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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: Renal tubular dysfunction was reported in transfusion-dependent thalassemia (TDT) patients and ranges from mild to severe. The objectives of our study were identification of the best marker of early renal tubular dysfunction in TDT patients among the three most commonly used urinary biomarkers, named neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and N-acetyl-D-glucosaminidase (NAG) and correlation of these biomarkers with different patient variables., Methodology: Sixty-one TDT patients and another 62 healthy children were enrolled in a cross-sectional study. Morning urine samples were taken for measurement of calcium, phosphorus, creatinine, microalbumin and markers of tubular dysfunction (NGAL, NAG and RBP). Urine NGAL/creatinine (UrNGAL/Cr), urine NAG/creatinine (UrNAG/Cr) and urine RBP/creatinine (UrRBP/Cr) ratios were used for accuracy. Patients were classified into 2 groups: group A, with tubular dysfunction and group b, without tubular dysfunction., Results: Group A showed statistically significant higher UrNGAL/Cr (p < 0.001), UrRBP/Cr (p < 0.001) and UrNAG/Cr (p <0.001) than group B. In group A, microalbuminuria was detected only in 7 patients (28%) while it was detected in 12 patients (33.3%) in group B. By using ROC curve analysis, the diagnostic cutoff values for UrNGAL/Cr, UrRBP/Cr and UrNAG/Cr were 3713.38, 1614.85 and 56.56 ng/g, respectively. We found a statistically significant superiority of UrNGAL/Cr over UrRBP/Cr (p < 0.001) and UrRBP/Cr over UrNAG/Cr (p < 0.001)., Conclusion: Evaluation of UrNGAL/Cr, UrRBP/Cr and UrNAG/Cr could early discriminate tubular dysfunction TDT patients from those with normal tubular function. UrNGAL/Cr is more accurate in early detection of tubular dysfunction when compared with the other two biomarkers., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Serological methods are unreliable for accurate determination of blood group antigens in multi-transfused thalassemia patients. The MNS blood group system has five high-frequency antigens. Many studies demonstrated that some antibodies including anti-S, anti-s, and anti-U may cause acute and delayed transfusion reactions and hemolytic disease of the fetus and newborn. This study aimed to determine the genotype of the MNS blood group in thalassemia patients with alloantibodies by molecular methods., Material and Methods: In this study, 104 blood samples from thalassemia patients were collected. The blood group phenotype for M, N, S and s antigens was determined by the tube hemagglutination method. MNS blood group genotyping was performed using PCR-SSP and DNA Sequencing methods., Results: All patients were genotyped with a total of 6 pairs of primers. Discrepancies between genotype and phenotype were observed in 22 patients with S/s alleles and 2 patients with M/N alleles, however, there was full accordance between the results of SSP-PCR and DNA sequencing. The frequency of MNS blood group alleles was determined as follows: 25 % MNSs, 23 % MNss, 21 % MMSs, 9% MMSS, 9% MMss, 8% NNss, 2%MNSS, and NNSS, NNSs, MM genotypes at 1% each., Conclusion: In conclusion, molecular genotyping is more reliable than serological methods in multiple transfusion patients and can lead to a more compatible blood unit for transfusion in these patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A high incidence of isolated left ventricular non-compaction (LVNC) has been reported in previous studies on smaller cohorts of patients with thalassemia by cardiac MRI but the clinical impact of the finding is unknown. This prospective cohort study evaluates the prevalence and clinical implication of the finding. Prospective cohort study with enrollment of all consecutive cases with thalassemia referred for cardiac MRI from September 2007 to November 2014. The presence of LVNC was assessed according to the Petersen method and the Jacquier method, with the proposed changes by Fazio, Grothoff, and Chiodi. A clinical follow-up was performed in all patients. We included 560 patients with thalassemia (473 with thalassemia major and 87 with thalassemia intermedia: mean age 31.9 ± 10.6 years, male/female = 250/310). A total number of 1683 MRI tests were performed. A diagnosis of LVNC was determined according to adopted MR criteria in 44 patients (7.9%). Patients with LVNC had a significantly lower ejection fraction (52.68 ± 5.17% vs. 56.90 ± 6.34%; p = 0.0005) and greater indexed LV ESV (48.16 ± 10.03 ml/m 2 vs. 40.02 ± 10.06 ml/m 2 ; p = 0.0022). After a mean follow-up time was 5.1 years, no significant change of MR parameters was detected as well as no clinical adverse events. LVNC is relatively frequent in patients with thalassemia. However, it is not associated with a worsening of LV function and adverse events after a long-term follow-up.

Heart disease remains a leading cause of morbidity and mortality in transfusion-dependent thalassemia (TDT), which can be attributed to several factors but primarily develops in the setting of iron overload. This was a retrospective cohort study utilizing Webthal ® patient data from five major centers across Italy. Patients without heart disease were followed-up for 10 years (2000-2010) and data were collected for demographics, splenectomy status, serum ferritin and hemoglobin levels, and comorbidities associated with heart disease. Among 379 patients analyzed (mean age 22.9 ± 5.1 years, 47.8% men), 44 (cumulative incidence: 11.6%) developed heart disease during the period of observation. Splenectomy (p = 0.002) and serum ferritin level (p < 0.001) were the only risk factors with significant association with heart disease. A serum ferritin threshold of ≥ 3000 ng/mL was the best predictor for the development of heart disease (86.4% sensitivity and 92.8% specificity, AUC: 0.912, 95% CI 0.852-0.971, p < 0.001). On multivariate analysis, only a serum ferritin level ≥ 3000 ng/mL remained significantly and independently associated with increased risk of heart disease (HR: 44.85, 95% CI 18.85-106.74), with a 5- and 10-year heart disease-free survival of 58 and 39%. The association between iron overload and heart disease in patients with TDT is confirmed, yet a new serum ferritin level of 3000 ng/mL to flag increased risk is suggested.

Disease-related complications and management are different among patients with thalassemia. This study was aimed to review the prevalence, clinical risk factors for the complications and the management in patients with thalassemia in Thailand. A multicenter cross-sectional study was conducted in patients with thalassemia aged ≥ 18 years old. Thalassemia-related complications and management were reviewed. The clinical parameters significantly associated with the complications were analyzed by logistic regression methods. The prevalence of thalassemia-related complications was 100% in patients with transfusion-dependent thalassemia (TDT) and 58.8% in patients with non-transfusion-dependent thalassemia (NTDT). Advanced age was statistically associated with extramedullary hematopoiesis in both TDT and NTDT patients. Splenectomy was a significant risk factor for pulmonary hypertension in both groups of patients. Severe iron overload started earlier in patients with TDT than NTDT and was associated with diabetes mellitus (adjusted odds ratio (AOR) = 6.2, p-value = 0.02). Disease-related complications are more prevalent in patients with TDT than patients with NTDT. Splenectomy and advanced age were important risk factors for developing major complications in both groups. Early screening and management for specific disease-related complications should be considered in patients with thalassemia according to their clinical risk factors., Competing Interests: No Novartis or any pharmaceutical company products nor honoraria were used to conduct any of the research as part of this publication. Chuncharunee S has received research funding and honoraria from Novartis Pharmaceuticals, Janssen-Cilag, Roche, and Celgene. Teawtrakul N received honoraria from Novartis and Janssen-Cilag. Siritanaratkul N. received research funding and honoraria from Novartis, Janssen-Cilag, Roche, and Pfizer. The remaining author declares no competing financial interests. There are no patents, products in development or marketed products to declare. This does not alter our adherence to the PLOS ONE policies on sharing data and materials.

Background: Extramedullary hematopoiesis (EMH) is common in non-transfusion-dependent thalassemia (NTDT) patients. Clinical presentations of EMH vary as MRI screening is not feasible. Hence, serum biomarkers are used to predict the risk of EMH., Materials and Methods: 52 NTDT patients, including 26 EMH (+) and 26 EMH (-), together with 26 healthy controls, were enrolled in this case-control study from 2013 to 2016. EMH was confirmed by computed tomography or MRI. Demographic, transfusion, genetic, laboratory, and liver iron concentration (LIC) data, as well as clinical complications, were analyzed., Results: EMH (+) patients had significantly higher serum ferritin (SF), growth differentiation factor 15 (GDF15), and erythropoietin (EPO) levels compared with EMH (-) patients and controls. The levels of erythroferrone (ERFE), hepcidin, and sTfR did not differ significantly between EMH (+) and EMH (-) patients (p>0.05). In NTDT patients, serum ERFE was not related to SF, LIC, hepcidin, sTfR, EPO, GDF15, and Hb levels. GDF15, EPO concentrations, and GDF15 to sTfR and GDF15 to EPO ratios are able to determine the presence of EMH with considerable sensitivity and specificity., Conclusions: GDF15, EPO, and GDF15 to EPO and GDF15 to sTfR ratios are potential biomarkers for the early prediction of NTDT in patients who are at risk for EMH.

Background: Thalassemia is inherited disorder characterized by haemolytic anaemia, due to complete absence or reduced β-globin chain synthesis, stimulating pathological bone marrow overstimulation and altered erythropoiesis. The change in bone mass ultimately results into miss interpretation of bone age once assed from x-ray radiograph. The aims compare skeletal age of thalassaemic children of 9-15 years with chronological age by x-ray wrist bones., Methods: This was cross sectional analytical study; the study was conducted in conjunction with Fatimid Hospital Peshawar Pakistan and Out Patients Department (OPD) of paediatrics for minor illness (other than Thalassemia) Khyber Teaching Hospital August 2014 to January 2015. A total 156 samples were selected convenient sampling to make comparison of bone age and chronological age between thalassaemic children (age 9-15years) and age sex matched normal control. A structure data collection check list was used to collect data X-ray findings (bone age). SPSS 20 was used for statistical analysis., Results: The results showed a total of 156 children with their mean age 11.9±2.2, male were 97 (62.2%) and females 59 (37.8%). Out of thalassaemic (n=76) majority 49 (62.8%) were male as compared to female 29 (37.2%). The mean chorological age among both of group were not significantly different (p=0.67). However, the bone age was significantly different from each other (p=0001). Pearson's correlation analysis revealed that was strong correlation between erupt teeth and bone age (r=0.462, p=0.0001)., Conclusion: Skeletal age assessment was found to be suboptimal along with chronological age in children and adolescents suffering from thalassemia.

Iron chelation can improve endothelial function. However, effect on endothelial function of deferiprone has not been reported. We hypothesized deferiprone could promote nitric oxide (NO) production in endothelial cells. We studied effects of deferiprone on blood nitrite and blood pressure after single oral dose (25 mg/kg) in healthy subjects and hemoglobin E/β-thalassemia patients. Further, effects of deferiprone on NO production and endothelial NO synthase (eNOS) phosphorylation in primary human pulmonary artery endothelial cells (HPAEC) were investigated in vitro. Blood nitrite levels were higher in patients with deferiprone therapy than those without deferiprone (P = 0.023, n = 16 each). Deferiprone increased nitrite in plasma and whole blood of healthy subjects (P = 0.002 and 0.044) and thalassemia patients (P = 0.003 and 0.046) at time 180 min (n = 20 each). Asymptomatic reduction in diastolic blood pressure (P = 0.005) and increase in heart rate (P = 0.009) were observed in healthy subjects, but not in thalassemia patients. In HPAEC, deferiprone increased cellular nitrite and phospho-eNOS (Ser1177) (P = 0.012 and 0.035, n = 6) without alteration in total eNOS protein and mRNA. We conclude that deferiprone can induce NO production by enhancing eNOS phosphorylation in endothelial cells.

Although disturbance of cardiac Ca 2+ regulation is involved in the pathophysiology of iron-overload cardiomyopathy, the obvious mechanisms involved in the dysregulation of iron-induced cardiac Ca 2+ are unclear. Moreover, the roles of the iron chelator deferiprone and the T-type calcium channel blocker efonidipine on cardiac intracellular Ca 2+ transients and Ca 2+ regulatory proteins in thalassemic mice are still unknown. We tested the hypothesis that treatment with either deferiprone or efonidipine attenuated cardiac Ca 2+ dysregulation and led to improved left ventricular (LV) function in iron-overloaded thalassemic mice. Wild-type (WT) mice and β-thalassemic (HT) mice were fed with either a normal diet (ND) or a high iron-diet (FE) for 90 days. Then, the FE-fed mice were treated with either deferiprone (75 mg/kg/day) or efonidipine (4 mg/kg/day) for 30 days. ND-fed HT mice had an increase in T-type calcium channels (TTCC) and an increased level of sarcoplasmic reticulum Ca 2+ -ATPase (SERCA), compared with ND-fed WT mice. Chronic iron feeding led to an increase in TTCC and expression of SERCA proteins in FE-fed WT mice. Moreover, chronic iron overload led to increased plasma non-transferrin bound iron (NTBI) and cardiac iron deposition, impaired cardiac intracellular Ca 2+ transients including decreased intracellular Ca 2+ transient amplitude, rising rate and decay rate, as well as impaired LV function as indicated by a decreased %LV ejection fraction (%LVEF) in both WT and HT mice. Our findings showed that treatment with either deferiprone (DFP) or efonidipine (EFO) showed similar benefits in reducing plasma NTBI and cardiac iron deposition, and improving %LVEF from 84.3 (WT) to 89.3 (DFP) and 89.2 (EFO) treatment; and from 84.2 (HT) to 88.8 (DFP) and 89.5 (EFO) treatment, however there was no improvement in the regulation of cardiac Ca 2+ in iron-overloaded thalassemic mice. These findings provide the understanding of the effects of these drugs on the iron-overloaded heart in thalassemic mice and suggest that an alternative intervention that could improve calcium regulation under this condition is needed to improve the therapeutic outcome. Moreover, whether the benefits of the TTCC blocker is via its inhibition of the TTCC alone or together with its ability to chelate iron are still unclear and need further investigation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

As more women with transfusion-dependent thalassemia are seeking pregnancy, ensuring the best outcomes for both the mother and baby requires concerted, collaborative efforts between practitioners and the family. Proactive counseling, early fertility evaluation, recent developments in reproductive technology, and optimal management of iron overload, have resulted in more successful pregnancies and the birth of healthy newborns. With advances in technology for prenatal screening and increased awareness to perform screening for hemoglobinopathies, healthy pregnancy outcomes have become the expectation. Topics that require further study include management that allows fertility preservation, improved non-invasive prenatal diagnosis methods for affected fetuses, the use of chelation therapy during pregnancy, and indications for and duration of anticoagulation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study aimed at assessing renal functions in patients with transfusion-dependent thalassemia (TDT). Fifty patients and 30 controls were enrolled in this prospective study. Serum levels of electrolytes and albumin were measured by a spectrophotometer. Serum levels of cystatin-C and urinary levels of β2-microglobulin were measured by nephelometric method. Thirty-eight patients were receiving deferasirox and 8 were on deferiprone. Serum electrolytes and albumin levels of the patients were found to be within normal ranges. Urinary β2-microglobulin and serum cystatin-C levels were significantly higher in patients than controls. They did not significantly differ between the subgroup of patients on deferiprone and the control group, whereas they were found to be higher in patients using deferasirox compared to controls. Urinary β2-microglobulin levels significantly increased in patients who were receiving high-dose deferasirox compared to those who were receiving a daily dose of 15-20 mg/kg or controls. Subclinical renal injury may be present in TDT patients.

Early detection of iron overload cardiomyopathy is an important strategy for decreasing the mortality rate of patients with transfusion-dependent thalassemia (TDT). Although cardiac magnetic resonance (CMR) T2* is effective in detecting cardiac iron deposition, it is costly and not generally available. We investigated whether heart rate variability (HRV) can be used as a screening method of iron overload cardiomyopathy in TDT patients. HRV, evaluated by 24-h Holter monitoring, non-transferrin bound iron (NTBI), serum ferritin, left ventricular (LV) ejection fraction (LVEF), and CMR-T2* were determined. Patients with a cardiac iron overload condition had a significantly higher low frequency/high frequency (LF/HF) ratio than patients without a cardiac iron overload condition. Log-serum ferritin ( r = -0.41, P =0.008), serum NTBI ( r = -0.313, P =0.029), and LF/HF ratio ( r = -0.286, P =0.043) showed a significant correlation with CMR-T2*, however only the LF/HF ratio was significantly correlated with LVEF ( r = -0.264, P =0.043). These significant correlations between HRV and CMR-T2* and LVEF in TDT confirmed the beneficial role of HRV as a potential early screening tool of cardiac iron overload in thalassemia patients, especially in a medical center in which CMR T2* is not available. A larger number of TDT patients with cardiac iron overload are needed to confirm this finding., (© 2018 The Author(s).)

Inherited haemoglobin disorders, including thalassaemia and sickle-cell disease, are the most common monogenic diseases worldwide. Several clinical forms of α-thalassaemia and β-thalassaemia, including the co-inheritance of β-thalassaemia with haemoglobin E resulting in haemoglobin E/β-thalassaemia, have been described. The disease hallmarks include imbalance in the α/β-globin chain ratio, ineffective erythropoiesis, chronic haemolytic anaemia, compensatory haemopoietic expansion, hypercoagulability, and increased intestinal iron absorption. The complications of iron overload, arising from transfusions that represent the basis of disease management in most patients with severe thalassaemia, might further complicate the clinical phenotype. These pathophysiological mechanisms lead to an array of clinical manifestations involving numerous organ systems. Conventional management primarily relies on transfusion and iron-chelation therapy, as well as splenectomy in specific cases. An increased understanding of the molecular and pathogenic factors that govern the disease process have suggested routes for the development of new therapeutic approaches that address the underlying chain imbalance, ineffective erythropoiesis, and iron dysregulation, with several agents being evaluated in preclinical models and clinical trials., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Osmotic fragility test (OFT) is widely considered as a sensitive indicator of red blood cells' sensitivity to the hypotonic solution. It is often used as a screening test for the diagnosis of hereditary spherocytosis (HS). Nowadays, the osmotic fragility test based on flow cytometric analysis (FCM OF) is widely used in laboratory practice. The purpose of this study was to optimize the assay sensitivity and to validate its clinical application in the diagnostic screening of childhood anemias., Methods: The study was conducted on 175 children suffering from various types of anemia (including 30 children with proven hereditary spherocytosis, HS) and 16 healthy subjects. All children were aged between 3 months and 17 years, including 94 boys and 97 girls. FCM OF was performed on every subject according to two different analysis time patterns (hemolysis was analyzed for 214 or 300 s) using Cytomics FC500 flow cytometer., Results: Significant higher sensitivity was demonstrated by the tests carried out according to the longer analysis time pattern (90.0 vs. 83.33%). The level of specificity of both the analysis patterns was similar. When an extended analysis time was used, the percentage of red cell survival levels in HS patients were significantly lowered compared to the same cases analyzed with shorter incubation times and all other non-HS anemic cases (9.31 ± 4.69 vs. 35.59 ± 15.30%, P < 0.05). During the shorter analysis time, the values obtained were 13.76 ± 7.92% for HS and 48.18 ± 19.04% for non-HS, P < 0.0001. The 300-s test is very useful in distinguishing thalassemia patients from patients with other types of anemias (94.74% sensitivity and 90.12% specificity) and provided the values of remaining red blood cells as 70.46 ± 12.29% for thalassemia and 27.16 ± 13.01% for nonthalassemia subjects, P < 0.0001., Conclusion: Flow cytometric osmotic fragility test with a longer (300-s) analysis time demonstrated an increased sensitivity in detecting HS in anemic children. © 2017 International Clinical Cytometry Society., (© 2017 International Clinical Cytometry Society.)

Patients with non-transfusion-dependent thalassemia (NTDT) are at risk of developing brain ischemia. Transcranial Doppler (TCD) has been established as a useful screening tool of cerebrovascular disease in patients with sickle cell disease. Proteins neuron specific enolase (NSE) and S100B are biomarkers that reflect CNS injury. The purpose of this study is to evaluate cerebral vessel vasculopathy and brain damage in NTDT patients using non-invasive methods as TCD and measurement serum levels of NSE and S100B. We included in our study 30 patients with NTDT, aged between 8 and 62 years old (mean: 29.4, median: 32) who presented in our Unit for regular follow-up. We performed in all patients a non-imaging TCD examination and have measured serum S100, NSE and lactate dehydrogenase (LDH) levels. We investigated the possible correlation between TCD results and S100B, NSE and LDH levels as well as between NSE-LDH and S100B-LDH levels by regression analysis. We found a statistically significant relationship for both NSE, S100B with LDH. We also found a statistically significant relationship for S100B and time-averaged mean velocity (TAMV)/peak velocity of left middle cerebral artery (MCA), NSE and pulsatility index (PI)/resistive index (RI) of the left posterior cerebral artery (PCA). TCD results correlated with biomarkers for brain ischemia. This finding enhances the role of TCD as a screening tool for brain ischemia in patients with NTDT., Competing Interests: The authors declare no conflict of interest.

Arterial aneurysms are more common than visceral venous aneurysms. Portal vein aneurysms being the most common type of visceral venous aneurysms. Here, we present an 18-year-old young woman with thalassaemia major, who presented with headache, palpitation, shortness of breath and a recent increase in blood transfusion rate. On clinical examination, she had hepatosplenomegaly. Ultrasonography revealed hepatosplenomegaly with fusiform dilatation of extrahepatic portal vein, which was confirmed to be portal vein aneurysm on contrast enhanced CT. Though portal vein aneurysms were previously thought to be rare, recently they are increasingly diagnosed with the use of cross-sectional imaging. Recognition of this finding can help to avoid potential confusion with other periportal cystic masses of different aetiologies, especially on sonography., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: Regular transfusion and iron chelation are the current treatment of severe forms of thalassemia. As a consequence of this demanding supportive treatment, there are several unmet therapeutic needs. Due to a deeper understanding in the pathophysiology of thalassemia, new therapeutic strategies have been developed that are now in pre-clinical and clinical trials. Areas covered: Activin receptor ligand traps (luspatercept and sotatercept), drugs targeting ineffective erythropoiesis, showed encouraging results in Phase I and II clinical trials. A phase III clinical trial is currently ongoing. Ruxolitinib, a Jak2 inhibitor, has been tested to limit stress erythropoiesis in a phase II clinical trial. In addition, improvement in iron chelation has been developed. Moreover, several trials of gene therapy are currently active in different countries with different lentiviral vectors. Expert opinion: The most promising molecules are the activin receptor ligand traps. Together with gene therapy these could be an alternative to bone marrow transplant, aiming towards a curative strategy. The main limit to gene therapy seems to be the conditioning regimen, thus an in vivo gene therapy would be more suitable. At pre-clinical level gene editing is showing extremely encouraging results.

Purpose: To evaluate possible benefits of using electrophysiological investigations for detecting retinal and visual pathway changes and correlating them with chelation modality in children with thalassemia., Methods: This study included 60 patients on single oral iron chelator (deferasirox) (Group 1), 60 on deferoxamine chelator (Group 2), and 60 controls (Group 3). Participants underwent full ophthalmologic examination, pattern visual-evoked potential, pattern electroretinogram, and multifocal electroretinogram., Results: Fundus showed no abnormalities. Multifocal electroretinogram mean P1 amplitude showed statistically significant differences in all 5 rings, amplitudes being significantly lower in Groups 1 and 2 than Group 3; moreover, significantly lower in Group 2 than Group 1. There was a statistically significant difference between groups regarding P50 wave latency and N35-P50 of pattern electroretinogram amplitude (P < 0.001 and P < 0.001, respectively). However, there were no statistically significant differences between groups regarding N95 wave of pattern electroretinogram and pattern visual-evoked potential waves' amplitude and latency. Multiple regression analyses illustrated that chelator was the most important determinant for multifocal electroretinogram and P50 parameters., Conclusion: Preclinical electrophysiologic changes existed in thalassemics, more obvious in those on deferoxamine. Electrophysiologic studies analysis denotes an early toxic macular insult rather than optic nerve affection. Thus, regular follow-up using multifocal electroretinogram and pattern electroretinogram is recommended.

The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS). In patients with sickle cell anemia (SCA), iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*<20 ms, in patients with thalassemia, SCA, or MDS. Patient inclusion criteria were an accurate record of erythrocyte concentrates (ECs) received, a transfusion history >8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15%) patients with thalassemia, none with SCA, and 4 (16%) with MDS. The liver iron content (LIC) ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29). Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P<0.001). Hepcidin was low in thalassemia, normal in SCA, and markedly elevated in MDS (P<0.001). Two mechanisms may explain that iron deposition largely spares the heart in SCA: the high level of erythropoiesis recycles the iron and the chronic inflammation retains iron within the macrophages. Thalassemia, in contrast, is characterized by inefficient erythropoiesis, unable to handle free iron. Iron accumulation varies widely in MDS syndromes due to the competing influences of abnormal erythropoiesis, excess iron supply, and inflammation.

The incidence of hepatocellular carcinoma (HCC) in patients with thalassemia is on the rise. The 2 well recognized HCC risk factors in thalassemia are iron overload and chronic viral infection with hepatitis C. The carcinogenicity of iron is related to its induction of oxidative damage, which results in genotoxicity, and to immunologic dysregulation, which attenuates cancer immune surveillance. Chronic hepatitis B and C infections lead to necroinflammation, which can prompt progression to HCC, but an independent role of hepatitis B virus in hepatic carcinogenesis among patients with thalassemia has not been demonstrated. Screening patients who have thalassemia using magnetic resonance imaging-based liver iron concentration measurement and liver ultrasound is recommended for early detection of iron overload and HCC, respectively. Prevention primarily resides in hepatitis B vaccination, donor blood screening, hepatitis treatment, and iron chelation. Although solid data is lacking on the outcomes of HCC treatment in patients with thalassemia, a personalized approach tailored to the individual patient's comorbidities remains necessary for treatment success. Treatment modalities for HCC include surgical resection, chemoembolization, and liver transplantation, among others. Multicenter studies are needed to better explore therapeutic targets that can improve the prognosis of these patients. Cancer 2017;123:751-58. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Many processes lead to anemia. This review covers anemias that are less commonly encountered in the United States. These anemias include hemoglobin defects like thalassemia, bone marrow failure syndromes like aplastic anemia and pure red cell aplasia, and hemolytic processes such as paroxysmal nocturnal hemoglobinuria. The pathogenesis, diagnostic workup, and treatment of these rare anemias are reviewed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Hyperhemolysis syndrome (HHS) is characterized by severe intravascular hemolysis with a decrease in the reticulocyte count, which is triggered and aggravated by transfusion and cannot be explained by standard immunohematological studies. A nationwide study was conducted in order to retrospectively identify thalassemia patients with HHS in Spain in order to assess pre-disposing mechanisms for this syndrome. For this, the expression of adhesion (CD49, CD36) and complement-related molecules (C3a, CD59) and the levels of reticulocyte apoptosis and macrophage activation were measured in 4 thalassemia patients with HHS, 14 patients without HHS, and 10 healthy subjects. Five of the six thalassemia patients had δβ-thalassemia. The patients were not alloimmunized prior to the syndrome, which was developed after the first transfusion in all but one case. Patients with δβ-thalassemia did not respond to corticoids or immunoglobulins; only splenectomy was successful. The expression of CD49 (α4β1 integrin) was far higher in patients who had experienced HHS (85.07 ± 18.46 vs. 46.28 ± 24.31; p < 0.01), and the difference remained significant after correcting by the number of molecules analyzed (Bonferroni p < 0.05). In our population, δβ-thalassemia was the most common hemoglobinopathy in patients with HHS. Furthermore, the risk to develop this syndrome may be associated with an increased expression of α4β1 integrin.

Short stature is one of the most common endocrinopathies in transfusion-dependent thalassemia (TDT). This study aimed to determine the longitudinal pattern of growth in pediatric patients with TDT and study the relationship between growth and hemoglobin level, serum ferritin level/iron overload parameters, and other clinical factors. The interval height-for-age Z-scores (HAZ) of 50 patients with TDT, of a mean age of 13.3±2.8 years, were analyzed using linear mixed model analysis. Nineteen patients (38%) had short stature with HAZ≤-2.0. The prevalence of short stature increased with age. The estimated mean HAZ decreased by 0.19 SD per year from the age of 5 years until approximately 14 years (95% confidence interval [CI], -0.22 to -0.16, P<0.001). Male sex (estimate, -0.28; 95% CI, -0.43 to -0.14; P<0.001), mean 3-year hemoglobin level ≤8 g/dL (estimate, -0.36; 95% CI, -0.53 to -0.19; P<0.001), mean 3-year ferritin level ≥1800 ng/mL (estimate, -0.44; 95% CI, -0.59 to -0.29; P<0.001), and cardiac T2* ≤20 ms (estimate, -1.05; 95% CI, -1.34 to -0.77; P<0.001) were significantly associated with short stature. In conclusion, short stature in patients with TDT is common and relates significantly with increasing age, male sex, hemoglobin level, and iron overload status.

Thalassemia syndromes are becoming more common in the United States as the population becomes more diverse. To provide appropriate care to this patient population, nurses must know that thalassemia syndromes are classified into two main types, α-thalassemia and β-thalassemia. α-Thalassemia is further delineated into four clinical patterns: silent carrier state, mild α-thalassemia, hemoglobin H disease, and hydrops fetalis. Understanding each of these complex anemias and their potential effects on a pregnant woman and her fetus will enable nurses to interpret these women's unique laboratory test results. Intervention when necessary with appropriate treatment may lead to optimal outcomes for women and newborns., (© 2016 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses.)

Context: Sickle cell disease (SCD) and thalassemia are rare but chronic blood disorders. Recent literature showed impaired quality of life (QOL) in people with these blood disorders. Assessing one of the determinants of QOL (i.e. illness perceptions) therefore, is an important next research area., Objective: We aimed to explore illness perceptions of people with a blood disorder with drawings in addition to the Brief Illness Perception Questionnaire (Brief IPQ). Drawings are a novel method to assess illness perceptions and the free-range answers drawings offer can add additional insight into how people perceive their illness., Method: We conducted a cross-sectional study including 17 participants with a blood disorder. Participants' illness perceptions were assessed by the Brief IPQ and drawings. Brief IPQ scores were compared with reference groups from the literature (i.e. people with asthma or lupus erythematosus)., Results: Participants with SCD or thalassemia perceived their blood disorder as being more chronic and reported more severe symptoms than people with either asthma or lupus erythematosus. In the drawings of these participants with a blood disorder, a greater number of blood cells drawn was negatively correlated with perceived personal control (P<0.05), indicating that a greater quantity in the drawing is associated with more negative or distressing beliefs., Conclusion: Participants with a blood disorder perceive their disease as fairly threatening compared with people with other chronic illnesses. Drawings can add additional insight into how people perceive their illness by offering free-range answers.

Regression of herniated disc fragments with subsequent improvement in clinical symptoms has been reported in the lumbar and cervical spine. Such regressions in the thoracic spine are extremely rare. We report a case of a 38-year-old patient with thalassaemia who had regression of a large calcified herniated thoracic disc causing cord compression, with subsequent herniation of a second calcified disc at a different level and discuss the possible aetiopathogenesis. This is the first such case reported in the thalassaemia population., (2016 BMJ Publishing Group Ltd.)

With repeated blood transfusions, patients with thalassemia major rapidly become loaded with iron, often surpassing hepatic metal accumulation capacity within ferritin shells and infiltrating heart and endocrine organs. That pathological scenario contrasts with the physiological one, which is characterized by an efficient maintenance of all plasma iron bound to circulating transferrin, due to a tight control of iron ingress into plasma by the hormone hepcidin. Within cells, most of the acquired iron becomes protein-associated, as once released from endocytosed transferrin, it is used within mitochondria for the synthesis of protein prosthetic groups or it is incorporated into enzyme active centers or alternatively sequestered within ferritin shells. A few cell types also express the iron extrusion transporter ferroportin, which is under the negative control of circulating hepcidin. However, that system only backs up the major cell regulated iron uptake/storage machinery that is poised to maintain a basal level of labile cellular iron for metabolic purposes without incurring potentially toxic scenarios. In thalassemia and other transfusion iron-loading conditions, once transferrin saturation exceeds about 70%, labile forms of iron enter the circulation and can gain access to various types of cells via resident transporters or channels. Within cells, they can attain levels that exceed their ability to chemically cope with labile iron, which has a propensity for generating reactive oxygen species (ROS), thereby inducing oxidative damage. This scenario occurs in the heart of hypertransfused thalassemia major patients who do not receive adequate iron-chelation therapy. Iron that accumulates in cardiomyocytes forms agglomerates that are detected by T2* MRI. The labile forms of iron infiltrate the mitochondria and damage cells by inducing noxious ROS formation, resulting in heart failure. The very rapid relief of cardiac dysfunction seen after intensive iron-chelation therapy in some patients with thalassemia major is thought to be due to the relief of the cardiac mitochondrial dysfunction caused by oxidative stress or to the removal of labile iron interference with calcium fluxes through cardiac calcium channels. In fact, improvement occurs well before there is any significant improvement in the total level of cardiac iron loading. The oral iron chelator deferiprone, because of its small size and neutral charge, demonstrably enters cells and chelates labile iron, thereby rapidly reducing ROS formation, allowing better mitochondrial activity and improved cardiac function. Deferiprone may also rapidly improve arrhythmias in patients who do not have excessive cardiac iron. It maintains the flux of iron in the direction hemosiderin to ferritin to free iron, and it allows clearance of cardiac iron in the presence of other iron chelators or when used alone. To date, the most commonly used chelator combination therapy is deferoxamine plus deferiprone, whereas other combinations are in the process of assessment. In summary, it is imperative that patients with thalassemia major have iron chelators continuously present in their circulation to prevent exposure of the heart to labile iron, reduce cardiac toxicity, and improve cardiac function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Over the past few decades, there has been a remarkable improvement in the survival of patients with thalassaemia in developed countries. Availability of safe blood transfusions, effective and accessible iron chelating medications, the introduction of new and non-invasive methods of tissue iron assessment and other advances in multidisciplinary care of thalassaemia patients have all contributed to better outcomes. This, however, may not be true for patients who are born in countries where the resources are limited. Unfortunately, transfusion-transmitted infections are still major concerns in these countries where paradoxically thalassaemia is most common. Moreover, oral iron chelators and MRI for monitoring of iron status may not be widely accessible or affordable, which may result in poor compliance and suboptimal iron chelation. All of these limitations will lead to reduced survival and increased thalassaemia-related complications and subsequently will affect the patient's quality of life. In countries with limited resources, together with improvement of clinical care, strategies to control the disease burden, such as public education, screening programmes and appropriate counselling, should be put in place. Much can be done to improve the situation by developing partnerships between developed countries and those with limited resources. Future research should also particularly focus on patient's quality of life as an important outcome of care., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Non-transfusion-dependent thalassemias (NTDT) encompass a group of hereditary chronic hemolytic anemia, which, as the name indicates, not require regular blood transfusion for survival. These include β-thalassemia intermedia, hemoglobin E/β-thalassemia, and Hemoglobin H disease (α- thalassemia intermedia). Individuals with structural variant of hemoglobin especially Hemoglobin S and Hemoglobin C associated with "α" or "β" thalassemia in heterozygous condition may also present with similar features of NTDT. NTDT patients are not immune to the development of transfusion unrelated complications in the long run. These hereditary chronic hemolytic anemias are still under-recognized in developing countries like India, where the disease burden might be high causing significant morbidity. The pathophysiologic hallmark that characterizes this group of disorders (ineffective erythropoiesis, hemolysis, chronic anemia) leads to a number of serious complications, similar to transfusion dependent thalassemia. So, timely diagnosis and institution of appropriate preventive/remedial measures as well as education of patient population can help decrease the morbidity to a significant extent. In the present review, focus will be on the pathophysiological mechanisms and available management options of NTDT from a developing country perspective like India.

Patients with non-transfusion-dependent thalassaemia (NTDT) have a genetic defect or combination of defects that affect haemoglobin synthesis, but which is not severe enough to require regular blood transfusions. The carrier frequency of NTDT is high (up to 80% in some parts of the world) but the prevalence of symptomatic patients varies with geography and is estimated to be from 1 in 100,000 to 1 in 100. NTDT has a variable presentation that may include mild to severe anaemia, enlarged spleen and/or liver, skeletal deformities, growth retardation, elevated serum ferritin and iron overload. The contributing factors to disease progression are ineffective erythropoiesis and increased haemolysis, which lead to chronic anaemia. The body's attempts to correct the anaemia result in constantly activated erythropoiesis, leading to marrow expansion and extramedullary haematopoiesis. Diagnosis of NTDT is largely clinical but can be confirmed by genetic sequencing. NTDT must be differentiated from other anaemias including sideroblastic anaemia, paroxysmal nocturnal haemoglobinuria, congenital dyserythropoietic anaemia, myelodysplastic syndromes and iron-deficiency anaemia. Management of NTDT is based on managing symptoms, and includes blood transfusions, hydroxyurea treatment, iron chelation and sometimes splenectomy. Prognosis for well managed patients is good, with most patients living a normal life. Since NTDT is mainly prevalent in sub-tropical regions, patients who present in other parts of the world, in particular the Northern hemisphere, might not been correctly recognised and it can be considered a 'rare' condition. It is particularly important to identify and diagnose patients early, thereby preventing complications.

A high tricuspid regurgitant jet velocity (TRV) signifies a risk for or established pulmonary hypertension (PH), which is a serious complication in thalassemia patients. The underlying pathophysiology in thalassemia subgroups and potential biomarkers for early detection and monitoring are not well defined, in particular as they relate to spleen removal. To better understand some of these unresolved aspects, we examined 76 thalassemia patients (35 non-transfused), 25 splenectomized non-thalassemia patients (15 with hereditary spherocytosis), and 12 healthy controls. An elevated TRV (>2.5 m/s) was found in 25/76 (33 %) of the patients, confined to non-transfused or those with a late start of transfusions, including patients with hemoglobin H-constant spring, a finding not previously described. These non or late-transfused patients (76 % splenectomized) had significantly increased platelet activation (sCD40L), high platelet count, endothelial activation (endothelin-1), and hemolysis (LDH, plasma-free Hb), while hypercoagulable and inflammatory markers were not significantly increased. The same markers were increased in the seven patients with confirmed PH on cardiac catheterization, suggesting their possible role for screening patients at risk for PH. A combination of hemolysis and absence of spleen is necessary for developing a high TRV, as neither chronic hemolysis in the non-splenectomized thalassemia patients nor splenectomy without hemolysis, in the non-thalassemia patients, resulted in an increase in TRV.

A marked decrease in β-globin production led to β-thalassemia, a hereditary anemic disease associated with bone marrow expansion, bone erosion, and osteoporosis. Herein, we aimed to investigate changes in bone mineral density (BMD) and trabecular microstructure in hemizygous β-globin knockout thalassemic (BKO) mice and to determine whether endurance running (60 min/day, 5 days/wk for 12 wk in running wheels) could effectively alleviate bone loss in BKO mice. Both male and female BKO mice (1-2 mo old) showed growth retardation as indicated by smaller body weight and femoral length than their wild-type littermates. A decrease in BMD was more severe in female than in male BKO mice. Bone histomorphometry revealed that BKO mice had decreases in trabecular bone volume, trabecular number, and trabecular thickness, presumably due to suppression of osteoblast-mediated bone formation and activation of osteoclast-mediated bone resorption, the latter of which was consistent with elevated serum levels of osteoclastogenic cytokines IL-1α and -1β. As determined by peripheral quantitative computed tomography, running increased cortical density and thickness in the femoral and tibial diaphyses of BKO mice compared with those of sedentary BKO mice. Several histomorphometric parameters suggested an enhancement of bone formation (e.g., increased mineral apposition rate) and suppression of bone resorption (e.g., decreased osteoclast surface), which led to increases in trabecular bone volume and trabecular thickness in running BKO mice. In conclusion, BKO mice exhibited pervasive osteopenia and impaired bone microstructure, whereas running exercise appeared to be an effective intervention in alleviating bone microstructural defect in β-thalassemia., (Copyright © 2014 the American Physiological Society.)

Background: Iron may damage sarcomeric proteins through oxidative stress. We explored the left ventricular (LV) torsional mechanics in patients with beta-thalassaemia major and its relationship to myocardial iron load. Using HL-1 cell and B6D2F1 mouse models, we further determined the impact of iron load on proteolysis of the giant sarcomeric protein titin., Methods and Results: In 44 thalassaemia patients aged 25 ± 7 years and 38 healthy subjects, LV torsion and twisting velocities were determined at rest using speckle tracking echocardiography. Changes in LV torsional parameters during submaximal exercise testing were further assessed in 32 patients and 17 controls. Compared with controls, patients had significantly reduced LV apical rotation, torsion, systolic twisting velocity, and diastolic untwisting velocity. T2* cardiac magnetic resonance findings correlated with resting diastolic untwisting velocity. The increments from baseline and resultant LV torsion and systolic and diastolic untwisting velocities during exercise were significantly lower in patients than controls. Significant correlations existed between LV systolic torsion and diastolic untwisting velocities in patients and controls, both at rest and during exercise. In HL-1 cells and ventricular myocardium of B6D2F1 mice overloaded with iron, the titin-stained pattern of sarcomeric structure became disrupted. Gel electrophoresis of iron-overloaded mouse myocardial tissue further showed significant decrease in the amount of titin isoforms and increase in titin degradation products., Conclusions: Resting and dynamic LV torsional mechanics is impaired in patients with beta-thalassaemia major. Cell and animal models suggest a potential role of titin degradation in iron overload-induced alteration of LV torsional mechanics.

Introduction: The objectives of this study were to demonstrate the presence of low bone mineral density (BMD) and to examine the association of known risk factors for low BMD in patients with beta thalassaemia major in Sri Lanka., Method: Thirty-eight patients were studied. Their examination and laboratory investigation findings were recorded (haematology, biochemistry, hormonal profile, COL1A1 rs1800012G>T genotype, dual energy X-ray absorptiometry (DXA) scanning)., Results: Mean age was 10.95 years (range 5-21.4). 20 (52.6%) were male. BMD was low (z score ≤-2.0) in 12 (31.5%). Regression analysis of BMD on known risk factors (age, sex, pubertal stage, ferritin level, average pre-transfusion haemoglobin, serum calcium level and COL1A1 rs1800012G>T genotype) controlling for confounding factors on each comparison, showed that only age was significantly associated with low BMD (p=0.005)., Conclusions: Approximately one-third of patients had a low BMD. Only age was significantly associated with a low BMD.

Unlabelled: Patients with transfusion-dependent thalassemia have abnormal growth, hormonal deficits, and increased bone loss. We investigated the relationship between skeletal muscle mass, fat mass, and bone mineral density in adult subjects with transfusion-dependent thalassemia based on their gonadal status. Our findings show that hypogonadism attenuates the strength of the muscle-bone relationship in males but strengthens the positive correlation of skeletal muscle mass and fat mass in female subjects., Introduction: Transfusion-dependent thalassemia is associated with a high prevalence of fractures. Multiple hormonal complications, in particular hypogonadism, can lead to changes in body composition and bone mineral density (BMD). We investigated for the first time the relationship between skeletal muscle mass (SMM), fat mass, and BMD in adult subjects with transfusion-dependent thalassemia based on their gonadal status., Methods: A retrospective cohort study of 186 adults with transfusion-dependent thalassemia was analyzed. Body composition and BMD were measured using dual energy X-ray absorptiometry. The association between skeletal muscle, fat, and BMD was investigated through uni-, multi-, and stepwise regression analyses after adjusting for multicollinearity. SMM was derived using the formula, SMM = 1.19 × ALST-1.65, where ALST is equivalent to the sum of both arm and leg lean tissue mass., Results: There were 186 subjects, males (43.5 %) and females (56.5 %), with a median age of 36.5. Hypogonadism was reported in 44.4 % of males and 44.7 % of females. SMM and BMD were positively correlated and strongest in eugonadal males (0.36 ≤ R (2) ≤ 0.59), but the association was attenuated in hypogonadal males. SMM (0.27 ≤ R (2) ≤ 0.69) and total fat mass (0.26 ≤ R (2) ≤ 0.55) were positively correlated with BMD in hypogonadal females, but the correlation was less pronounced in eugonadal females. Leg lean tissue mass and arm lean tissue mass in males and females, respectively, were most highly correlated to BMD in the stepwise regression analysis., Conclusion: Hypogonadism attenuates the strength of the muscle-bone relationship in males but strengthens the positive correlation of skeletal muscle mass and fat mass in female subjects. This study supports the notion that exercise is important for maintaining BMD and the need to optimize treatment of hypogonadism in patients with transfusion-dependent thalassemia.

The present paper reports a rare combination of Cooley's disease (thalassemia B) and the decompensated variant of chronic tonsillitis in a 14-year old girl. The patient presented with the severe form of hypochromic anemia and degenerative changes of erythrocytes. She was treated by means of bilateral tonsillectomy associated with the high risk of postoperative hemorrhage. In the preoperative period, the child received drop intravenous infusion of tranexam at a dose of 15 mg/kg body weight together with hemostatic agents. Hemorrhage during the surgical intervention was stopped by pressing tampons impregnated with tranexamic acid known to exert local and systemic hemostatic and antifibrinolytic action. The patient was discharged from the hospital for the further treatment of the primary disease.

Objective: A meta-analysis was conducted to investigate the efficacy and safety of three main iron chelators, namely, deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX) for thalassemia major (TM) patients., Methods: Randomized controlled trials comparing mono-therapy DFO, DFP, DFX and combined DFP with DFO therapy in TM patients from January 1990 to December 2012 were searched and selected. Two independent authors assessed data from extracted randomized trials for efficacy and safety in the measurements of serum ferritin (SF), live iron concentration (LIC), myocardial iron content (MIC), left ventricular ejection fraction (LVEF) and adverse events (AEs)., Results: Sixteen studies were selected. In the comparison of DFP versus DFO treatment groups, a significant difference was revealed on MIC and LVEF (P=0.01 and P=0.007, respectively) but not on SF or LIC level (P=0.65 and P=0.37, respectively). In comparing combined therapy (DFP plus DFO) versus DFO, a significant difference was shown on MIC and LVEF measurements (P<0.00001 and P=0.003, respectively), but not on SF or LIC levels (P=0.93 and P=0.62, respectively). Moreover, the combined DFP with DFO treatment had significantly higher risk than DFO treatment (RR 1.46 with 95%CI 1.04 to 2.04). When comparing DFX with DFO, a significant difference was shown on the SF level (P=0.003), and there was no difference between DFX and DFO in safety evaluation (RR 1.53 with 95%CI 0.31 to 7.49)., Conclusion: Findings indicated that the most effective and safe iron chelators remains to be proven, and further large-scale, long-term studies are needed.

A major clinical feature of patients with thalassemia is growth retardation due to anemia, therefore, the hematological parameters, weanling weight and post-weanling weight of pups obtained from vitrified warmed embryo transfers were studied for the first time in this report. Two-cell embryos of four transgenic (TG) thalassemic mouse lines (BKO, 654, E2, and E4) were produced by breeding four lines of TG thalassemic males to wild-type (WT) females (C57BL/6J) and were cryopreserved by vitrification in straws using 35% ethylene glycol. After transfer of vitrified-warmed embryos, hematological parameters, spleen index, weanling and post-weanling weight were determined in TG and WT viable pups. In the BKO and 654 mice significantly abnormal hematological parameters and spleen index were observed compared to WT, E2 and E4 mice. The weanling and post-weanling weights of BKO and 654 pups were significantly less than that of the age-matched WT pups. However, no significant differences in weanling and post-weanling weight were found between WT and E2-TG or E4-TG pups. In conclusion, the four transgenic mice lines produced from cryopreserved embryo transfer retain the phenotype of the natural breeding mice indicating that these banked embryos are appropriate for thalassemia model productions.

Pain reports have become increasingly common and problematic in thalassemia. As patients are living longer,there is a growing need to study pain and to explore its impact on patient lives. The Brief Pain Inventory(BPI) was used quarterly to assess pain and pain interference in patients with thalassemia in North America.The Medical Outcomes Study 36-Item Short Form Health Survey and the Hospital Anxiety and Depression Scale were used to assess quality of life, anxiety and depression. Of the 252 participants, 56% reported pain at least once over the course of this study, with 32% reporting severe pain (≥7/10); 16% reported pain at all four visits. Increased pain severity significantly interfered with daily life (P< 0.001; regression analysis) and participants with more sites of pain showed an increase in the amount of daily activities affected by pain(P50.001). Participants reporting more visits with pain reported a significantly higher impact on affective and physical function (P< 0.001). Physical quality of life decreased with increasing numbers of visits with pain (P< 0.001). Those who reported one or more sites of pain showed increased symptoms of both depression(P< 0.001) and anxiety (P50.003). Participants reporting at least two visits with pain had higher symptoms of anxiety (P50.002) and those with at least three visits reported higher symptoms of depression(P50.003). Pain is prevalent in thalassemia and is often a chronic condition that interferes with life. The study highlights the significance of pain in thalassemia and its impact, which should be considered in future research and treatments.

The thalassaemias are blood disorders with hereditary transmission. Their distribution is global, with particular incidence in areas affected by malaria. Their diagnosis is mainly based on haematologic and genetic analyses. The aim of this study was to differentiate between persons with the thalassaemia trait and normal subjects by inspecting characteristics of haemochromocytometric data. The paper proposes an original method that is useful in screening activity for thalassaemia classification. A complete working system with a friendly graphical user interface is presented. A unique feature of the presented work is the adoption of a two-layered classification system based on Radial basis function, which improves the performance of the system., (© 2013 Elsevier Ltd. All rights reserved.)

Thalassemia is the most common monogenic inherited disease worldwide and it affects most countries to various extents. This review summarizes the current approaches to phenotypic and genotypic diagnosis of thalassemia in clinical practice. Prevention strategies that encompass carrier screening, genetic counseling and prenatal diagnosis are discussed. The importance of public education and an awareness of a changing perception regarding this group of diseases are emphasized. It also addresses the impact of the rapidly increasing knowledge in disease severity modification by hemoglobin F (Hb F).

Unlabelled: Thalassemia bone disease is well described, but the prevalence of nephrolithiasis has not been characterized. The association between nephrolithiasis, reduced bone density, and increased fractures has been demonstrated through this retrospective study of 166 participants with transfusion-dependent thalassemia. The findings support the need for increased vigilance of kidney and bone disease in this cohort., Introduction: Previous studies have revealed that thalassemia is associated with reduced bone mineral density (BMD) and fractures. Many causes are implicated including hypogonadism, growth hormone deficiency, marrow expansion, and iron overload. Nephrolithiasis is associated with reduced BMD and increased fractures in the general population. However, the prevalence of nephrolithiasis and its association with bone density and fractures have not been characterized in thalassemia., Methods: We have addressed this question by performing a retrospective cohort study of 166 participants with transfusion-dependent thalassemia who had undergone dual-energy X-ray absorptiometry between 2009 and 2011. Logistic regression modeling was used to adjust for potential confounders., Results: We found a high prevalence of kidney stones (18.1 %) which was greater in males compared to females (28.7 vs 9.7 %, respectively). Renal stones were associated with reduced femoral neck Z-score and fractures in men after adjusting for potential confounders. These results indicate that nephrolithiasis is highly prevalent in patients with transfusion-dependent thalassemia and is significantly associated with reduced BMD and increased fractures., Conclusions: The findings from this study strongly support the need for ongoing surveillance of BMD, fractures, and nephrolithiasis in the management of transfusion-dependent thalassemia.

Despite receiving no or only occasional blood transfusions, patients with non-transfusion-dependent thalassemia (NTDT) have increased intestinal iron absorption and can accumulate iron to levels comparable with transfusion-dependent patients. This iron accumulation occurs more slowly in NTDT patients compared to transfusion-dependent thalassemia patients, and complications do not arise until later in life. It remains crucial for these patients' health to monitor and appropriately treat their iron burden. Based on recent data, including a randomized clinical trial on iron chelation in NTDT, a simple iron chelation treatment algorithm is presented to assist physicians with monitoring iron burden and initiating chelation therapy in this group of patients., (Copyright © 2013 Wiley Periodicals, Inc.)

Objective: The epsilon gamma delta beta (εγδβ)-thalassemias are rare sporadic disorders caused by deletion of the β-globin gene cluster. The main clinical feature is marked prenatal and neonatal anemia that resolves spontaneously within a few months. Reports originating mainly from Europe have so far identified 30 such deletions The aim of the present work was to describe a novel 1.78-Mb deletion, the longest ever reported, and to detail the clinical features in 12 members of an extended Bedouin family., Methods: The deletion was identified by globin gene multiplex ligation-dependent probe amplification (MLPA) of the β-globin cluster and further characterized by comparative genomic hybridization. Past and present clinical and laboratory data of ten symptomatic and two asymptomatic patients were collected., Results: A 1.78-Mb εγδβ-deletion, the largest ever described, was identified in all patients. Although other genes were included in the deletion, no other symptoms were observed. Of the ten symptomatic fetuses and neonates, three died of the disease. The remainder required packed cell transfusions during the first months of life. Pregnancy complications included intrauterine growth restriction and oligohydramnios, as well as additional neonatal complications including prematurity and persistent pulmonary hypertension of the neonate., Conclusions: We suggest that εγδβ-thalassemia be added to the list of hemoglobinopathies that can cause neonatal anemia and that MLPA of the β-globin cluster be used to confirm its diagnosis. Careful surveillance during pregnancy is important to reduce neonatal mortality and morbidity, especially given the dramatic improvement that occurs later., (© 2012 John Wiley & Sons A/S.)

It is common knowledge that thalassemic patients are under significant oxidative stress. Chronic hemolysis, frequent blood transfusion, and increased intestinal absorption of iron are the main factors that result in iron overload with its subsequent pathophysiologic complications. Iron overload frequently associates with the generation of redox-reactive labile iron, which in turn promotes the production of other reactive oxygen species (ROS). If not neutralized, uncontrolled production of ROS often leads to damage of various intra- and extracellular components such as DNA, proteins, lipids, and small antioxidant molecules among others. A number of endogenous and exogenous defense mechanisms can neutralize and counteract the damaging effects of labile iron and the reactive substances associated with it. Endogenous antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, and ferroxidase, may directly or sequentially terminate the activities of ROS. Nonenzymatic endogenous defense mechanisms include metal binding proteins (ceruloplasmin, haptoglobin, albumin, and others) and endogenously produced free radical scavengers (glutathione (GSH), ubiquinols, and uric acid). Exogenous agents that are known to function as antioxidants (vitamins C and E, selenium, and zinc) are mostly diet-derived. In this review, we explore recent findings related to various antioxidative mechanisms operative in thalassemic patients with special emphasis on protein antioxidants.