bims-conane Biomed News
on Congenital anemias
Issue of 2024–12–15
ten papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. 10-Year Risk of Gallstones in Congenital Red Blood Cell Disorder Patients: A Nationwide Cohort Study.
  2. Luspatercept: a treatment for ineffective erythropoiesis in thalassemia.
  3. Standardization of hemoglobin A2 and hemoglobin F: Achievements and perspectives.
  4. Evaluating the Role of Red Blood Cell Lifespan in Transfusion-Dependent β-Thalassemia and Impact of Thalidomide Treatment.
  5. An erythroid-specific lentiviral vector improves anemia and iron metabolism in a new model of XLSA.
  6. The role of miR-129-5p in regulating γ-globin expression and erythropoiesis in β-thalassemia.
  7. Real-world experience with iron chelation therapy in transfusion-dependent thalassemia: impact of the oral chelators' era.
  8. Advances in the generation of erythrocytes from stem cells in vitro.
  9. β-Thalassemia minor is associated with high rates of worsening anemia in pregnancy.
  10. The value of Mentzer index in the diagnosis of children thalassemia minor.
  1. Am J Hematol. 2024 Dec 09.
    10-Year Risk of Gallstones in Congenital Red Blood Cell Disorder Patients: A Nationwide Cohort Study.
    Anders Blach Naamansen, Dennis Lund Hansen, Jesper Petersen, Andreas Glenthøj, Henrik Toft Sørensen, Henrik Frederiksen.
      Chronic hemolysis potentially elevates the risk of gallstones in several types of congenital red blood cell (RBC) disorders. However, the magnitude of the risk is unknown. We investigate the risk of gallstone disease in congenital RBC disorder patients, compared with general population comparators. Patients were identified from the Danish National Patient Registry covering all Danish hospitals and the National Reference Laboratory for RBC disorders during 1980-2016. Patients were matched by sex, age, and region of origin with up to 50 general population comparators. Gallstone events were identified using hospital-registered diagnoses and surgery codes. Our study included 9354 congenital RBC disorder patients, grouped according to type of congenital RBC disorder, and 416 994 general population comparators. The cumulative 10-year incidence of gallstone disease was 4.2% in patients with congenital RBC disorders and 1.7% among comparators. Adjusted csHR's [95% confidence interval] were 8.1 [6.8, 9.7] for hereditary spherocytosis; 3.3 [1.6, 6.8] for glucose-6-phosphate dehydrogenase deficiency; 21.6 [10.6, 44.1] for pyruvate kinase deficiency; 3.7 [1.9, 7.0] for sickle cell disease; 0.8 [0.4, 1.6] for sickle cell trait; 1.5 [1.1, 2.2] for α-thalassemia trait; 1.8 [1.4, 2.3] for β-thalassemia minor; and 2.1 [1.8, 2.6] for other congenital hemolysis. We found a markedly higher risk of hospital-registered gallstone diseases in nearly all groups of patients with congenital RBC disorders compared with the general population.
    Keywords:  Congenital red blood cell disorders; chronic hemolysis; gallstones
    DOI:  https://doi.org/10.1002/ajh.27558
  2. Hematology Am Soc Hematol Educ Program. 2024 12 06. 2024(1): 419-425
    Luspatercept: a treatment for ineffective erythropoiesis in thalassemia.
    Khaled M Musallam, Ali T Taher.
      Patients with β-thalassemia continue to have several unmet needs. In non-transfusion-dependent patients, untreated ineffective erythropoiesis and anemia have been associated with a variety of clinical sequelae, with no treatment currently available beyond supportive transfusions. In transfusion-dependent forms, lifelong transfusion and iron chelation therapy are associated with considerable clinical, psychological, and economic burden on the patient and health care system. Luspatercept is a novel disease-modifying agent targeting ineffective erythropoiesis that became recently available for patients with β-thalassemia. Data from randomized clinical trials confirmed its efficacy and safety in reducing transfusion burden in transfusion-dependent patients and increasing total hemoglobin level in non-transfusion-dependent patients. Secondary clinical benefits in patient-reported outcomes and iron overload were also observed on long-term therapy, and further data from real-world evidence studies are awaited.
    DOI:  https://doi.org/10.1182/hematology.2024000567
  3. Clin Chim Acta. 2024 Dec 09. pii: S0009-8981(24)02340-4. [Epub ahead of print]567 120087
    Standardization of hemoglobin A2 and hemoglobin F: Achievements and perspectives.
    IFCC-ICSH Joint Working Group for the Standardization of HbA2 and of the IFCC Working Group for the Standardization of HbF
      The establishment of reference systems for the standardization of hemoglobin A2 (HbA2) and fetal hemoglobin (HbF), both critical for improving diagnostic accuracy in conditions such as β-thalassemia and sickle cell disease, are described. Efforts were led by the IFCC and other groups to address and reduce the variability in laboratory measurements of these hemoglobins. This document outlines the production of certified reference materials (CRMs) for HbA2 and the development of a reference measurement procedure using isotope dilution mass spectrometry. Similarly, standardizing HbF is essential for supporting diagnostic and therapeutic strategies, particularly in managing sickle cell disease. HbF levels can predict disease outcomes and guide treatment plans. Significant challenges remain in achieving consistent measurement across laboratories, and the process for standardization for this minor hemoglobin has just begun. We are confident that the implementation of these reference systems will provide improved accuracy and traceability in the future.
    Keywords:  Certified reference materials; Gene therapy; HbA(2); HbF; Reference intervals; Reference measurement procedure; Traceability; β-thalassemia
    DOI:  https://doi.org/10.1016/j.cca.2024.120087
  4. Am J Hematol. 2024 Dec 09.
    Evaluating the Role of Red Blood Cell Lifespan in Transfusion-Dependent β-Thalassemia and Impact of Thalidomide Treatment.
    Kun Yang, Yuping Gong, Jian Xiao.
      
    Keywords:  red blood cell lifespan; thalidomide; transfusion‐dependent β‐thalassemia
    DOI:  https://doi.org/10.1002/ajh.27557
  5. Blood. 2024 Dec 10. pii: blood.2024025846. [Epub ahead of print]
    An erythroid-specific lentiviral vector improves anemia and iron metabolism in a new model of XLSA.
    Carlo Castruccio Castracani, Laura Breda, Tyler Ellis Papp, Amaliris Guerra, Enrico Radaelli, Charles-Antoine Assenmacher, Giovanni Finesso, Barbara L Mui, Ying K Tam, Simona Fontana, Chiara Riganti, Veronica Fiorito, Sara Petrillo, Emanuela Tolosano, Hamideh Parhiz, Stefano Rivella.
      X-linked sideroblastic anemia (XLSA) is a congenital anemia caused by mutations in ALAS2, a gene responsible for heme synthesis. Treatments are limited to pyridoxine supplements and blood transfusions, offering no definitive cure except for allogeneic hematopoietic stem cell transplantation, only accessible to a subset of patients. The absence of a suitable animal model has hindered the development of gene therapy research for this disease. We engineered a conditional Alas2-KO mouse model using tamoxifen administration or treatment with lipid nanoparticles (LNP) carrying Cre-mRNA and conjugated to an anti-CD117 antibody. Alas2-KOBM animals displayed a severe anemic phenotype characterized by ineffective erythropoiesis (IE), leading to low numbers of red blood cells (RBC), hemoglobin (Hb), and hematocrit (HCT). In particular, erythropoiesis in these animals showed expansion of polychromatic erythroid cells, characterized by reduced oxidative phosphorylation, mitochondria's function, and activity of key Tricarboxylic Acid (TCA) cycle enzymes. In contrast, glycolysis was increased in the unsuccessful attempt to extend cell survival despite mitochondrial dysfunction. The IE was associated with marked splenomegaly and low hepcidin levels, leading to iron accumulation in the liver, spleen, and bone marrow and the formation of ring sideroblasts. To investigate the potential of a gene therapy approach for XLSA, we developed a lentiviral vector (X-ALAS2-LV) to direct ALAS2 expression in erythroid cells. Infusion of BM cells with 0.6-1.4 copies of the X-ALAS2-LV in Alas2-KOBM mice improved CBC levels, tissue iron accumulation, and survival rates. These findings suggest our vector could be curative in XLSA patients.
    DOI:  https://doi.org/10.1182/blood.2024025846
  6. Hum Mol Genet. 2024 Dec 08. pii: ddae180. [Epub ahead of print]
    The role of miR-129-5p in regulating γ-globin expression and erythropoiesis in β-thalassemia.
    Jingmin Li, Meihuan Chen, Wantong Zhao, Aixiang Lv, Siyang Lin, Yanping Zheng, Meiying Cai, Na Lin, Liangpu Xu, Hailong Huang.
      The regulation of γ-globin expression is crucial due to its beneficial effects on diseases like β-thalassemia and sickle cell disease. B-cell lymphoma/leukemia 11A (BCL11A) is a significant suppressor of γ-globin, and microRNAs (miRNAs) targeting BCL11A have been shown to alleviate this suppression. In our previous high-throughput sequencing, we identified an 11.32-fold increase in miR-129-5p expression in β-thalassemia patients. However, the regulatory mechanisms of miR-129-5p in the context of erythroid differentiation remain to be elucidated. Our study aimed to elucidate the role of miR-129-5p in γ-globin regulation and erythropoiesis. We measured miR-129-5p levels in peripheral blood from β-thalassemia major and intermedia patients. Fluorescence in situ hybridization, dual-luciferase reporter assays, miRNA pull down assays and western blot analyses were conducted to examine the effects of miR-129-5p on γ-globin expression and BCL11A repression. Cell proliferation, apoptosis, and erythroid differentiation were assessed using cell counting kit-8, Wright-Giemsa, and benzidine staining, and flow cytometry assays. The expression levels of miR-129-5p were significantly elevated in β-thalassemia patients and positively correlated with γ-globin synthesis while negatively correlating with liver damage. miR-129- 5p enhanced γ-globin gene expression in K562 and HUDEP-2 cells by effectively repressing BCL11A. Overexpression of miR-129-5p inhibited cell proliferation, induced cell cycle arrest at the G1/G0 phase, promoted apoptosis and stimulated erythroid differentiation and maturation. Conversely, inhibition of miR-129-5p produced opposite cellular effects. miR-129-5p acts as a positive regulator of erythroid differentiation and γ-globin synthesis. It offers a promising miRNA target for activating the γ-globin gene and reducing ineffective erythropoiesis in β-thalassemia patients.
    Keywords:  BCL11A; erythroid differentiation; miR-129-5p; β-thalassemia; γ-globin
    DOI:  https://doi.org/10.1093/hmg/ddae180
  7. Ann Hematol. 2024 Dec 14.
    Real-world experience with iron chelation therapy in transfusion-dependent thalassemia: impact of the oral chelators' era.
    Morgan Pines, Dorothy Kleinert, Charlene Thomas, Cheryl Mensah, Khaled M Musallam, Sujit Sheth.
      Iron overload is a common complication in patients with transfusion-dependent-thalassemia that can lead to end-organ damage. Management of iron overload has considerably evolved since the early 2000s with the approval of oral iron chelators and widespread use of MRI monitoring. We conducted a retrospective cohort study of 144 patients with transfusion-dependent-thalassemia treated at a single center in the US and followed since initiation of regular transfusion therapy. Patients who were receiving deferoxamine monotherapy and then switched to/added an oral chelator had a mean decrease in liver iron concentration (LIC) by 0.02 mg/g dry weight (dw) per month (0.24 mg/g dw per year) and a mean increase in cardiac T2* by 0.07 ms per month (1.68 ms per year) after starting an iron chelator (p < 0.001 for both). There was a statistically significant decrease in the proportion of patients with clinically-relevant cardiac iron overload (cardiac T2* < 20 ms and < 10 ms) from 2006-2010 to 2016-2020, with a trend towards a decrease in the proportion of patients with clinically-relevant hepatic iron overload (LIC > 15 mg/g dw). The introduction of oral chelators has transformed management in patients with transfusion-dependent thalassemia and led to persistent improvements in iron burden over the years.
    Keywords:  Deferasirox; Deferiprone; Heart; Iron overload; Liver
    DOI:  https://doi.org/10.1007/s00277-024-06092-1
  8. Hematology. 2024 Dec;29(1): 2427932
    Advances in the generation of erythrocytes from stem cells in vitro.
    Yating Ling, Hailin Du, Yu Zhang, Qiang Fu, Chengtao He.
      Red blood cell transfusion is the main treatment to improve anemia caused by many reasons and has important clinical application value. However, the supply of red blood cells at home and abroad is currently very tight. Therefore, the utilization of stem cells to prepare erythrocytes for clinical use is expected to become a new mode of blood supply and security in the future. This review describes the process of erythropoiesis regulation in vivo, summarizes the latest research progress of in vitro erythropoiesis, and points out the current challenges of in vitro erythropoiesis, which is expected to provide a new idea for solving the problem of insufficient clinical erythropoiesis supply.
    Keywords:  CD34+; Erythrocytes; differentiation; in vitro induction; red blood; stem cells; ‌cytokine; ‌hiPSCs
    DOI:  https://doi.org/10.1080/16078454.2024.2427932
  9. Blood. 2024 Dec 09. pii: blood.2024026736. [Epub ahead of print]
    β-Thalassemia minor is associated with high rates of worsening anemia in pregnancy.
    Arielle L Langer, Brynn B Goggins, Erica B Esrick, Geoffrey Fell, Nancy Berliner, Katherine E Economy.
      We identified 347 pregnancies in patients with beta thalassemia minor. Hemoglobin was below 9 g/dL in 31% during third trimester and 7.6% at delivery. Postpartum hemorrhage occurred in 8.9%. Forty-six percent of intravenous iron administration was to iron-replete patients.
    DOI:  https://doi.org/10.1182/blood.2024026736
  10. Hematology. 2024 Dec;29(1): 2405750
    The value of Mentzer index in the diagnosis of children thalassemia minor.
    Tao Wu, Zhenmin Ren, Yandie Feng, Defa Li, Yunsheng Chen.
       OBJECTIVE: To explore the effect of the Mentzer Index (MI) in screening for children thalassemia (TT) minor.
    METHODS: We determined the MI cutoff value of diagnosing TT minor in children by utilizing a receiver operating characteristic (ROC) curve. Samples with MI values below this threshold, and no detectable gene mutations or IDA were further analyzed using Sanger sequencing or specific primer GAP-PCR.
    RESULTS: In the differential diagnosis of silent α-thalassemia (α-TT) and IDA, the area under the ROC curve (AUC) for the Mentzer index (MI) was 0.561. The most Youden index indicates an MI cutoff value of 16.833, with a sensitivity of 1.000 and a specificity of 0.278. For distinguishing α-TT minor from IDA, the AUC was 0.909, with an MI cutoff value of 12.24, a sensitivity of 0.875, and a specificity of 0.778. When distinguishing β-TT minor from IDA, the AUC was 0.907, with an MI cutoff value of 11.82, a sensitivity of 0.917, and a specificity of 0.768. Utilizing these MI cutoff values, three cases of rare TT genotype were identified, including a previously unreported heterozygous mutation of IVS-II-55 (T > G) in the alpha2 (αIVS-II-55(T > G)/αα).
    CONCLUSION: The diagnostic precision of MI is limited when differentiating between silent α-TT and IDA, but it is higher when distinguishing between α-TT minor, β-TT minor, and IDA. This study established a cutoff value for MI in our laboratory, providing reliable data for screening for TT minor and discovering rare TT genotypes among children in the local area.
    Keywords:  Mentzer index; ROC curve; Sanger sequencing; Thalassemia minor; cutoff value; genetic testing; iron deficiency anemia; rare thalassemia genotypes
    DOI:  https://doi.org/10.1080/16078454.2024.2405750
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