likely diagnosis of thalassemia, and 422 α-thalassemia, 80 β-thalassemia, and 21 α/β-thalassemia cases were confirmed by molecular analysis, including 277 α-thalassemia silent carriers, 135 α-thalassemia trait carriers, 10 Hemoglobin H disease, and 80 β-thalassemia trait carriers. The screening sensitivity, specificity, positive, and negative predictive value for α-thalassemia and β-thalassemia were 84.83%, 99.14%, 95.98%, 96.41%, and 88.75%, 98.73%, 76.34%, and 99.48%, respectively. The optimized interpretation model showed higher performance for thalassemia carriers, though some neonates with silent α-thalassemia genotypes (-α 3.7 /αα, -α 4.2 /αα, and α WS α/αα) and β -28 /β N genotype were still missed. The screening performance among different regions was comparable., Conclusions: Capillary hemoglobin electrophoresis with the optimized interpretation model shows reliable performance for newborn thalassemia screening. It is applicable to large-scale population screening., (© 2021 John Wiley & Sons Ltd.)

Background: Studies on the increased body iron load in patients with thalassemia major have thoroughly demonstrated the problems caused by iron overload. In patients who undergo hematopoietic stem cell transplantation (HSCT) as curative therapy, iron overload continues long after transplantation. There are few pediatric studies on chelation therapy in the posttransplant period. In this study, we present the outcomes of our patients who received posttransplant oral chelation therapy., Patients and Methods: This retrospective observational study evaluated the outcomes of pediatric patients with thalassemia major who used oral chelation therapy after allogeneic HSCT at the Akdeniz University Pediatric Bone Marrow Unit between January 2008 and October 2019., Results: Deferasirox therapy was initiated in 58 pediatric patients who underwent HSCT for thalassemia. Pretreatment mean serum ferritin was 2166±1038 ng/mL. Treatment was initiated at a mean of 12±6.7 months after transplantation and continued for a mean of 15.7±11.5 months. At treatment discontinuation, the mean serum ferritin was 693±405 ng/mL and the mean reduction was -1472.75±1121.09 ng/mL (P<0.001 vs. posttreatment). Serum ferritin was below 500 ng/mL in 52% of the patients at treatment discontinuation. Manageable side effects such as nausea, vomiting, liver enzyme elevation, and proteinuria were observed in 17% of the patients, while one patient developed ototoxicity., Conclusions: Deferasirox therapy effectively reduces iron overload in the posttransplant period. Studies evaluating the effects of early treatment on the graft may help to establish guidelines for posttransplant chelation therapy. Clear guidelines are needed regarding when to initiate and discontinue treatment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To evaluate any association between pre-transfusion hemoglobin (Hb) levels and thalassemia complications and to identify the Hb cutoff values to predict thalassemia complications., Methods: We performed a cross-sectional study in thalassemia patients who attended the Adult Hematology Clinic of the tertiary care University Hospital from October 2017 to October 2018. A point-biserial correlation was used to identify any association between Hb levels and thalassemia complications. A receiver operating characteristic (ROC) curve was used to identify the diagnostic ability of Hb levels to predict thalassemia complications and identify Hb cutoff values., Results: Out of the 102 patients, there were 53 transfusion dependent thalassemia (TDT) patients and 49 non-transfusion dependent thalassemia (NTDT) patients. In theTDT group, Hb levels showed a negative correlation with severe hepatic iron overload and hypogonadism. The cutoff Hb levels to predict severe hepatic iron overload and hypogonadism were ≤7.01 and 6.81 g/dL, respectively, at which points the area under the ROC curve (AUC) were 0.721 and 0.708, respectively. In the NTDTgroup, Hb levels were negatively correlated with hepatic iron overload, osteoporosis, and pulmonary hypertension. The cutoff values of Hb levels to predict hepatic iron overload, osteoporosis, and pulmonary hypertension were ≤8.24, 7.16, and 7.16 g/dL, respectively, at which points the AUC were 0.923, 0.715, and 0.725, respectively., Conclusions: Lower Hb level was associated with more frequent complications in both TDT and NTDT patients. The Hb cutoff levels to predict these complications were identified.

Background and Objectives: The status of red blood cell alloimmunization in patients with constitutional anemias including hemoglobinopathies is not known in Norway. The study objective was to investigate the impact of a strategy based on phenotype-matching for C, c, E, e, K, Jka, Jkb, Fya, Fyb, S and s on alloimmunization., Materials and Methods: We reviewed transfusions of 40 patients retrospectively using the computerized blood bank management system and medical records; including diagnosis, age at start of transfusion therapy, gender, number and age of packed red blood cell units transfused, follow-up time, phenotypes of the donors and patients, antigen-negative patients exposed to antigen-positive packed red blood cell units, transfusion reactions and alloantibody specificities., Results: Forty patients received 5402 packed red blood cell units. Alloimmunization frequency was 20 % for the whole group, being 7%, 25 % and 30 % in patients with sickle cell disease (n = 14), thalassemia (n = 16) and other conditions (n = 10), respectively. The alloantibodies detected were anti-E, -c, -C, -Cw, -K, -Jka and -Lua., Conclusion: Good communication between the clinicians and the transfusion services is essential for successful management of patients with constitutional anemias. Providing full phenotype-matched units was not always possible. Extended pheno-/genotyping before the first transfusion and providing antigen-negative units for antigen-negative patients for at least C, c, E and K in every red cell transfusion would probably have reduced the alloimmunization rate. Non-phenotype-matched transfusions seem to be the main reason for alloimmunization. Finding markers for identifying responders prone to alloimmunization will ensure targeted transfusion strategies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Alloimmunization prevalence is conventionally used to identify RBCs alloimmunization risk factors among thalassemia patients, but it may be confounded by differences in transfusion exposure especially between non-transfusion dependent thalassemia (NTDT) and transfusion dependent thalassemia (TDT) patients. To better identify thalassemia patients with high alloimmunization risks, we used cumulative incidence of first alloimmunization as a function of RBCs transfused to compare alloimmunization risks between TDT and NTDT and to evaluate other risk factors. We also proposed practical strategies to prevent alloimmunization in thalassemia., Study Design and Methods: Adult TDT and NTDT patients who had received ≥2 transfusions and no alloimmunization before their first transfusion were included. Alloimmunization was defined as the development of clinically significant alloantibodies. We estimated the first alloimmunization incidence from transfusion by Kaplan-Meier analysis with the horizontal axis expressed as cumulative non-antigen-matched RBC units transfused. We compared this incidence between TDT and NTDT, and analyzed for other alloimmunization risk factors and the alloantibody specificities/frequencies., Results: The alloimmunization prevalence was similar between TDT and NTDT (27% vs. 30% respectively, p = .726). However, for the same transfusion exposure, NTDT had higher alloimmunization incidence than TDT (hazard ratio 8.59, 95% confidence interval [2.25-32.74], p = .002), independent of age at first transfusion and last follow-up, gender, and splenectomy. Anti-E, anti-c, anti-Mi a , and anti-Jk a were most frequent., Discussion: NTDT has the highest alloimmunization risk and would benefit the most from extended RBC antigen-matching, especially C, c, E, and e. Other blood group antigen-matching should be guided by the patient/donor disparities and alloantibody frequencies in different populations., (© 2021 AABB.)

This study was organized to determine the efficacy and safety of deferasirox (DFX) in reducing the SF of patients with transfusion-dependent thalassemia (TDT). This is a retrospective, descriptive study of 101 transfusion- dependent patients with thalassemia major who were followed for 48 months. Twenty-nine patients who used an alternative chelator either alone or combined, who were not compliant to the treatment, changed the drug due to adverse reactions, and had multiple transfusions and did not complete 4 years of DFX use were excluded. A total 72 out of 101 patients completed the study. SF decreases were noted for the 6-12 and >18-year age groups, from a median of 1532 ng/mL to 1190 ng/mL, and from 1386 ng/mL to 1165 ng/mL, respectively (p > 0.05). The proportion of patients with SF concentrations >2000 ng/mL is decreased (29% at baseline decreased to 15% at the end of the study) during the 48 months. The median SF of those who used <30 mg/kg/day (n = 38) increased from 767 ng/mL to 1006 ng/mL, whereas the >30 mg/kg/day (n = 34) group's SF concentrations decreased from a median of 1575 ng/mL to 1209 ng/mL (p = 0.029). The decrease of median SF values for Syrian patients was statistically significant (p = 0.043). Most common adverse events were gastric irritation symptoms (19.4%). The total DFX discontinuation ratio was calculated as 9.7%. Although dosages between 25-30 mg/kg/day are adequate to stabilize SF concentrations higher dosages are needed to achieve a statistically significant decrease.

Extracellular vesicles (EVs) are bioactive, submicron-sized membrane vesicles released from all cell types upon activation or apoptosis. EVs including microparticles (MPs) and exosomes have emerged as important mediators of cell-to-cell communication in both normal and pathological states including thalassemia (thal). However, the role of EVs derived from β-thal patients with iron overload (+ IO) and without iron overload (-IO) on cardiac cells is unclear. We hypothesized plasma EVs in thal patients containing ferritin (iron storage protein) and a denaturated hemoglobin-hemichrome that induce cardiac cell proliferation. The origins and numbers of EVs isolated from plasma of normal, thal (+ IO), and (- IO) patients were compared and determined for their iron and iron-containing proteins along with their effects on cardiac and endothelial cells. Data shows that MPs were originated from many cell sources with marked numbers of platelet origin. Only the number of RBC-derived MPs in thal (+ IO) patients was significantly high when compared to normal controls. Although MPs derived from both normal and thal patients promoted cardiac cell proliferation in a dose-dependent manner, only exosomes from thal patients promoted cardiac cell proliferation compared to the untreated. Moreover, the exosomes from thal (+ IO) potentially induce higher cardiac cell proliferation and angiogenesis in terms of tube number than thal (- IO) and normal controls. Interestingly, ferritin content in the exosomes isolated from thal (+ IO) was higher than that found in the MPs isolated from the same patient. The exosomes of thal patients with higher serum ferritin level also contained greater level of ferritin inside the exosomes. Apart from ferritin, there were trends of increasing hemichrome and iron presented in the plasma EVs and EV-treated H9C2 cells. Findings from this study support the hypothesis that EVs from β-thal patients carry iron-load proteins that leads to the induction of cardiac cell proliferation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Thalassaemia trait (TT) is potential to be missed clinically, especially normocytic thalassaemia. We aimed to establish discriminant functions (DFs) and an algorithm for detecting microcytic or normocytic TT in epidemiological screening., Methods: The receiver operating characteristics (ROC) curve analysis was used to determine the diagnostic performance of the proposed formulas in differentiating TT and nonthalassaemia (non-TT). DFs combined the two blood count parameters with the highest performance, based on the area under the curve (AUC) value, into mathematical formulas, using logistic regression. The diagnostic efficacy of DFs was subsequently evaluated in 761 participants, and reliability (including adjusted agreement [AA] and Kappa values) and validity (including sensitivity, specificity, likelihood ratio and Youden's Index) were calculated., Results: Among microcytic participants, the proposed DFs showed good diagnostic performance (in females: AUC = 0.892 [DF1 = 0.015 × RDW-CV/RBC - 0.096 × RDW-SD/RBC + 1.29], in males: AUC = 0.861 [DF2=-0.025 × RDW-SD/RBC - 0.035 × MCV/RBC + 1.415]). Youden's Index, AA and Kappa values for microcytic TT detection were 0.72, 0.86, and 0.72 and 0.63, 0.81 and 0.63 for females and males, respectively. In normocytic participants with RDW-CV/RBC ≤ 3.54, DF3=-0.38 × MCH-0.02 × MCHC+17.37 achieved AUC = 0.857 in females, whereas DF4 = 0.007 × MCV-0.113 × MCH+2.829 achieved AUC = 0.969 in males. The Youden's Index, AA and Kappa values for the proposed DFs for thalassaemia detection were 0.69, 0.84 and 0.67 in females, 0.76, 0.91 and 0.71 in males, respectively., Conclusion: The proposed DFs performed well in the detection of TT among participants with microcytic and normocytic parameters and could be utilized in epidemiological study for TT., (© 2021 John Wiley & Sons Ltd.)

Introduction: To clarify mechanisms of ineffective erythropoiesis on iron metabolism, studies on erythroid factors that regulating hepcidin suppression have been carried out. The aim of the current study is to identify associations between erythropoiesis and iron homeostasis parameters in β-thalassemias., Materials and Methods: This study consisted of 83 subjects: 21 thalassemia major (TM), 20 thalassemia intermedia (TI), 20 thalassemia trait (TT), and 22 healthy subjects (HS). Erythroferrone (ERFE), hepcidin, growth differentiation factor-15 (GDF15), erythropoietin (EPO), and iron status parameters were measured., Results: Our results showed that TM and TI patients had higher hepcidin than the TT and control groups. The hepcidin/ferritin in TM patients was significantly lower than the other groups. GDF15 in TM and TI patients was significantly higher than in the TT and control groups. Also, TI group had significantly higher ERFE concentration and EPO activity when compared with the TM, TT, and HS groups. EPO activity showed positive correlation with ERFE and GDF15 concentrations. We could not find any correlation between ERFE and hepcidin concentrations., Conclusions: ERFE may be one of the parameters used to demonstrate erythropoietic activity level in thalassemias. More detailed studies are needed to clarify the role of ERFE in iron metabolism in the patients with thalassemias., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: : HPLC is one of the most important tools for accurate diagnosis of hemoglobinopathies and thalassemias. The advantage of the HPLC system is the excellent resolution, reproducibility &quantification of several normal and abnormal hemoglobin., Results: BIO RAD Variant II analyzer was used. Sickle cell syndromes including double heterozygous states accounted for 56.13% of total cases. HbSS, HbS/β 0 -th, HbS/β + -th β-thal trait comprises 29%, 6.5%, 5.1%& 10% of total cases respectively with mean MCV (fl) = 84, 68,71,64 respectively. The Mean HbA2 for β-thal trait, HbE trait &HbE-β thal showed 5.1 ± 1.1, 19 ± 9 & 24 ± 8 respectively. HbF is increased in 8.6% case (excluding SC syndromes & β-thal disorders), of these 5.5% were infants & 12 cases of Aplastic Anemias. Peak P2 >7% (2.4% cases) was seen in uncontrolled diabetes mellitus which on quantification showed HbA1C = 8 ± 2.1 mmol/L., Discussion: : HPLC in correlation with CBC parameters & family studies can aid in the diagnosis of majority of Hemoglobinopathies and thalassemic syndrome. The CBC & HPLC parameters of the present study are in good correlation with the research conducted by Tejinder Sing, RiouJ & Alla Joutovsky. Present study showed HPLC comprehensively characterizing HbS, A, A2, F, S, C, D from each other & was also applicable for the quantification of HbA1c for the monitoring of Diabetes Mellitus., Conclusion: : The merits of HPLC are small quantity of sample required, economical, less TAT, accurate categorization of HbS, HbA2 & F. But one has to be aware of the limitations and problems associated with this method due to variant hemoglobin within the same retention windows. The present findings show HPLC as an excellent & powerful diagnostic tool for the direct identification of hemoglobin variants with a high degree of precision in the quantification of normal and abnormal hemoglobin fractions.

Deferasirox (DFX) is the newest among three different chelators available to treat iron overload in iron-loading anaemias, firstly released as Dispersible Tablets (DT) and more recently replaced by Film-Coated Tablets (FCT). In this retrospective observational study, pharmacokinetics, pharmacodynamics, and safety features of DFX treatment were analyzed in 74 patients that took both formulations subsequently under clinical practice conditions. Bioavailability of DFX FCT compared to DT resulted higher than expected [C max : 99.5 (FCT) and 69.7 (DT) μMol/L; AUC: 1278 (FCT) and 846 (DT), P < 0.0001]. DFX FCT was also superior in scalability among doses. After one year of treatment for each formulation, no differences were observed between the treatments in the overall iron overload levels; however, DFX FCT but not DT showed a significant dose-response correlation [Spearman r (dose-serum ferritin variation): - 0.54, P < 0.0001]. Despite being administered at different dosages, the long-term safety profile was not different between formulations: a significant increase in renal impairment risk was observed for both treatments and it was reversible under strict monitoring (P < 0.002). Altogether, these data constitute a comprehensive comparison of DFX formulations in thalassaemia and other iron-loading anaemias, confirming the effectiveness and safety characteristics of DFX and its applicability for treatment tailoring.

Background: The average hemoglobin content of red cell concentrates (RCC) varies depending on the method of preparation. Surprisingly less data are available concerning the clinical impact of those differences., Study Design and Methods: The effects of two types of RCC (RCC-A, RCC-B) on transfusion regime were compared in a non-blinded, prospective, randomized, two-period, and crossover clinical trial. RCC-A was obtained by whole blood leukoreduction and subsequent plasma removal, RCC-B removing plasma and buffy coat first, followed by leukoreduction. Eligible patients were adult, with transfusion-dependent thalassemia (TDT)., Results: RCC-A contained 63.9 (60.3-67.8) grams of hemoglobin per unit (median with 1 st and 3 rd quartile), RCC-B 54.5 (51.0-58.2) g/unit. Fifty-one patients completed the study. With RCC-B, the average pre-transfusion hemoglobin concentration was 9.3 ± 0.5 g/dl (mean ± SD), the average transfusion interval 14.2 (13.7-16.3) days, the number of RCC units transfused per year 39.3 (35.4-47.3), and the transfusion power index (a composite index) 258 ± 49. With RCC-A, the average pre-transfusion hemoglobin concentration was 9.6 ± 0.5 g/dl (+2.7%, effect size 0.792), the average transfusion interval 14.8 (14.0-18.5) days (+4.1%, effect size 0.800), the number of RCC units transfused per year 34.8 (32.1-42.5) (-11.4%, effect size -1.609), and the transfusion power index 272 ± 61 (+14.1%, effect size 0.997). All differences were statistically highly significant (p < .00001). The frequency of transfusion reactions was 0.59% with RCC-A and 0.56% with RCC-B (p = 1.000)., Conclusion: To reduce the number of RCC units consumed per year and the number of transfusion episodes, TDT patients should receive RCC with the highest average hemoglobin content., (© 2021 The Authors. Transfusion published by Wiley Periodicals LLC. on behalf of AABB.)

Background: Delta-chain (δ-chain) variants are a group of rare hemoglobin (Hb) variants resulting from mutations within the δ-globin gene. Although quantification of Hb A2 levels is a useful screening tool for the beta-thalassemia trait, the coinheritance of a δ-globin gene mutation can lead to misinterpretation of diagnostic results. Objective: To identify an unreported Hb A2 variant in Thailand and to develop a high resolution melting (HRM) curve assay for the four δ-globin chain variants found in the Thai population. Materials and Methods: Allele-specific polymerase chain reaction (ASPCR) was used to analyze a total of 18 DNA samples for Hb variants comprising 10 wild-type controls, 4 Hb A2-Melbourne, 1 Hb A2-Lampang, 2 Hb A2-Kiriwong, and an unknown variant via HRM assays. Results: The unreported Hb A2 variant in Thailand was found to be Hb A2-Walsgrave resulting from δ-globin gene mutation at codon 52 (GAT>CAT). This was also confirmed using ASPCR. In addition, we demonstrated that the HRM curve profile for Hb A2-Melbourne, Hb A2-Lampang, Hb A2-Walsgrave, and Hb A2-Kiriwong could be identified so as to distinguish the mutant alleles from one another and from wild-type alleles. Conclusion: This HRM assay detected both known and unknown mutations with simultaneous differentiation between heterozygous and homozygous alleles on a polymerase chain reaction fragment spanning four of the δ-globin variants found in Thailand. This assay may help to support the prevention and control of thalassemias and hemoglobinopathies in Thailand.

Background: Measurements of copper and zinc in transfusion-dependent thalassemia (TDT) show contradictory results., Aim of the Study: To examine serum levels of these minerals in TDT in relation to iron overload indices and erythron variables., Methods: This study recruited 60 children with TDT and 30 healthy controls aged 3-12 years old., Results: Zinc was significantly higher in TDT children than in controls, while copper and the copper to zinc ratio were significantly lowered in TDT. Serum zinc was significantly associated with the number of blood transfusions and iron overload variables (including serum iron and TS%) and negatively with erythron variables (including hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin). Serum copper was significantly and negatively associated with the same iron overload and erythron variables. The copper to zinc ratio was significantly correlated with iron, TS%, ferritin, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. Albumin levels were significantly higher in TDT children than in control children., Conclusion: Our results suggest that the increase in zinc in children with TDT may be explained by iron loading anemia and hemolysis and the consequent shedding of high amounts of intracellular zinc into the plasma. Increased albumin levels and treatment with Desferral may further contribute towards higher zinc levels in TDT. We suggest that the elevations in zinc in TDT are a compensatory mechanism protecting against infection, inflammation, and oxidative stress. Previous proposals for prophylactic use of zinc supplements in TDT may not be warranted., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Background: Migration has impacted the spread of thalassaemia which is gradually becoming a global health problem. Italy, with an approximate estimation of 7,000 patients, does not have an accurate national record for haemoglobinopathies. This cross-sectional evaluation includes data for approximately 50% of beta-thalassaemia patients in Italy to provide an overview of the burden of thalassaemia syndromes., Materials and Methods: The analysis included data on epidemiology, transfusions and clinical parameters from 3,986 thalassaemia patients treated at 36 centres in Italy who were alive on 31 st December 2017. The study used WebThal, a computerised clinical record that is completely free-of-charge and that does not have any mandatory fields to be filled., Results: For patients with thalassaemia major, 68% were aged ≥35 years and 11% were aged ≤18 years. Patients with thalassaemia intermedia were slightly older. Transfusion data, reported in a subgroup of 1,162 patients, showed 9% had pre-transfusion haemoglobin <9 g/dL, 63% had levels between ≥9 and <10 g/dL, and 28% had levels ≥10 g/dL. These 1,162 patients underwent 22,272 transfusion days during 2017, with a mean of 19 transfusion days/year/patient (range 1-54 days). Severity of iron overload was reported in 756 patients; many had moderate or mild liver iron load (74% had liver iron <7.5 mg/g dry weight). In the same cohort, 85% of patients had no signs of cardiac iron load (MRT2* >20 ms), and only 3% showed signs of high-risk heart condition (T2* <10 ms). Most patients had normal alanine amino transferase levels due to treatment with the new anti-hepatitis C virus (HCV) drugs., Discussion: This study provides an overview of the current health status of patients with thalassaemia in Italy. Moreover, these data support the need for a national comprehensive thalassaemia registry.

Although an increased fibroblast growth factor 21 (FGF21) level was related to mild cognitive impairment (MCI) in metabolic syndrome patients, any association regarding FGF21 and MCI in thalassemia patients as well as mechanistic insight are questionable. Therefore, the objectives of this study were: (1) to investigate the prevalence and associative risk factors of MCI in thalassemia patients, (2) to evaluate the association between levels of FGF21 and MCI in thalassemia patients, and (3) to investigate brain FGF21 signaling in iron-overload thalassemia. Thalassemia patients were enrolled onto the study (n = 131). Montreal cognitive assessment (MoCA) was used to determine cognitive performance. Plasma FGF21 level was determined in all patients. Iron-overload β-thalassemic (HT) mice were used to investigate brain FGF21 level and signaling, the expression of synaptic proteins, and Alzheimer's like pathology. We found that 70% of thalassemia patients developed MCI. FGF21 level was positively correlated with the MCI. Interestingly, brain FGF21 resistance, as indicated by increased brain FGF21 levels with impaired FGF21 signaling, was found in iron-overload HT mice. The reduced synaptic protein expression and increased Alzheimer's like pathology were also observed. These suggest that FGF21 may play a role in MCI in thalassemia patients.

Hepcidin is a key iron-regulatory hormone, the production of which is controlled by iron stores, inflammation, hypoxia and erythropoiesis. The regulation of iron by hepcidin is of clinical importance in thalassemia patients in which anemia occurs along with iron overload. The present study aimed to evaluate the correlation between serum hepcidin and ferritin levels in thalassemia patients. This cross-sectional study investigated 64 patients with thalassemia; 16 β-thalassemia major (BTM), 31 β-thalassemia/hemoglobin (Hb) E (BE), and 17 Hb H + AE Bart's disease (Hb H + AE Bart's). The levels of serum hepcidin and ferritin, and Hb of the three groups were measured. The median values of serum ferritin and Hb were significantly different among the three groups, whereas serum hepcidin values were not observed to be significantly different. The correlation of the serum hepcidin and ferritin levels was not statistically significant in any of the three groups of thalassemia patients with BTM, BE, or Hb H + AE Bart's (r = -0.141, 0.065 and -0.016, respectively). In conclusion, no statistically significant correlations were observed between serum hepcidin with any variables including serum ferritin, Hb, age, labile plasma iron (LPI), and number of blood transfusion units among the three groups of thalassemia patients. Likely, the regulation of hepcidin in thalassemia patients is affected more by erythropoietic activity than iron storage., (© 2021 The Author(s).)

Background: Thalassemia is a severe disease that occurs due to abnormalities in hemoglobin genes. Various genetic factors in different populations lead to different clinical manifestations of thalassemia disease, particularly among people who have a long history of migration and who have married among tribes, such as the hill tribe people in Thailand. This genetic epidemiological study aimed to estimate the prevalence of various forms of thalassemia among the six main hill tribe populations in Thailand., Methods: A cross-sectional study was conducted to obtain information and blood specimens from school children belonging to one of the six main hill tribes in Thailand: Akha, Lau, Hmong, Yao, Karen, and Lisu. Hill tribe children who were attending grades 4-6 in 13 selected schools in Chiang Rai Province, Thailand, were invited to participate in the study. A validated questionnaire and 3 mL blood specimens were collected after obtaining information consent forms from both the children and their parents on a voluntary basis. A complete blood count (CBC) was performed, followed by osmotic fragility (OF) and dichlorophenol indophenol precipitation (DCIP) tests to screen for thalassemia. High-performance liquid chromatography (HPLC) and real-time quantitative polymerase chain reaction (qPCR) were used to identify hemoglobin type and α-thalassemia, respectively. A t-test, chi-square and logistic regression were used to detect the associations between variables at the significance level of α = 0.05., Results: A total of 1,200 participants from 6 different tribes were recruited for the study; 50.0% were males, and 67.3% were aged 11-12 years. The overall prevalence of thalassemia carriers according to the screening tests was 9.8% (117 of 1,200). Among the cases, 83 were A2A (59 cases were α-thalassemia 1 carrier or α-thalassemia 2 carrier or homozygous α-thalassemia 2, and 24 cases were β-thalassemia trait with or without α-thalassemia); 1 case was EE (homozygous Hb E with or without α-thalassemia); 31 cases were EA (30 cases were the Hb E trait, and 1 case was Hb E trait with or without α-thalassemia); 1 case was A2A Bart's H (Hb H disease α-thalassemia 1/α-thalassemia 2); and 1 case was A2A with abnormal Hb. The prevalence of the α-thalassemia 1 trait among the hill tribe population was 2.5%. The greatest prevalence of the α-thalassemia 1 trait was found in the Karen (3.0%) and Hmong (3.0%) tribes., Conclusions: The prevalence of some forms of thalassemia in the hill tribe population is higher than that in the Thai and other populations. Effective and available thalassemia screening tests, including essential information to protect the next generation through the specific counseling clinic, are crucial, particularly due to increasing marriages within these populations., Competing Interests: The authors have declared that no competing interests exist.

The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion-dependent thalassaemia (TDT)], Group B [transfused non-TDT (NTDT)] and Group C (non-transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left-ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients' treatment., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Sickle cell disorders are the most frequently encountered hemoglobin variants in Jordan. Both alpha and beta thalassemias are also prevalent in this population. However, studies on the interaction between these hemoglobin disorders are lacking., Aim: To determine the genotypes responsible for Sickle cell disease in Jordan, by retrospectively reviewing the data from a major referral center in the country's capital., Methods: A total 29,712 peripheral blood samples referred and investigated for hemoglobinopathies over a 10-year period at Princess Iman Center at Amman, Jordan were retrospectively reviewed. In addition to full blood counts, high performance liquid chromatography, those who were identified with sickle cell hemoglobin were studied using polymerase chain reaction and reverse hybridization to determine the various sickle cell disease genotypes., Results: Out of the (29,712) blood samples, 450 were sickle cell trait, while 216 had sickle cell disease. Of the latter: 120 were found to be cases of Sickle cell anemia (Hb SS), 66 were compound heterozygous for Sickle cell and a beta thalassemia mutation (Sickle/β-thalassemia), while 30 had concomitant alpha thalassemia (HbSS/alpha thalassemia). The most frequent genotype associated with sickle/β-thalassemia was HbS/ IVS-110 (G>A), followed by Hb S/IVS-I-6 (T>C), HbS/IVS-II-745 (C>G) and HbS/ IVS-II-1 (G>A). While the most frequent alpha genotype detected in HbSS/α-thalassemia samples was (-α 3.7 /αα) followed by (-α 3.7 /-α 3.7 ). Hb SS patients had the severest hematological phenotype compared to those with sickle/β-thalassemia and sickle/ α-thalassemia. Furthermore, within the sickle/β-thalassemia subgroup the least severe hematological phenotype was encountered in HbS/IVS-1-6 (T>C), while the most severe in HbS/IVS-II-1 (G>A) genotype., Conclusion: The most frequent Sickle cell disease genotype in Jordanians is Sickle cell anemia (HbSS), followed by Sickle/β-thalassemia and least frequent is HbSS/alpha thalassemia. The concomitant identified thalassemia mutations were consistent with their spectrum among the Jordanian population., Competing Interests: None declared., (© 2021 Raida I. Oudat, Heba S. Abualruz, Nazih KH. Abu Al-Shiek, Eman A. AL-Mashaqba, Rawan A. AL-Hiari, Hala A. Alsoukhni, Ma’mon A. Abu Hammad.)

Objectives: To establish, in an unselected population of London haemoglobinopathy patients, transfusion requirements, blood antigens/alloantibodies, transfusion modalities, burden of transfusion reactions and donor exposure., Background: Haemoglobinopathy patients are among the most highly transfused patient populations, and the overall population and number of patients on long-term transfusion programmes are increasing. To provide a safe and efficacious transfusion service for patients, it is important to understand current practice, morbidity associated with transfusion, efficacy of different transfusion modalities and geno-/phenotype requirements., Methods: Data on 4451 transfusion episodes in 760 patients from 12 London hospitals were collected retrospectively over a 6-month period in 2011., Results: Alloimmunisation prevalence was 17% for sickle cell disease (SCD) and 22% for thalassaemia, most commonly anti-Rh/Kell/Kp a /C w . Rh phenotypes differed between SCD (R o r 59.8%/R 1 r 15.9%/R 2 r 15.6%) and thalassaemia (R 1 R 1 29.6%/R 1 r 28.4%/R 1 R 2 15.4%). Recording of pheno-/genotypes fell below recommendations. A 2-weekly manual exchange and 3-weekly automated exchange came closest to achieving presumptive targets. In adults with thalassaemia, the mean blood requirement was 36 units per year; for SCD, erythrocytapheresis was carried out every 7 weeks with 66 units; for manual exchange, it was 38 units every 4 weeks; and for simple transfusion, it was 30 units p.a. every 4 weeks., Conclusion: Transfusion modality choice was influenced by the resources available-children mostly received simple transfusions, and adults received erythrocytapheresis; the relationships between frequency of exchanges/transfusion modality/target HbA% were not simple, possibly reflecting the difference in recipient erythropoiesis and consequent transfusion modality selection bias; adherence to existing and current guidelines regarding geno-/phenotyping was limited; and alloimmunisation had a low incidence and high prevalence in both disorders., (© 2020 British Blood Transfusion Society.)

Conclusions: Blood transfusion, the main therapy for patients with severe thalassemia, is challenged by alloantibodies that can lead to hemolytic transfusion reactions. The use of prophylactic antigen-matched units is recommended, but serologic typing, before the first transfusion, is rarely performed and is not reliable after chronic transfusion. Patient DNA-based typing is a promising strategy, but clinical outcome data are lacking. The aim of this study was to determine the benefits of antigenmatched transfusion guided by DNA-based typing in terms of new alloantibody formation and increases in mean pretransfusion hemoglobin (Hb) levels. We performed DNA-based typing on samples from 24 transfusion-dependent patients with thalassemia who had no serologic phenotyping performed before the first transfusion. These patients were then transfused with antigen-matched donor RBC units that were typed serologically. New alloantibody formation and mean pre-transfusion Hb levels were evaluated after implementing this extended common antigen-matching transfusion protocol. Sixty-three percent of the patients in this study were diagnosed as having beta-thalassemia Hb E. Alloantibodies were already present in 87.5 percent (21/24) of these patients, and most of these antibodies were multiple and/ or unidentified. After the enrollment, there were 717 transfusion episodes comprising 1209 RBC units. The number of RBC units transfused to each patient ranged from 22 to 119 units. At the median duration of 25.5 months (range 10-34 months), no new alloantibodies were detected since the beginning of the protocol. Seventy-four transfusion episodes in six patients were crossmatch-positive due to autoantibodies (patients 2, 4, 8, 9, and 14) or anti-Chido (patient 18) that had been identified before the study. There were no hemolytic transfusion reactions in this study. Five patients (patients 1, 2, 12, 15, and 20) showed increased mean pre-transfusion Hb levels (≥1 g/dL) and one patient (patient 16) had longer intervals between transfusions (compared with those before the protocol), suggesting longer RBC survival, although there was no statistical difference in the whole group. Our study highlights the benefits of DNA-based typing in chronically transfused patients with thalassemia who had no phenotyping data before the first transfusion. Patient DNA-based typing for antigen-matched transfusion is safe in thalassemia and allows us to obtain better-matched blood units for complicated patients.

Hydroxyurea (HU) activates the γ-globin gene, resulting in increased Hb F synthesis. The SOX6 gene is a member of the Sox (Sry-type HMG box) family of transcription factors, characterized by minor groove binding domain. The DNA binding domain of this gene is encoded by exon 14. We assessed the relationship between response to HU and exon 14 of the SOX6 gene sequence variations in patients with non transfusion-dependent thalassemia (NTDT). One hundred NTDT patients from southern Iran underwent HU therapy randomly participated in this cross-sectional study between February 2013 and October 2014. Based on response to HU therapy, the patients were divided into two groups: good and poor responder. Sequence variations of exon 14 of the SOX6 gene was assayed by the Sanger sequencing technique. From all evaluated single nucleotide polymorphisms (SNPs) as above, we found no significant association between sequence variations of exon 14 of the SOX6 gene and response to HU therapy ( p  > 0.05). It seems that no SNPs in exon 14 of the SOX6 gene is associated with response to HU in NTDT patients, but more studies are needed for further evaluation.

Background: Despite the significant advances in thalassemia pathobiology and efficacy of chelation regimens, complications of transfusion therapy have attenuated the reproductive health of thalassemia patients. Depending on clinical profiles, we aimed to assess the fertility status and stresses among thalassemia patients who desired to have children., Material and Methods: A total of 213 couples in reproductive ages were enrolled in this study in Tehran. Patients' demographic, clinical, fertility and spouse's health status were documented. We evaluated the pituitary-gonadal axis, serum ferritin, liver enzymes, and alloimmunization before planning a pregnancy and reported them as a function of spontaneous conception and transfusion dependency., Results: Data showed that 131 patients (62%) had 228 spontaneous pregnancies leading to 198 (86.6%) successful pregnancies. A significant difference was observed in spontaneous pregnancy with respect to fertility complications and transfusion dependency. In addition, the clinical conditions of spouses in patients with any spontaneous pregnancy were more thalassemia carriers (P < .05). Moreover, serum ferritin levels had a significant negative correlation with the levels of Testosterone, Estradiol, luteinizing hormone, and follicle-stimulating hormone. Furthermore, a significant positive correlation was reported with the level of liver enzymes. Finally, alanine transaminase and aspartate transaminase had a significant negative correlation with pituitary hormones., Conclusion: We suggest that organised instruction in addition to good iron chelation, especially during the puberty period, would reduce the oxidative damage and related complications in thalassemia patients. Moreover, infertility seems to be attributed to iron deposition in various endocrine organs, pituitary, reproductive system and the liver, contributing to hormonal metabolism., (© 2020 British Blood Transfusion Society.)

Objectives: To report the clinical and virologic epidemiology of a recent epidemic of hepatitis C in thalassaemia patients in Sri Lanka., Background: Transfusion-dependent thalassaemia patients remain at risk for hepatitis C virus (HCV). Here, we report a cluster of recent HCV infections in Sri Lankan thalassaemia patients and examine the phylogenetic relationship of viral sequences., Methods: We conducted two prospective cross-sectional surveys of 513 patients in four Sri Lankan thalassaemia centres in 2014/2015 and re-surveyed one centre in 2016. We screened for anti-HCV antibodies using the CTK Biotech enzyme-linked immunosorbent assay (ELISA) kits and confirmed active infection by reverse transcription-polymerase chain reaction (RT-PCR) for HCV-RNA. HCV genomes were sequenced by unbiased target enrichment., Results: Anti-HCV antibodies were found in 116/513 (22.6%) of patients initially tested. Active hepatitis C infection was found in 26 patients with no cases of active hepatitis B infection. Of 26 patients with HCV, two were infected with genotype 1(a), and the rest had 3(a). In a single centre (Ragama), 122 patients (120 new cases and two previously tested, but negative) were retested for anti-HCV antibodies. 32/122 (26.2%) patients were seropositive. Twenty-three (23/122; 18.8%) of these new cases were confirmed by HCV PCR (all genotype 3[a])., Conclusion: There is a significant cluster of recent HCV cases in multiply transfused thalassaemia patients in several centres in Sri Lanka. Most of the viruses shared a close phylogenetic relationship. The results are consistent with recent continuing transfusion-transmitted HCV infection. Routine surveillance for HCV of chronically transfused patients is required irrespective of screening of blood products., (© 2020 British Blood Transfusion Society.)

Introduction: Thalassemia traits and iron deficiency anemia are the most common types of hypochromic microcytic anemia with similar clinical and laboratory features. It is vital to establish a new screening model based on HbA 2 levels and red cell indices for the differentiation of TT from IDA in hypochromic microcytic anemia cases., Method: The data comprised of the red blood cell indices and HbA 2 prenatal diagnostic test results of 810 individuals who were identified to conform to the following criteria: MCV < 80 fl or MCH < 26 pg. We launched a new model consisting mainly of significative red cell indices and HbA 2 levels, as well as proposing cutoff values by using decision trees and logistic regression analyses. Next, we evaluated our new method by comparing the sensitivity, specificity, positive, and negative predictive values with those of the previous formulas., Results: We put forward a new model and compared it with 5 efficient formulas. The new model exhibited the highest accuracy (0.918), with its sensitivity and specificity calculated as 0.917 and 0.921, respectively. Our new model's Youden index was 0.838, which is higher than the other formulas' Youden indices., Conclusions: The new screening model, based on HbA 2 levels and red cell indices, is suitable for the screening of thalassemia patients in the hypochromic microcytic anemia group and has the best efficiency in distinguishing TT and IDA., (© 2020 John Wiley & Sons Ltd.)

Objective: To evaluate the effect of a new type of automatic glycated hemoglobin analyzer on the separation of abnormal hemoglobin., Methods: Samples diagnosed as hemoglobin variants by capillary electrophoresis and gene testing were selected, and HbA1c analyzer was used for separation and detection., Results: A total of 13 hemoglobin variants in 40 samples could be separated from the normal peaks., Conclusions: The variant mode of hemoglobin HbA1c can identify a variety of hemoglobin variants, and the type of variants can be preliminarily determined according to the retention time and characteristic peak shape of the variants., (© 2020 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Many mathematical formulas containing simple red blood cell parameters have been proposed for differentiating between iron deficiency and thalassemia in patients with microcytic anemia. Approximately half of these formulas do include red cell distribution width (RDW), along with other red cell parameters. In the present study we investigated the role of RDW, expressed in relative or in absolute units in relation with the formulas' discriminant performance. We used a database containing over 2200 subjects with microcytic anemia, for whom a final diagnosis (iron-deficiency anemia, thalassemia, both or other) was available. Performance of the discriminant formulas was assessed by Receiver Operator Curve analysis. Substitution of relative by absolute RDW resulted in statistically significant performance increase (area under the ROC curve) in 16 out of 23 formulas, predominantly due to increased specificity. Relevant performance deterioration was seen in only three formulas that had low initial performance already with the original relative RDW. For optimal differential diagnostic performance, an RDW-based formula for distinguishing thalassemia from iron-deficiency anemia in microcytic anemia should contain 'absolute' instead of relative RDW.

Objective: To establish a new indicator derived from reticulocyte hemoglobin (Ret-He) content and red blood cell (RBC) indices for screening for iron deficiency anemia (IDA) in an area in whch thalassemia is prevalent., Methods: Blood specimens from 304 women aged between 18 and 30 years residing in northeast Thailand were collected and measured for RBC and reticulocyte parameters. Iron deficiency was diagnosed when a participant had a serum ferritin level of less than 15 ng per mL. Thalassemia genotypes were defined by hemoglobin (Hb) and DNA analyses., Results: Of the total participants, 25% had iron deficiency (ID) and 50% carried the thalassemia gene. Various mathematical formulas were established and analyzed using the receiver operating characteristic (ROC) curve. The formula derived from Ret-He: (Ret-He/RDW-SD) × 10, was the best predictor for identifying ID among participants (area under the curve [AUC] = 0.812). Further testing of this indicator among individuals with positive thalassemia-screening results revealed stronger performance with an AUC of 0.874., Conclusions: The findings indicate that the formula derived from Ret-He might be applicable for screening ID in areas in which thalassemia is prevalent., (© American Society for Clinical Pathology 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pathogenesis of different diseases showed that some of them, especially thalassemia (T) and rheumatoid arthritis (RA) have an implicit association with oxidative stress and altered levels of reactive oxygen species (ROS). Introducing ROS level and the balance between ROS and antioxidants as essential metrics, an attempt was made to classify T and RA from normal individuals (treated as controls)(C) using synchronous fluorescence spectroscopy (SFS) and Raman line intensity of water. This non-invasive and label-free approach was backed up by a categorization algorithm that helped in the prediction of disease types from serum samples. The predictive system constituted principal component analysis (PCA) with four parameters, namely spectral intensity ratios of reduced nicotinamide adenine dinucleotide (NADH) to tryptophan (Trp) (NADH/Trp), kynurenine (Kyn) to tryptophan (Kyn/Trp), kynurenine to NADH (Kyn/NADH), and logarithmic changes in Raman line intensity of water (Rline), with the index headers containing the disease types. Rline has a positive correlation with both Kyn/Trp and Kyn/NADH and a negative correlation with NADH/Trp ratio, implying its direct or indirect association with oxidative stress. In addition to the classification of T, RA, and C a sub-classification of T into beta major and E-beta in their post and pre-splenectomized surgical stages could also be realized. Furthermore, receiver operating characteristic (ROC) analysis was deployed to ascertain that the misclassification error (ME) was negligible for the disease types. Graphical Abstract A schematic representation of the workflow converging into the categorical classification of disease classes.

Hypothesis: Dried blood droplet morphology may potentially serve as an alternative biomarker for several patho-physiological conditions. The deviant properties of the red blood cells and the abnormal composition of diseased samples are hypothesized to manifest through unique cell-cell and cell-substrate interactions leading to different morphological patterns. Identifying distinctive morphological trait from a large sample size and proposing confirmatory explanations are necessary to establish the signatory pattern as a potential biomarker to differentiate healthy and diseased samples., Experiments: Comprehensive experimental investigation was undertaken to identify the signatory dried blood droplet patterns. The corresponding image based analysis was in turn used to differentiate the blood samples with a specific haematological disorder "Thalassaemia" from healthy ones. Relevant theoretical analysis explored the role of cell-surface and cell-cell interactions pertinent to the formation of the distinct dried patterns., Findings: The differences observed in the dried blood patterns, specifically the radial crack lengths, were found to eventuate from the differences in the overall interaction energies of the system. A first-generation theoretical analysis, with the mean field approximation, also confirmed similar outcome and justified the role of the different physico-chemical properties of red blood cells in diseased samples resulting in shorter radial cracks., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

BACKGROUND Beta-hemoglobinopathies and glucose-6-phosphate dehydrogenase (G6PD) deficiency are genetic disorders that cause hemolytic anemia when exposed to oxidative stress. Their co-existence is, however, not proven to enhance the severity of anemia. CASE REPORT We report the case of a young man with no known co-morbidities, who came with fever and cough and was diagnosed with COVID-19 pneumonia. He was found to have hemoglobin D thalassemia and G6PD deficiency during further evaluation. Hydroxychloroquine therapy started initially, was discontinued after 3 doses once the G6PD deficiency was diagnosed. His hospital course showed a mild drop in hemoglobin with evidence of hemolysis on peripheral smear. However, the hemoglobin improved without any need for transfusion. CONCLUSIONS Hydroxychloroquine therapy can induce hemolytic crises in patients with underlying G6PD deficiency or hemoglobinopathies and should be avoided or closely monitored. Immediate intervention to stop hydroxychloroquine after 3 doses saved our patient from a major hemolytic crisis. The significance of this case report is that it is the first report that outlines the clinic course of COVID-19 pneumonia in a patient with underlying hemoglobin D disease and G6PD deficiency.

Background: Regular transfusions are the gold standard therapy for β-thalassemia and are often complicated by secondary-iron overload and alloimmunization. We assessed the frequency of regulatory T cells (Tregs) and the levels of cytokines implicated in Th-responses in 49 patients 33 TDT and 16 NTDT in order to investigate the contribution of transfusion and its complications on immune responses., Materials and Methods: Tregs were characterized with flow cytometry. Soluble IL-4, IL-6, IL-10, IL-17A, and TGF-β1 were assessed by ELISA. Clinical data including alloimmunization, age of onset of transfusion splenectomy hepatitis B and C infection, iron overload assessment with MRI T2* (liver and heart) were recorded from the patients' files., Results: Tregs levels, IL-6, IL-10, TGFβ and serum ferritin were higher in the TDT compared to the NTDT group (all p < 0.05). There was no difference of Tregs and circulating cytokines in patients in correlation with the extend of iron overload (assessed by T2*liver), the type of chelator or the development of alloantibodies., Discussion: Tregs levels are higher in TDT patients compared to NTDT, a difference which could be ascribed to transfusion. Tregs levels and the cytokines analyzed may play little role in alloimmunization and are not impacted by the extend of iron overload., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

Aims: Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency or thalassemia have a shorter red blood cell lifespan; therefore, HbA1c is underestimated in these patients. To address these issues, we sought an early indicator for G6PD deficiency or thalassemia in DM patients., Methods: A total of 4908 patients with DM and 1848 subjects without DM were included in this study. Fasting glucose (FG) levels, HbA1c levels, hemogram profiles and G6PD activities were measured. Genotypic analyses of G6PD deficiency and thalassemia were performed., Results: DM patients with G6PD deficiency had significantly higher FG/HbA1c ratios than did those without G6PD deficiency (26.54 vs. 18.36; p < 0.0001). We divided the FG level into four categories: ≤150, 151-250, 251-350, and ≥351 mg/dL. Among all groups, only patients with DM and G6PD deficiency had higher FG/HbA1c ratios than those of patients with DM alone or DM with thalassemia. To evaluate the reliability of the FG/HbA1c ratio, receiver operating characteristic analyses were performed. The areas under the curve for detecting FG ≤ 150, 151-250, 251-350, and ≥351 mg/dL with G6PD deficiency based on the FG/HbA1c ratio were 0.839 (p < 0.001), 0.888 (p < 0.001), 0.891 (p < 0.001), and 0.640 (p = 0.3954), respectively. G6PD deficiency was confirmed by genetic analysis. We found common mutations that influenced G6PD activity and HbA1c levels., Conclusions: The FG/HbA1c ratio is a good indicator of DM with G6PD deficiency. If this ratio is determined to be high in a clinical setting, then the clinician must consider whether the patient has a G6PD deficiency, and HbA1c reference values must be adjusted to avoid misdiagnosis and incorrect treatment decisions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)