Thalassemia Research Articles

Outcomes of Hematopoietic Stem Cell Transplantation in Patients With Thalassemia Major: How Do Anti-HLA Antibodies Impact?: The Impact of Anti-HLA Antibodies on Transplantation Outcomes in Thalassemia Major.

To investigate the effects of anti-human Leucocyte Antigen (HLA) antibody positivity on early hematopoietic stem cell transplantation (HSCT) results in patients with thalassemia major (TM). One hundred and twenty-four HLA-matched HSCTs were performed in patients with TM between 2015 and 2022. Ninety-one patients were screened for anti-HLA antibodies by testing panel reactive antigens (PRA). Demographic and transplantation characteristics of patients were recorded. The presence of PRA was tested with the Antibody Testing Assay (Luminex LIFECODES HLA Antibody Identification System). The number of PRA-positive patients was 54. There was no relationship between acute graft versus host disease (GVHD), chronic GVHD, grade of GVHD, and viral reactivation of the patients. However, platelet engraftment took around 3 days longer in the PRA-positive group (p = 0.05). The median number of erythrocyte transfusions was significantly higher in PRA-positive patients in the post-transplant period (p = 0.003), as was the median number of platelet transfusions (p = 0.003). Treosulfan conditioning increased the stable mixed chimerism (MC) rate by 3.8-fold (p = 0.011). In contrast, reduced rates of MC were found in patients who received matched unrelated donor cells or peripherally derived stem cells (p = 0.011 and p = 0.039, respectively) in the posttransplantation period in TM patients. PRA-positivity did not affect MC (p = 0.478). However, 80% of patients who had primary graft failure (n = 5; p = 0.59) and 75% of patients who died (n = 4) were PRA positive (p = 0.64), but these results were statistically insignificant due to the low number of patients. Anti-HLA antibodies primarily delayed platelet engraftment in TM patients and increased the erythrocyte and thrombocyte transfusion requirements. Although PRA positivity was more common in patients with primary graft failure or who died, there was no statistically significant impact of PRA positivity on chimerism, acute or chronic GVHD, viral activation, or mortality rates.

Shear Wave Elastography in the Assessment of Liver Iron Overload in Children With Beta Thalassemia Major

Abstract Shear wave elastography (SWE) is an ultrasound method that effectively demonstrates liver fibrosis. This prospective study aimed to compare magnetic resonance imaging T2* and SWE results of the liver in children with thalassemia major (TM). Patients with TM who had regular follow-ups were included. SWE was performed first, followed by MRI T2*. In addition, a healthy control group of the same age group, known to have no liver disease, was recruited. For these participants, only SWE was performed, and their results were compared with the SWE parameters of the TM patients. The study included 38 patients and 25 individuals who made up the control group. The groups with mild, moderate, and severe iron overload according to MRI T2* were compared in terms of SWE with parameters, and no statistically significant difference was found. However, when comparing the SWE parameters between the control group and patients, the median, average, and standard values were found to be statistically significantly higher in the patient group (P < 0.001, P < 0.001, P = 0.026). When comparing MRI T2* results, the median, average, and standard values were found to be statistically significantly higher in the patients with normal and mild iron overload (P < 0.001, P < 0.001, P = 0.033). SWE is an effective, more accessible, and easy-to-apply method for demonstrating early changes in the liver in pediatric patients with TM. This study serves as a guide for more comprehensive studies that may investigate the effect of SWE in this patient group.

Demographics, clinical profiles and healthcare utilization of patients with beta thalassemia major: A single centered study

Thalassemia is an inherited autosomal recessive blood disorder that occurs due to abnormal form of hemoglobin in the blood. It is an autosomal recessive condition caused by decreased formation of alpha or beta chains of hemoglobin. Pakistan continues to suffer from a high thalassemia burden with statistics rising every year. With around 10 million carriers across the country, it is reported that each year, around 5000 children are diagnosed with thalassemia. The aim of this study is to bridge the gap between the problems faced by thalassemic patients in Pakistan and the facilities not available to them as compared to the developed countries. Method: A cross- sectional study was conducted with the duration of this study was 12 months. The data was collected from six tertiary care hospitals and eight Thalassemia centers, with the selection based on the accessibility of data. The inclusion criteria for the study was: a clinical diagnosis of Beta Thalassemia Major and age group between 1-18 years, irrespective of gender. The exclusion criteria included patients who were over 18 years of age and had comorbidities or complications other than Beta Thalassemia Major, as well as those who did not give consent. A questionnaire was circulated to record the data. It had two parts. The first part included demographics and the second part had close-ended questions related to the treatment of Thalassemia. Results: The total number of participants were 255 in which 122 (47.8%) were males and 133 (52.2%) were females. A positive correlation was observed between age and hospital visits, showing that an increase in age was associated with an increase in hospital visits among Beta Thalassemia patients (p value< 0.05) (CL:95%). Positive correlation was observed between the age of patients and the number of Liver Function tests. (p-value<0.05) (CL: 95%), viral profile done per year and age among B-thalassemia major patients. (p-value< 0.05) (CL:95%) and between age and cbc conducted per month (p-value < 0.05). Another positive correlation was observed between weight and frequency of blood transfusions in B-thalassemia major patients (p-value< 0.05) (CL:95%) and weight and liver function tests conducted per year among thalassemia patients. (p-value< 0.05) (CL:95%). Conclusion: This study aims to highlight the problems faced by thalassemia patients in Pakistan and the facilities not available to them compared to developed countries. A cross-sectional study was conducted for 12 months, collecting data from six tertiary care hospitals and eight Thalassemia centers. A questionnaire was used to record data on demographics and close-ended questions related to thalassemia treatment. Positive correlations were observed between age and hospital visits, liver function tests, viral profiles, and CBCs conducted. Weight was positively correlated with the frequency of blood transfusions and liver function tests conducted per year.

Prevalence of beta thalassemia, heart failure and valvular abnormalities in children at tertiary care hospital

Objective: to evaluate, stratified by age and educational attainment, the distribution of pediatric beta-thalassemia, heart failure, and valve anomalies in order to find any appreciable variations in the prevalence rates. Methods: A study using a cross-sectional design was carried out on 115 youngsters. There were two age categories of participants: 43.5 percent were between the ages of 2 and 9 and 56.5% were those over 10. Children's educational status was divided into two categories: those who attend school (8.7%) and those who do not (91.3%). Medical records were used to gather information on the prevalence of valvular anomalies, heart failure, and beta-thalassemia. P-values and other statistical analyses were used to assess the significance of variations in prevalence rates among different age and educational groups. Result: 17.4% of participants in the research had beta-thalassemia; there were no significant variations in this condition between age groups (p=0.101) or educational attainment (p=0.820). Children who attended school had a higher prevalence of heart failure (69.6%) than children who did not attend school (34.4%), however this difference was not statistically significant (p=0.625). Children who did not attend school (38.2%) had considerably higher rates of valve anomalies than children who attended school (8.6%); a p-value of less than 0.001 indicated a highly significant difference. Conclusion: The study finds no significant changes in the prevalence of beta-thalassemia or heart failure across age and educational status, but it does show a substantial difference in the prevalence of valvular anomalies between children who attend school and those who do not. These results highlight how crucial it is to address socio-economic and educational gaps in order to improve health outcomes for communities that are already at risk.

Beta Thalassemia in Children: Established Approaches, Old Issues, New Non-Curative Therapies, and Perspectives on Healing.

Despite a decrease in prevalence and incidence rates, beta thalassemia continues to represent a significant public health challenge worldwide. In high-resource settings, children with thalassemia have an open prognosis, with a high chance of reaching adulthood and old age with a good quality of life. This is achievable if transfusion therapy is properly managed, effectively mitigating ineffective erythropoiesis and its associated complications while also minimizing excessive iron accumulation. Adequate iron chelation is essential to maintain reactive forms of iron within the normal range throughout life, thus preventing organ damage caused by hemosiderosis, which inevitably results from a regular transfusion regimen. New therapies, both curative, such as gene therapy, and non-curative, such as modulators of erythropoiesis, are becoming available for patients with transfusion-dependent beta thalassemia. Two curative approaches based on gene therapy have been investigated in both adults and children with thalassemia. The first approach uses a lentivirus to correct the genetic defect, delivering a functional gene copy to the patient's cells. The second approach employs CRISPR/Cas9 gene editing to directly modify the defective gene at the molecular level. No non-curative therapies have received approval for pediatric use. Among adults, the only available drug is luspatercept, which is currently undergoing clinical trials in pediatric populations. However, in many countries around the world, the new therapeutic options remain a mirage, and even transfusion therapy itself is not guaranteed for most patients, while the choice of iron chelation therapy depends on drug availability and affordability.

Dengue fever with atypical manifestations in a child with beta thalassemia major post splenectomy

Dengue is one of the significant public health concerns in endemic countries. With plasma leakage as the primary pathophysiology in the process of severe dengue infection with hemoconcentration and thrombocytopenia being the significant laboratory diagnostic features in children, the presentation in children with underlying hemato-oncological conditions is atypical and often, anemia is found in these children, instead of hemoconcentration. We describe a young boy with beta thalassemia major who underwent splenectomy for hypersplenism 5-months ago with dengue illness, characterized by features mimicking a severe post splenectomy opportunistic infection with fever, loose stools and abdomen tenderness. Leucopenia, thrombocytopenia, minimal pleural effusion, ascites and gall bladder wall edema prompted us to think of dengue and was found to be positive. Child improved with appropriate supportive care measures. Pediatricians should be aware of the differences in the presentation of tropical infections in children with hemato-oncological disorders. Tropical infections should be kept in mind even in children with underlying hemato-oncological conditions, to ensure diagnosis and appropriate management.

Chelation: The Double-Edged Sword. A Case Report of Invasive, Disseminated Mucor Mycosis in a Beta Thalassemia Major During Transplant

Chelation: The Double-Edged Sword. A Case Report of Invasive, Disseminated Mucor Mycosis in a Beta Thalassemia Major During Transplant

Genetic Modifiers of Hemoglobin Expression from a Clinical Perspective in Hemoglobinopathy Patients with Beta Thalassemia and Sickle Cell Disease.

Hemoglobinopathies, namely β-thalassemia and sickle cell disease (SCD), are hereditary diseases, characterized by molecular genetic aberrations in the beta chains of hemoglobin. These defects affect the normal production of hemoglobin with severe anemia due to less or no amount of beta globins in patients with β-thalassemia (quantitative disorder), while SCD is a serious disease in which a mutated form of hemoglobin distorts the red blood cells into a crescent shape at low oxygen levels (qualitative disorder). Despite the revolutionary progress in recent years with the approval of gene therapy and gene editing for specific patients, there is an unmet need for highlighting the mechanisms influencing hemoglobin production and for the development of novel drugs and targeted therapies. The identification of the transcription factors and other genetic modifiers of hemoglobin expression is of utmost importance for discovering novel therapeutic approaches for patients with hemoglobinopathies. The aim of this review is to describe these complex molecular mechanisms and pathways affecting hemoglobin expression and to highlight the relevant investigational approaches or pharmaceutical interventions focusing on restoring the hemoglobin normal function by linking the molecular background of the disease with the clinical perspective. All the associated drugs increasing the hemoglobin expression in patients with hemoglobinopathies, along with gene therapy and gene editing, are also discussed.

Beta thalassemia minor: a potential risk factor for osteopenia and osteoporosis

A 74-year-old male patient with beta thalassemia minor presented in 2022 for a follow-up of osteoporosis diagnosed prior to 2004. At the time of presentation, his medical history included: radiation exposure to his head and neck, goiter, prostate cancer status post resection in 2019 without a history of anti-androgen therapy, and atrial fibrillation, for which he had been prescribed apixaban since 2021. Treatment with risedronate occurred from approximately 2004 to about 2011, with improvement in bone density to osteopenia. He had also taken vitamin D and calcium supplementation and engaged in regular weight-bearing exercise. The patient had no other known risk factors for decreased bone mineral density preceding the onset of his osteoporosis, and a previous workup for secondary causes of his osteoporosis etiology proved negative. We propose that beta thalassemia minor is potentially a risk factor for osteopenia and osteoporosis, and that bisphosphonates can be considered for management when therapeutic intervention is indicated. Even in the absence of other known risk factors, clinicians should consider periodically screening beta thalassemia minor patients with DXA for evaluation of bone health.

The Relationship Between Ghrelin and Iron Metabolism In Beta Thalassemia Major Patients

IntroductionStudies in beta thalassemia major (β-TM) patients have shown that the responses of HIF2α, hepcidin and ferroportin molecules to high iron levels are impaired. In recent years, studies conducted in patients with iron deficiency anemia have investigated the relationship between ghrelin hormone and iron metabolism. In this study, we aimed to contribute to the etiopathogenesis of this disease by examining the changes in ghrelin hormone levels in patients with β-TM.Material and methodsFifty-two β-TM and 23 controls were included in our study. Blood counts, routine biochemical parameters, HIF2α, hepcidin and ghrelin levels were studied in blood samples taken from the volunteers.ResultsErythrocyte indexes, serum bilirubin, iron, unsaturated iron binding capacity, total iron binding capacity and ferritin levels showed significant differences between two groups (p<0.05) . There was no significant difference between two groups for serum HIF2α and hepcidin levels. When two groups were compared, ghrelin levels were found to be significantly higher in patients (p<0.05). When the correlation between parameters was examined in all subjects, a weak positive correlation was found between ghrelin and HIF2α (r=0.263) (p<0.05) and a significant positive correlation was found between ghrelin and ferritin (r=0.417) (p<0.05).ConclusionsOur study showed that there is a positive correlation between ghrelin and ferritin levels. Elevated ghrelin levels in patients with β-TM may have an important role in regulating impaired iron metabolism. Molecular level studies are needed to determine synthesis pathways.

Gene Therapy: A Revolutionary Step in Treating Thalassemia.

Beta thalassemia is an inherited blood disorder that results in inefficient erythropoiesis due to genetic mutation that leads to the reduction or absence of the hemoglobin beta-globulin protein. Approximately 8.5% of UAE residents suffer from β-thalassemia, a significant health and financial problem. The treatment options available for β-Thalassemia major are limited and associated with a wide range of complications. β-thalassemia gene therapy is emerging as a potential novel treatment option that eliminates the complications caused by the current long-term treatment modalities and the associated economic burden. This paper reviews the scientific literature related to emerging gene therapy for β-Thalassemia by analyzing all the articles published from January 2010 to December 2023 in the English language on Databases like PubMed, Scopus, ProQuest, and CINAHL. The use of gene therapy has demonstrated promising outcomes for a permanent cure of β-Thalassemia. To conclude, gene therapy is an innovative solution. It demonstrates a promising future, but does come with its own setbacks and is something that must be tackled in order to revolutionize it in the medical world. FDA-approved ZYNTEGLO is a potentially one-time curative treatment for β-Thalassemia. Although cutting-edge, its use is limited because of the high cost-a price of USD 2.8 million per patient.

Immunological Changes and Complement Proteins in Major Thalassemia Patients Proteins Post-Splenectomy

Background: Thalassemia is one of the most prevalent genetic disorders worldwide, with infections being a leading cause of mortality due to compromised immune function. Specific Background: Prior studies suggest that major thalassemia patients are highly susceptible to microbial infections, possibly due to altered immunological profiles, particularly immunoglobulin (IgG, IgM) and complement (C3, C4) levels. Knowledge Gap: However, the specific immunological changes pre- and post-splenectomy in these patients remain underexplored. Aims: This study aims to assess the levels of immunoglobulins (IgG and IgM) and complement proteins (C3 and C4) in major thalassemia patients both before and after splenectomy compared to healthy controls. Results: Our analysis of 50 thalassemia patients (34 males, 16 females) and 30 healthy individuals revealed that thalassemia patients exhibited significantly lower levels of C3 and C4 (88.52±24.49, 21.20±6.66) compared to healthy controls (123.50±19.04, 32.87±9.77). IgG and IgM were elevated in patients (1288.12±467.87, 153.46±51.29) compared to controls (1129.93±295.96, 148.67±50.17). Post-splenectomy, patients showed a significant decline in IgG (1001.56±154.14) and IgM (110.08±25.83) levels, along with further decreases in C3 (83.28±24.13) and C4 (17.48±4.86). Novelty: This study provides novel evidence of the immunological shifts in thalassemia patients post-splenectomy, demonstrating significant reductions in both immunoglobulins and complement proteins, thereby elevating the risk of infection. Implications: These findings highlight the spleen's crucial role in maintaining immune competence and suggest that splenectomy in thalassemia patients requires careful post-operative immune monitoring to mitigate infection risks. Highlights: Splenectomy lowers IgG, IgM, C3, and C4 levels in thalassemia patients. Post-splenectomy patients face higher infection risk due to immune weakening. Highlights spleen's crucial role in immune defense for thalassemia patients. Keywords: Thalassemia, Splenectomy, Immunoglobulins, Complement Proteins, Immune Competence

The Utility of Micro-R/Hypo-He Ratio Cut-off for Distinguishing Iron Deficiency Anemia and Minor Thalassemia

Thalassemia is a genetic disease with impaired synthesis of the globin chain that causes anemia. Thalassemia and Iron Deficiency Anemia (IDA) are both microcytic hypochromic anemia but have different proportions of hypochromic and microcytic erythrocytes due to differences in disease mechanisms. Research parameters of the hematology analyzer: %Micro-R, %Hypo-He, and MH ratio can be used as early screening for thalassemia and IDA. This study aimed to evaluate the cut-off of %Micro-R, %Hypo-He, and MH ratio to differentiate thalassemia from IDA. A cross-sectional study was carried out on 217 subjects. Subjects were divided into two groups, thalassemia and IDA based on hemoglobin electrophoresis, hematology examination, and Mentzer index. Differences and cut-off values of %Micro-R, %Hypo-He, and MH ratio between the two groups were analyzed. The number of collected data was 134, consisting of 89 thalassemia patients and 45 IDA patients. Thalassemia patients had a median %Micro-R value of 51.2 (4.3-79.0), %Hypo-He value of 7.2 (0.2-50.2), and MH ratio of 7.17 (1.10-64.50), higher than IDA patients (p=0.000; p=0.176; p=0.000). The optimal cut-off value for %Micro-R in discriminating thalassemia trait from IDA was >12.7, with the area under the ROC curve (AUC) of 0.945, sensitivity of 92.1%, and specificity of 82.2%. The cut-off value for MH ratio > 3.27 with AUC 0.833, sensitivity of 85.4%, and specificity 77.8% showed lower performance of cut-off value compared to %Micro-R. The algorithm using %Micro-R and MH ratio was proposed for thalassemia trait screening. High %Micro-R and MH are suggestive of thalassemia trait than of IDA.

Comparison of Characteristics and Outcomes of Hepatitis B and Hepatitis C Patients in the Fars Hepatitis Registry

Background: Hepatitis, which refers to liver inflammation, can have various causes, with viral hepatitis being the most common. Objectives: This study aimed to compare demographic and laboratory variables, risk factors, and outcomes between Hepatitis B (HBV) and Hepatitis C (HCV) patients in the Fars hepatitis registry. Methods: In this cross-sectional study, a total of 6,690 eligible patients, consisting of 3,840 (57.4%) with HBV and 2,820 (42.6%) with HCV, were assessed from the database covering the period from 1995 to 2023. Comparisons between HBV and HCV were made using the Chi-square test, Fisher's exact test, or independent sample t-test with SPSS software. Results: The average age of the patients was 52.56 years (standard deviation: 13.24). Significant differences were found between HBV and HCV patients regarding sex, marital status, education level, family history of HBV and HCV, smoking status, drug use, and body mass index (P < 0.001 for all). Hepatitis B patients had a higher prevalence of dental procedures (P < 0.001) and uncertain sexual contacts (P = 0.009), while blood transfusion, intravenous drug use, major thalassemia (P < 0.001 for all), tattoos (P = 0.004), and hemodialysis (P = 0.001) were more common in HCV patients. Hepatitis C patients showed higher levels of liver enzymes (P < 0.001) and total bilirubin (P = 0.002) but lower levels of albumin (P < 0.001) and prothrombin time (P = 0.034) compared to HBV patients. Cirrhosis was also more common in HCV patients (P < 0.001). Conclusions: Our findings highlight different patterns of demographic factors, risk factors, and outcomes between HBV and HCV patients, which could influence their prevention and management strategies.

Plasma sphingomyelin levels were negatively correlated with ferritin levels in splenectomized thalassemia patients

Abstract Beta thalassemia results from decreased production of beta chains due to either mutations or deletions in the beta-globin gene, leading to impaired production of hemoglobin A. Thalassemia patients take frequent blood transfusions to compensate for hemolytic anemia and iron overload. Iron overload is monitored by serum ferritin levels in these patients. Extra-medullary hematopoiesis in beta thalassemia major leads to hypersplenism which often necessitates splenectomy to increase red cell life span and decrease transfusion need. Sphingomyelin is the second most abundant phospholipid in human plasma after phosphatidylcholine. In contrast to the well-defined roles of sphingolipids in cell membranes, their possible physiological role in lipoprotein metabolism has recently gained attention. Increased circulating levels of sphingomyelins and ceramides were observed in obesity, diabetes, and cardiovascular diseases. Although lipid abnormalities such as hypocholesterolemia and relatively increased triglycerides were reported in beta-thalassemia patients, there is no study investigating sphingolipid levels in thalassemia. Therefore, we investigate certain long chain and very long chain sphingomyelins and ceramides in beta-thalassemia patients who are under routine follow-up in our hospital. Thalassemia major patients who applied to the hospital for regular blood transfusion and gave consent were included in the study. Blood samples were obtained before transfusion. Plasma sphingomyelin (C16, C18 and C24) and ceramide (C16, C18, C20, C22, C24) species were measured by triple quadruple LC-ESI-MS/MS (Shimadzu, Japan). D-erythrosphingosine-D9 (Matreya) was used as an internal standard, all other lipid standards were from Avanti. Body iron stores of the patients were monitored by serum ferritin levels. A total of thirty patients were included in the study. All patients typically received regular erythrocyte suspension transfusions every three weeks and continuous oral iron chelation therapy. Twenty of the patients had a previous splenectomy. The mean age was 34.5 ±8.1 years in the splenectomy group and 32.8 ±8 years in the group without splenectomy. Mean ferritin levels were not different between the groups, being 1073.2±563.5 µg/L in splenectomy and 1709 ±1660.4 µg/L in non-splenectomy groups. All measured sphingolipid levels were similar between splenectomy and non-splenectomy groups. When correlation analysis was performed between measured sphingolipid and ferritin levels, significant negative correlations were found between sphingomyelin C16 (r= -0.591 p<0.006) and C18 (r= -0.594 p<0.006) with ferritin levels in the splenectomy group. However, this negative correlation was absent in the non-splenectomy group. In conclusion, we found that iron overload is associated with lower plasma sphingomyelin levels in splenectomized thalassemia patients. We have been working on the lipidomic analysis of the plasma and erythrocytes of thalassemia patients and other hemolytic anemias. The results may further help to get a better picture of lipid metabolism in thalassemia.

Reemergence of Hemoglobin Yukuhashi

Abstract The abnormal hemoglobin, Hb Yukuhashi, identified in Japan in 1963, exhibits slower migration compared to Hb A and is associated with target cells on peripheral smear. A similar hemoglobin, Hb Dhofar, is found in an Omani tribesman and is defined as a substitution of arginine for proline at the 58th amino acid position of the beta-globin chain. Despite both Yukuhashi and Dhofar seemingly arising from the same exonic point mutation, variations in expression were clarified through beta-globin gene amplification. Hb Dhofar, unlike Yukuhashi, was linked to a splice-site mutation at codon 29, explaining its reduced expression. Despite these hemoglobins’ structural alterations, their functional properties on a molecular level, including oxygen affinity and heme-heme interaction, remained largely unaffected. While mutations at codon 58 have been observed alongside other mutations in Hb Dhofar and Hb C-Ziguinchor, this case represents the first sequencing and report of a beta-globin gene mutation solely at codon 58, as only Yukuhashi’s protein coding region had been sequenced, not the whole gene. “Hemoglobin D” was detected on newborn screening of a male child with no other significant medical history or physical abnormalities. Capillary Electrophoresis and Cation-Exchange HPLC showed abnormal hemoglobin fractions, with 20.1% in the S Zone and 25.7% in the D-window, respectively. This led to a presumptive diagnosis of Hemoglobin Dhofar trait; however, discrepancies in hematologic parameters and relative hemoglobin levels were noted. Genetic testing of the Beta Globin gene confirmed a C to G substitution at codon 58 but lacked the characteristic codon 29 mutations associated with Hemoglobin Dhofar. The patient, was discovered to possess a mutation at codon 58 on the beta globin gene, a mutation not previously reported in isolation. In contrast to previous studies on Hb Dhofar, where variant Hb levels were lower and accompanied by abnormal RBC indices indicative of beta thalassemia trait, this case exhibited higher variant Hb levels with normal RBC indices, suggestive of a typical beta globin variant. The mutation at codon 58 did not significantly alter intermolecular interactions of the globin which may mean the variant is clinically asymptomatic in nature. Continued follow-up is necessary to confirm this suspicion, although initial assessments at 3 and 6 months of age showed normal RBC parameters. This case represents the first instance of an isolated mutation at codon 58 of the beta globin gene, emphasizing the need to consider this mutation in interpreting hemoglobinopathy screening results.

Critical appraisal of the utility of 13 discriminant formulas for distinguishing beta thalassemia trait from iron deficiency in patients with microcytic anemia and the introduction of a new formula in a USA population

Abstract Iron deficiency anemia (IDA) and beta thalassemia trait (ß-TT) are two frequent causes of microcytic anemia that often pose a diagnostic dilemma with implications for management. Many discriminant formulas have been proposed for distinguishing these two conditions. However, there is a need for independent verifications of these formulas to determine their applicability to other populations, particularly more diverse populations, as seen in the United States. To date, no study has been performed in the United States to evaluate the utility of these formulas in distinguishing both conditions. The study objective was to evaluate the utility and predictive values of 13 discriminant indices and formulas for distinguishing ß-TT from IDA in a US population. We investigated 13 formulas comprising only hematologic parameters available on all analyzers. The investigational population consisted of 238 patients with microcytic anemia; 165 with a hemoglobin electrophoresis diagnosis of ß-TT and 73 diagnosed with IDA by clinician review or iron studies. The study population comprised 55% black or African American, 35% White, 5% Asian, 1.2% Native American, and 2.5% unidentified. Receiver operating characteristic curves were employed to evaluate the diagnostic performances of the formulas. All investigated formulas had poor sensitivities but high specificities. The three best-performing indices or formulas from those previously proposed for distinguishing ß-TT from IDA were the RBC (sensitivity 62.2%, specificity 87.1%), Green and King (MCV2×RDW/100 hemoglobin, Hb) with a sensitivity of 65.4% and specificity of 82.6%, and Wongprachum et al. (MCV×RDW/RBC) – 10 Hb) with a sensitivity of 63.6% and specificity of 82.6%. Areas under the curve (AUCs) were 0.68 for the RBC and, 0.67 for both Green and King and Wongprachum formulas. The Youden indices were 0.49, 0.48, and 0.46, respectively. The Mentzer index had a sensitivity of 63.4%, specificity of 81.7% and Youden index of 0.45. We introduced a new formula comprising the sum of three of the most readily obtained red cell parameters (RBC + Hb + MCV). It had a Youden index of 0.95, sensitivity of 96.8, specificity of 98.0, and AUC of 0.97, significantly outperforming other formulas in our study population (p=0.00). This is the first study in the USA evaluating the utility of multiple indices for distinguishing ß-TT from iron deficiency anemia. The best performing formulas in other studies did not perform well in our population. This necessitated an introduction of a new formula that demonstrates excellent potential to address the unique diversity of the US population.

Early Detection of Myocardial Involvement in Thalassemia Intermedia Patients: Multiparametric Mapping by Magnetic Resonance Imaging.

No study has assessed myocardial T1 and T2 values in patients with beta-thalassemia intermedia (β-TI). To assess the prevalence of myocardial involvement in β-TI patients by T2* relaxometry and native T1 and T2 mapping and to determine the correlation of myocardial relaxation times with demographic and clinical parameters. Prospective matched-cohort study. 42 β-TI patients (27 females, 39.65 ± 12.32 years), enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 42 age- and sex-matched healthy volunteers (27 females, 40.01 ± 11.36 years) and thalassemia major (TM) patients (27 females, 39.27 ± 11.57 years). 1.5 T/multi-echo gradient echo, modified Look-Locker inversion recovery, multi-echo fast-spin-echo, cine balanced steady-state-free precession, and late gadolinium enhancement (LGE) sequences. Hepatic, pancreatic, and left ventricular (LV) T2* values, LV native T1 and T2 values, biventricular ejection fractions and volumes, and presence and extent of replacement myocardial fibrosis. Comparisons between two groups were performed with two-sample t tests, Wilcoxon's signed rank tests, or χ2 testing. Correlation analysis was performed using Pearson's or Spearman's test. P < 0.05 was considered statistically significant. β-TI patients had significantly higher LV T2 values than healthy subjects (56.84 ± 4.03 vs. 52.46 ± 2.50 msec, P < 0.0001) and significantly higher LV T1 values than TM patients (1018.32 ± 48.94 vs. 966.66 ± 66.47 msec, P < 0.0001). In β-TI, female gender was associated with significantly increased LV T1 (P = 0.041) and T2 values (P < 0.0001), while splenectomy and presence of regular transfusions were associated with significantly lower LV T1 values (P = 0.014 and P = 0.001, respectively). In β-TI patients, all LV relaxation times were significantly correlated with each other (T2*-T1: P = 0.003; T2*-T2: P = 0.003; T1-T2: P < 0.0001). Two patients with a reduced LV T2* also had a reduced LV T1, while only one had a reduced LV T2. Three patients had a reduced LV T1 but a normal LV T2*; 66.7% of the patients had an increased LV T2. All LV relaxation times were significantly correlated with pancreas T2* values (T2*: P = 0.033; T1: P < 0.0001; T2: P = 0.014). No LV relaxation time was associated (P > 0.05) with hepatic iron concentration, biventricular function parameters, or LGE presence. The combined use of all three myocardial relaxation times has potential to improve sensitivity in the detection of early/subclinical myocardial involvement in β-Tl patients. 2 TECHNICAL EFFICACY: Stage 2.

Speckle-tracking echocardiography as screening tool for myocardial fibrosis and Iron overload in transfusion-dependent beta-thalassemia

BackgroundTransfusion-dependent beta thalassemia (TDT) is a genetic disorder characterized by low haemoglobin levels, often leading to myocardial iron overload (MIO) and myocardial fibrosis (MF). Cardiac Magnetic Resonance (CMR) represents the gold standard for MIO and MF assessment, although its limited availability and high costs pose challenges. Left Ventricular Global Longitudinal Strain (LV GLS) measured by Speckle Tracking Echocardiography (STE) could offer a valuable alternative. MethodsA monocentric diagnostic accuracy study was conducted to compare the performance of LV GLS with CMR using T2* for evaluating MIO and late gadolinium enhancement (LGE) for detecting MF. Between January 2022 and January 2023, 44 consecutive patients with TDT were enrolled. For each participant was performed LV GLS with STE, including CMR with T2* technique and LGE sequences. ResultsCMR identified MIO in 8 patients (18 %) and MF in 5 (11 %). LV GLS STE was normal in patients without MIO (−20.6 ± 3.1 %) or MF (−20.6 ± 2.8 %), significantly differing from those with MIO (−18.2 ± 2.1 %, p = 0.043) and MF (−16.4 ± 1.7 %, p = 0.002). ROC analysis indicated an optimal LV GLS STE cutoff of −19.8 % for MIO (AUC = 0.76, 95 % CI: 0.59–0.93, p = 0.054) with an overall diagnostic accuracy of 64 % and an optimal cutoff of −18.3 % for MF (AUC = 0.93, 95 % CI: 0.85–1.00, p = 0.009) with an accuracy of 86 %. ConclusionsThe findings of this pilot study indicate that LV GLS with STE, may be a cost-effective screening tool for the early detection of MIO and MF in TDT patients.

Hepcidin/Ferritin Ratio in Patients with Beta Thalassemia. A Single-Center Experience

Abstract Background Hepcidin, a main regulator of iron hemostasis, can potentially be used as a marker for iron overload in patients with thalassemia; hence can be used to evaluate the efficacy of chelation therapy. Aim We hypothesize that serum hepcidin and hepcidin/ferritin ratio might be better markers for iron load and iron load distribution characteristics in different thalassemia syndromes. Subsequently we aimed to estimate serum hepcidin, ferritin, and hepcidin: ferritin ratio in patients with beta-thalassemia syndromes. Patients and Methods A prospective study was conducted on 42 patients with beta- thalassemia major and 40 patients with beta-thalassemia intermedia compared to 20 age and gender-matched healthy controls. For all patients, serum ferritin, and hepcidin were measured by ELISA assay then the hepcidin /ferritin ratio was calculated. Results All patients (100%) with beta-thalassemia major and 26 patients (65%) with beta- thalassemia intermedia were transfusion dependent. Sixty-one patients (74%) were on regular iron chelators, 49 of them (80%) were on desafirox with a median dose of 20 mg/kg, 40 patients (100%) of beta thalassemia intermedia were on hydroxyurea. Patients with thalassemia syndromes had higher mean serum ferritin (3000 ng/ml), median serum hepcidin of 162 ng/ml, lower mean hemoglobin (8.2 gm/dl) and hepcidin: ferritin ratio of 0.15 compared to control (P &amp;lt; 0.001) who had median serum ferritin (73 ng/ml), median serum hepcidin of (62.8 ng/ml), mean hemoglobin (11.03 gm/dl) and hepcidin: ferritin ratio of 0.71. Beta thalassemia major patients had a higher median serum hepcidin level of 256 ng/ml, and a lower hepcidin /ferritin ratio of 0.18 compared to patients with beta-thalassemia intermedia (p &amp;lt; 0.001, p &amp;lt; 0.001 respectively). Hepcidin level was negatively correlated with the age of onset, frequency of transfusion. Conclusion Serum hepcidin level was elevated in beta-thalassemia children with more evident elevation in beta-thalassemia major patients. Also hepcidin: ferritin ratio was elevated in normal controls and low in thalassemia intermedia differentiating both entities. The younger the age of onset of Thalassemia, the higher the need for transfusion, and the dose of desafirox, the higher was the hepcidin level.