bims-conane Biomed News
on Congenital anemias
Issue of 2025–05–25
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo



  1. Br J Haematol. 2025 May 20.
      Non-transfusion-dependent thalassaemia (NTDT) can result in serious complications and comorbidities that can impact patients' quality of life. Mitapivat, a first-in-class, oral, small-molecule allosteric activator of red blood cell pyruvate kinase, is under investigation in adults with thalassaemia. Through its mechanism of action, mitapivat increases adenosine triphosphate, leading to improvements in red blood cell health, ineffective erythropoiesis and haemolysis. An open-label, multicentre, phase 2 study (NCT03692052) is evaluating mitapivat 100 mg twice daily in adults with NTDT. We previously reported a statistically significant haemoglobin response (a ≥1.0 g/dL increase in haemoglobin concentration from baseline at ≥1 assessments between Weeks 4 and 12 [inclusive]) during the 24-week core period. Here, we report efficacy and safety results up to Week 156 and to data cut-off date respectively. Of 20 patients enrolled, 17 continued in the extension period. Median change from baseline in haemoglobin concentration at Week 156 was 1.2 g/dL. Patients receiving mitapivat demonstrated sustained improvements in haemoglobin concentrations and markers of erythropoietic activity, haemolysis and iron homeostasis. Five patients (29%) had a grade ≥3 treatment-emergent adverse event; none were considered treatment related. Treatment with mitapivat was well tolerated, with a safety profile consistent with previous studies of mitapivat in pyruvate kinase deficiency.
    Keywords:  efficacy; mitapivat; non‐transfusion‐dependent thalassaemia; pyruvate kinase; safety
    DOI:  https://doi.org/10.1111/bjh.20058
  2. Fetal Pediatr Pathol. 2025 May 19. 1-28
       BACKGROUND: Neonatal red blood cell (RBC) disorders encompass a diverse range of inherited and acquired conditions with significant clinical implications. Due to the unique morphological and biochemical characteristics of neonatal erythrocytes, accurate diagnosis is often challenging but critical for effective management.
    OBJECTIVE: This review aims to synthesize current knowledge on the diagnosis of neonatal RBC disorders, highlighting the integration of traditional morphological analysis with advanced biochemical and molecular techniques.
    METHODS: A comprehensive literature review was conducted to examine diagnostic approaches to neonatal enzymopathies, membrane disorders, and hemoglobinopathies. The roles of peripheral blood smear (PBS) analysis, enzyme activity assays, and genetic testing-including next-generation sequencing (NGS)-were evaluated in the context of current clinical practice.
    DISCUSSION: Peripheral blood smear examination remains a foundational tool for identifying characteristic RBC morphologies. Enzymatic deficiencies such as G6PD and pyruvate kinase deficiency, membrane disorders including hereditary spherocytosis and elliptocytosis, and hemoglobinopathies such as thalassemias and sickle cell disease require integrated diagnostic strategies. Advances in molecular diagnostics have enhanced diagnostic precision and expanded the ability to perform early, genotype-driven interventions.
    CONCLUSIONS: A multidisciplinary diagnostic approach that combines morphology, biochemistry, and genetics is essential for the accurate identification and management of neonatal RBC disorders. Bridging traditional microscopy with modern genomic tools offers the potential for earlier diagnosis, personalized treatment, and improved clinical outcomes in neonatal hematology.
    Keywords:  Neonatal hematology; erythrocyte morphology; hemoglobinopathies; inherited hemolytic anemias; neonatal anemia diagnostics; next-generation sequencing in hematology; red blood cell disorders
    DOI:  https://doi.org/10.1080/15513815.2025.2503178
  3. Br J Haematol. 2025 May 19.
      Splenectomy is a major element in the treatment of hemoglobinopathies, such as transfusion dependent thalassaemia (TDT), non-transfusion dependent thalassaemia (NTDT), sickle cell anaemia (SCA), other red cell disorders like spherocytosis or other haematological diseases of autoimmune origin. A recent, long-year study describes a large series of splenectomized patients in Italy. The authors of this systematic work found that the probability of a post-splenectomy complication depends on the underlying disease and not on the age of the patient at splenectomy. Thus, splenectomy should be performed, when clinically indicated, regardless of the patient's age. The following commentary provides a critical evaluation of the results of the published study, discussing also the novelty, quality and limitations of this important work, in the perspective of current knowledge. Commentary on: Casale et al. Underlying disease is the main risk factor in post-splenectomy complication risk: Data from a national database. Br J Haematol 2025 (Online ahead of print). doi: 10.1111/bjh.20114.
    Keywords:  autoimmune haematological disease (AHD); congenital haemolytic anaemia (CHA); infection; non‐transfusion‐dependent thalassaemia (NTDT); post‐splenectomy complications; sickle cell anaemia (SCA); splenectomy; thrombosis; transfusion‐dependent thalassaemia (TDT); trauma
    DOI:  https://doi.org/10.1111/bjh.20159
  4. BMC Pediatr. 2025 May 20. 25(1): 405
       BACKGROUND: Patients with thalassemia acquire cellular oxidative damage mainly from the degradation of excessive uncoupled hemoglobin (Hb) chains and iron overload. The oxidative damage of red blood cells (RBCs) and platelets potentially results in the worsening of ineffective erythropoiesis, hemolysis, and the occurrence of thromboembolic events. Vitamin E (VitE) is an antioxidant that inhibits membrane lipid peroxidation. It is widely used as a supplement in thalassemia; however, its benefits in improving cellular oxidative damage remain unclear.
    METHODS: We conducted a double-blind, randomized, controlled trial registered in the Thai Clinical Trials Registry (TCTR20220801001) on 01/08/2022. We randomized transfusion-dependent (TD) β- and α-thalassemia (aged 10-25 years) to receive oral VitE 400 IU/day or placebo at a 1:1 ratio for 6 months. Cellular oxidative damage markers, including phosphatidyl serine (PS)-bearing RBCs, PS-bearing RBC vesicles, PS-bearing platelets, PS-bearing microparticles (MPs), PS-bearing RBC-MPs, PS-bearing platelet MPs (PMPs) and platelet activation, were measured before and after the intervention as the primary outcomes.
    RESULTS: Seventy-four TD thalassemia patients were categorized into 63 β-thalassemia (10 splenectomy, β-Thal-S; and 53 non-splenectomy, β-Thal-NS) and 11 α-thalassemia (non-splenectomy, α-Thal-NS). Randomized from all patient groups, 36 received VitE and 38 received a placebo. A significant reduction in PS-bearing RBCs and PS-bearing RBC vesicles was observed in the β-Thal-NS receiving VitE. This occurred parallel with a substantial decrease in malondialdehyde levels, as a marker of lipid peroxidation, found only in the β-Thal-NS but not in β-Thal-S and α-Thal-NS groups. In the β-Thal-NS group, VitE had improved RBC pathology as demonstrated by the inverse correlation between post-treatment VitE levels and PS-bearing RBCs (p = 0.001) as well as reticulocyte count (p = 0.006), although Hb levels remained unchanged. The VitE treatment did not result in improving platelet pathology or reducing MPs. No adverse event was reported in both VitE and placebo groups.
    CONCLUSIONS: VitE 400 IU/day was well-tolerated and associated with improved oxidative damage of the RBCs in TD β-Thal-NS patients. Accordingly, advice for VitE supplementation in young TD β-Thal-NS patients can be beneficial.
    Keywords:  Food supplements; Oxidative stress; PS-bearing RBC; Red cell pathology; Thalassemia; Vitamin E
    DOI:  https://doi.org/10.1186/s12887-025-05741-2
  5. iScience. 2025 Apr 18. 28(4): 112138
      Ribosomal protein haploinsufficiency causes Diamond-Blackfan anemia (DBA) and other ribosomopathies. DBA has been linked to p53 activation and reduced GATA1 expression, but these mechanisms do not fully explain the disease. This study unveils that deficiencies in small (RPS) or large (RPL) ribosomal subunit proteins cause a p53-independent loss of ATF4, a master regulator of stress responses and erythropoiesis, by reducing the pool of actively translating ATF4 mRNAs. This defect is more pronounced in RPS deficiencies because the loss of 40S, but not 60S, subunits cause a destabilization of ATF4 transcripts. ATF4 downregulation occurs in early hematopoietic progenitors and correlates with the severity of erythroid differentiation defects in patients with DBA. It is also linked to the de-repression of fetal hemoglobin in erythroid cells, a frequent feature in patients with DBA. Our findings indicate that impaired ATF4 expression might be a primary contributor to DBA and explain the aggravated erythroid failure of RPS-mutant patients.
    Keywords:  Biochemistry; molecular biology; omics
    DOI:  https://doi.org/10.1016/j.isci.2025.112138
  6. BMC Pediatr. 2025 May 19. 25(1): 404
       BACKGROUND: Biliary obstruction is a rare complication in patients with hereditary spherocytosis (HS). The clinical course and optimal treatment strategies for HS patients complicated by biliary obstruction remain unclear.
    METHODS: We conducted a retrospective review of 16 pediatric HS patients complicated by biliary obstruction who were treated at our hospital between January 2018 and October 2024. Based on previously published clinical severity classifications, patients were divided into Group A (non-severe group: trait, mild, and moderate) and Group B (severe group).
    RESULTS: The study included 16 patients with a mean age of 9.0 ± 3.2 years, evenly distributed between the two groups (8 patients each). Preoperative routine blood tests showed no significant differences between the groups; however, Group B exhibited higher bilirubin levels and lower liver enzyme levels. Genetic testing was performed in 12 patients, revealing SPTB gene mutations in 7 (58.3%). Conservative management effectively resolved biliary obstruction in 10 patients (62.5%) within 14 days. Invasive interventions, such as endoscopic retrograde cholangiopancreatography (ERCP) or cholecystostomy, were required in 6 patients, with conjugated bilirubin levels normalizing within five days post-procedure. Complications occurred in two patients with prolonged intervals between diagnosis and surgery (> 3 months): one required stent replacement due to blockage after ERCP, and the other developed a gallbladder-skin fistula and coagulation disorder following laparoscopic cholecystostomy. Of the 14 patients who underwent subsequent splenectomy and/or cholecystectomy, 12 recovered without complications. Notably, the 6 patients who underwent splenectomy alone without cholecystectomy did not experience biliary colic during a mean follow-up period of 3.4 years (range: 0.5 - 5.5 years).
    CONCLUSIONS: Biliary obstruction can complicate HS in pediatric patients regardless of anemia severity, particularly in those with SPTB gene mutations. Conservative management is effective in most cases, while invasive procedures are required for refractory cases. Shortening the interval between diagnosis and subsequent surgery may help prevent complications. Splenectomy alone appears to be a viable option once biliary obstruction is resolved.
    Keywords:  Biliary obstruction; Cholelithiasis; Gallstone; Hereditary spherocytosis
    DOI:  https://doi.org/10.1186/s12887-025-05760-z
  7. BMJ Case Rep. 2025 May 22. pii: e265294. [Epub ahead of print]18(5):
      A man in his 60s with dry eye symptoms was noted to have angioid streaks under the peripapillary retina. Congenital dyserythropoietic anaemia was the major health issue throughout his life, requiring venesection for iron overload, but no transfusions for many years. Close inspection of the eyes with optical coherence tomography also detected small subclinical optic disc drusen, which have not been reported in association with congenital dyserythropoietic anaemia. Together, optic disc drusen and angioid streaks represent an ectopic calcification phenotype in the eye and can be seen in the more common inherited condition of pseudoxanthoma elasticum or other inherited haemolytic anaemias such as sickle cell or thalassaemia. These associations highlight the role of pyrophosphate as a physiological inhibitor of calcification, and deficiencies of serum pyrophosphate lead to excessive and ectopic calcification. This raises intriguing hypotheses for the treatment of optic disc drusen, angioid streaks and other conditions of ectopic calcification.
    Keywords:  Haematology (incl blood transfusion); Retina; Visual pathway
    DOI:  https://doi.org/10.1136/bcr-2025-265294