bims-conane 2025-09-14 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2025–09–14
ten papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

The Efficacy and Safety of Deferasirox Monotherapy as a Second-Line Treatment in Transfusion-Dependent Thalassemia with Iron Overload.
Molecular Insights into the Pathophysiology of Dysregulated Erythropoiesis: The Crucial Role of Iron Homeostasis.
Glycated albumin as a diagnostic tool for diabetes mellitus in transfusion-dependent β-thalassemia patients.
Congenital Dyserythropoietic Anemia Type III Associated With a Novel KIF23 Variant (c.2132A>G; p.Gln711Arg): A Case Report.
Pyruvate Kinase Deficiency: Markedly Decreased Reticulocyte PK Activity and Limited Specificity of the PK/HK Ratio.
Integrated Approach for Biochemical and Functional Characterization of Six Clinical Variants of Glucose-6-Phosphate Dehydrogenase.
[Diagnosis of non-autoimmune hemolysis in the adult].
High-Resolution Genetic Profiling of Hb J-Meerut and Other Hemoglobin Variants in the Tharu Population via HPLC and DNA Sequencing.
Is splenectomy one of the contributory factors to pulmonary hypertension? An analysis of splenectomized hemolytic anemia and immune thrombocytopenia patients.
Abatacept Improves Post-Transplant Survival and Reduces Endothelial Injury Syndromes in Beta-Thalassemia major.

J Clin Med. 2025 Sep 03. pii: 6212. [Epub ahead of print]14(17):

The Efficacy and Safety of Deferasirox Monotherapy as a Second-Line Treatment in Transfusion-Dependent Thalassemia with Iron Overload.

Manatchaya Pongamnuaykrit, Adisak Tantiworawit, Piangrawee Niprapan, Teerachat Punnachet, Nonthakorn Hantrakun, Pokpong Piriyakhuntorn, Thanawat Rattanathammethee, Sasinee Hantrakool, Chatree Chai-Adisaksopha, Ekarat Rattarittamrong, Lalita Norasetthada, Pimlak Charoenkwan.

  Deferasirox (DFX) is an oral iron chelator for thalassemia patients with iron overload. DFX was FDA-approved as a first-line treatment for chronic iron overload. In Thailand, DFX was indicated as second-line therapy for patients unresponsive to deferiprone. Objectives: This study aimed to investigate the efficacy and safety of DFX monotherapy. Methods: All transfusion-dependent thalassemia patients who received second-line DFX monotherapy were identified from the thalassemia registry between May 2007 and May 2022. The primary endpoint was the change in body iron stores, measured by serum ferritin at week 24. At treatment end, patients with a serum ferritin (SF) level < 1000 ng/mL in transfusion-dependent thalassemia (TDT) were categorized as the ferritin response group. Multivariate analysis identified factors driving group differences. Results: Forty-two patients were enrolled with a mean age of 35.5 (13-57) years. Of these, 73.81% had beta-thalassemia. The median initial DFX dose was 20.26 (17.85-22.22) mg/kg/day, with a median treatment follow-up of 2 (1.80-2.45) years. Median SF was decreased from 2516 (1712 to 3065) ng/mL to 1027.5 (598-1867) ng/mL (p < 0.001). Of 21 (50%) patients in the ferritin response group, independent factors were age > 15 years and lower initial SF, with OR = 7.13 (95% CI 1.05-48.49, p = 0.045) and OR = 0.93 (95% CI 0.87-1.00, p = 0.039). The most common adverse events were gastric irritation symptoms (11.90%). Conclusions: Deferasirox is an effective oral iron chelator for thalassemia, with manageable side effects. Half of patients reached target SF levels. Adults (>15 years) with lower initial SF levels had a better response to DFX.

Keywords:  deferasirox; thalassemia; transfusion-dependent thalassemia

DOI:  https://doi.org/10.3390/jcm14176212
Mol Cell Biol. 2025 Sep 10. 1-14

Molecular Insights into the Pathophysiology of Dysregulated Erythropoiesis: The Crucial Role of Iron Homeostasis.

Tohru Fujiwara, Hideo Harigae.

  Erythropoiesis, i.e., process of red blood cell (RBC) production, is highly dependent on iron, with 60-70% of the total body iron incorporated into hemoglobin. Iron homeostasis is tightly regulated, given that both iron overload and deficiency can impair RBC development and function. Iron-loading anemias, such as sideroblastic anemia and thalassemia, are associated with ineffective erythropoiesis and systemic iron overload. Recent studies also highlight the role of ferroptosis, i.e., iron-dependent cell death, in erythroid failure under conditions of iron overload. Transcriptional repressor BTB and CNC homology 1 (BACH1), which is regulated by intracellular heme, is a potential key mediator of ferroptosis. In iron deficiency, limited iron availability impairs heme and globin biosynthesis, mitochondrial function, and erythropoietin responsiveness, while also inducing widespread changes in gene expression through DNA methylation, all of which contribute to dysregulated erythropoiesis. Under iron deficiency, BACH1 plays a critical role in maintaining the balance between heme and globin by suppressing globin gene expression, thereby preventing the aggregation of toxic non-heme globin. This review summarizes the current understanding of the mechanisms by which iron imbalance contributes to erythropoietic failure and highlights BACH1 as a potential integrative regulator in the pathophysiology of anemia in both iron-overload and iron-deficient states.

Keywords:  BACH1; Iron; anemia; ferroptosis; heme

DOI:  https://doi.org/10.1080/10985549.2025.2553648
Endocrine. 2025 Sep 09.

Glycated albumin as a diagnostic tool for diabetes mellitus in transfusion-dependent β-thalassemia patients.

Gianluca Marzi, Martina Verrienti, Filomena Longo, Camilla Alice Cattaneo, Alberto Gobbo, Katalin Vetralla, Gian Pietro Franzè, Alberto Cossu, Martina Culcasi, Maria Chiara Zatelli, Maria Rosaria Ambrosio.



Keywords:  Beta thalassemia; Diabetes; Glycated albumin; Iron overload; Transfusion

DOI:  https://doi.org/10.1007/s12020-025-04410-9
Clin Case Rep. 2025 Sep;13(9): e70875

Congenital Dyserythropoietic Anemia Type III Associated With a Novel KIF23 Variant (c.2132A>G; p.Gln711Arg): A Case Report.

Ahmad Hamammdi, Kareem Sultan Tamimi, Adam Qabaha, Omar Bsharat, Kareem Ibraheem, Ahmad Batran.

  Congenital dyserythropoietic anemia type III (CDA III) is an extremely rare inherited disorder characterized by ineffective erythropoiesis, multinucleated erythroblasts in the bone marrow, and variable clinical gravity. We report the case of a 6-year-old boy, presenting with abdominal distension, failure to thrive, dark urine, intermittent itching, and recurrent infections. Physical examination revealed pallor, hepatomegaly, and splenomegaly. Laboratory investigations showed mild normocytic anemia, high liver enzymes, and erythroid hyperplasia. The sequencing of the whole exoma identified a variant of uncertain meaning in the KIF23 gene, which is implicated in cytokinesis and attached to the pathogenesis of CDA III. The patient remains clinically stable in support management, without the current need for transfusion. This case highlights the importance of advanced genetic tests in the diagnosis of rare hematological conditions and expands the potential spectrum of mutations associated with CDA III. Early recognition and long-term monitoring are essential for guiding management and monitoring complications such as iron overload and splenomegaly.

Keywords:  KIF23 mutation; anemia; dyserythropoietic; genetic testing; hematology; kinesins

DOI:  https://doi.org/10.1002/ccr3.70875
Int J Mol Sci. 2025 Sep 04. pii: 8606. [Epub ahead of print]26(17):

Pyruvate Kinase Deficiency: Markedly Decreased Reticulocyte PK Activity and Limited Specificity of the PK/HK Ratio.

Larisa Koleva, Ivan A Dolgikh, Aleksandra V Kryukova, Dmitry S Prudinnik, Elizaveta A Bovt, Soslan S Shakhidzhanov, Svetlana G Mann, Nataliya S Smetanina, Fazoil I Ataullakhanov, Elena I Sinauridze.

  Diagnosis of pyruvate kinase deficiency (PKD) remains challenging in clinical practice. The pyruvate kinase (PK) to hexokinase (HK) activity ratio (PK/HK) was proposed to reduce the confounding effect of reticulocytosis on PK activity measurement. However, decreased PK activity and PK/HK ratios have also been observed in other anemias, raising doubts about their diagnostic value. We assessed the diagnostic accuracy of PK/HK ratio versus PK activity in differentiating PKD from other hereditary anemias. This study included 41 patients with molecularly confirmed PKD and 62 patients with other anemias. We also evaluated the influence of reticulocytosis and transfusions on erythrocyte PK activity. The PK/HK ratio showed 73% specificity, while PK activity alone achieved 95%. In PKD patients, reticulocytosis did not affect PK activity because reticulocyte PK activity was already markedly reduced (23-fold) compared with controls. In other anemias, decreases in PK activity were present in both reticulocytes and erythrocytes, but to a lesser extent. Transfusions contribute more to the false-normal result of PK activity than reticulocytosis. Measuring reticulocyte-specific PK activity during regular transfusions provided reliable results, as only patient-derived reticulocytes are present in the blood. PK activity demonstrates higher specificity than PK/HK ratio in diagnosing PKD. Reticulocytosis is not a confounder, while transfusions remain the main limitation. Reticulocyte-specific PK activity measurement may improve diagnostic accuracy in transfused patients.

Keywords:  PK activity in reticulocytes; PK/HK ratio; differential diagnosis of PK deficiency; hereditary hemolytic anemias; pyruvate kinase deficiency; red blood cells

DOI:  https://doi.org/10.3390/ijms26178606
Int J Mol Sci. 2025 Aug 30. pii: 8464. [Epub ahead of print]26(17):

Integrated Approach for Biochemical and Functional Characterization of Six Clinical Variants of Glucose-6-Phosphate Dehydrogenase.

Beatriz Hernández-Ochoa, Mónica Guadalupe Gualos-González, Jhuremy Alexandra Moreno-Hernández, Laura Morales-Luna, Montserrat Vázquez-Bautista, Luis Miguel Canseco-Ávila, Verónica Pérez de la Cruz, Roberto Arreguin-Espinosa, Elizabeth Hernández-Urzua, Sergio Enríquez-Flores, Ignacio De la Mora-De la Mora, Noemí Cárdenas-Rodríguez, Cindy Bandala, Lucia De Franceschi, Abraham Vidal-Limon, Saúl Gómez-Manzo.

  Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a widespread enzymopathy affecting approximately 500 million individuals that represents a significant global health issue. Among the more than 230 identified mutations in the G6PD gene, six class A variants-G6PD Utrecht (Pro409Ser), G6PD Suwalki (Pro409Arg), G6PD Merlo (Pro409Gln), G6PD Kawasaki (Gly410Ala), G6PD Shinagawa (Gly410Asp), and G6PD Riverside (Gly410Cys)-are located in the beta-loop near the NADP+ binding site. These mutations are of particular interest due to their association with severe hematologic phenotypes, including chronic hemolytic anemia, as well as their proposed role in the allosteric regulation of G6PD multimerization. This study presents a comprehensive biochemical and functional characterization of these clinically relevant G6PD variants. The variant enzymes were cloned, expressed, and purified for characterization. Kinetic parameters and thermal stability assays, complemented by molecular dynamics simulations (MDS), were employed to elucidate the structural impacts of the mutations. Our results demonstrate that these mutations significantly impair protein function, characterized by reduced affinity for glucose-6-phosphate (G6P) and NADP+, as well as altered thermal stability compared with wild-type G6PD. MDS revealed that point mutations in the βN- and βM-sheets in the NADP+s region propagate subtle conformational changes, ultimately affecting the NADP+c region and the G6P binding cavity. Furthermore, secondary structure element analyses of the simulation data showed that Pro409 and Gly410 point mutations propagate several changes around residues 195-210 (G6P binding site) and 380-400 (NADP+s), explaining their effect on overall catalytic performance. These findings enhance our understanding of the molecular mechanisms underlying G6PD deficiency and its clinical implications, providing a foundation for future therapeutic strategies aimed at mitigating the effects of these variants.

Keywords:  G6PD variants; molecular dynamics simulations; structural characterization

DOI:  https://doi.org/10.3390/ijms26178464
Rev Med Interne. 2025 Sep 09. pii: S0248-8663(25)00721-0. [Epub ahead of print]

[Diagnosis of non-autoimmune hemolysis in the adult].

Marc Ruivard, Marc Michel, Loïc Garçon.

  The diagnosis of hemolysis is still based on straightforward biochemical parameters: haptoglobin (the most sensitive), lactate dehydrogenase (LDH), and unconjugated bilirubin. Anemia is not always present. Reticulocyte counts typically exceed 120×109/L, except in cases of associated vitamin deficiency or during the very early phase of acute hemolysis. When the Direct Antiglobulin Test is negative, a non-autoimmune cause of hemolysis should be considered. A thorough history, careful physical examination, and meticulous review of the peripheral blood smear help to rule out major emergencies such as malaria, thrombotic microangiopathy, severe infections, delayed hemolytic transfusion reaction, or toxic hemolysis. In the absence of a mechanical valve or other intravascular device that could induce hemolysis, second-line laboratory tests should be pursued: hemoglobin phenotyping, eosin-5'-maleimide (EMA) binding test, screening for paroxysmal nocturnal hemoglobinuria (PNH), and enzymatic assays. These tests usually lead to the diagnosis of most corpuscular non-autoimmune hemolytic anemias, including hemoglobinopathies (such as sickle cell disease, thalassemia syndromes, hemoglobin C disease, or unstable hemoglobins), membranopathies (such as hereditary spherocytosis or stomatocytosis), and enzyme deficiencies. The diagnosis of rare causes of hemolysis should be considered at a later stage or in specific contexts, such as alcoholism (Zieve's syndrome), advanced cirrhosis (spur cell anemia), or acute hemolysis in a young patient (Wilson's disease).

Keywords:  Frottis sanguin; Hemoglobinopathies; Hémoglobinopathies; Hémolyse non auto-immune; Membranopathies; Non-autoimmune hemolysis; Peripheral blood smear

DOI:  https://doi.org/10.1016/j.revmed.2025.08.001
Diagnostics (Basel). 2025 Sep 08. pii: 2268. [Epub ahead of print]15(17):

High-Resolution Genetic Profiling of Hb J-Meerut and Other Hemoglobin Variants in the Tharu Population via HPLC and DNA Sequencing.

Nitu Nigam, Rashmi Kushwaha, Arti Gupta, M L B Bhatt, Bhupendra Singh, Sanjay Nigam, Kirti Upadhyay, Amro Amara, Sumit Rungta.

  Background/Objectives: Hemoglobinopathies, including thalassemia and sickle cell disease, are among the most common inherited disorders worldwide. This study aimed to profile hemoglobin variants in the Tharu community of Lakhimpur Kheri, Uttar Pradesh, with particular focus on the rare variant Hb J-Meerut [α 120 (H3) Ala→Glu (α1)]. Methods: A cross-sectional study was conducted during a community health camp in February 2024. Peripheral blood samples were collected from 505 individuals, of which 445 were analyzed using complete blood count (CBC) and high-performance liquid chromatography (HPLC). Suspected variants were confirmed by Sanger sequencing. Results: Hemoglobinopathies were identified in nearly one-fifth of participants. The major variants detected were sickle cell trait, β-thalassemia trait, and Hb J-Meerut. Sequencing confirmed Hb J-Meerut in the majority of suspected cases. HPLC profiles showed clear differences between groups, supporting its role as a reliable screening tool. Conclusions: Community-based screening combining HPLC and sequencing provides an effective approach for identifying both common and rare hemoglobin variants. Early detection of silent carriers such as Hb J-Meerut is essential for targeted genetic counseling and preventive strategies in high-risk populations.

Keywords:  DNA sequencing; Hb J-Meerut; hemoglobin variants; high-performance liquid chromatography (HPLC); sickle cell trait; β-thalassemia

DOI:  https://doi.org/10.3390/diagnostics15172268
Ann Hematol. 2025 Sep 09.

Is splenectomy one of the contributory factors to pulmonary hypertension? An analysis of splenectomized hemolytic anemia and immune thrombocytopenia patients.

Zeliha Birsin, Ayşe Salihoğlu, Kardelen Ohtaroğlu Tokdil, Betül Zehra Pirdal, Seçkin Bilgiç, Burçak Kılıçkıran Avcı, Deniz Özmen, Ahmet Emre Eşkazan, Muhlis Cem Ar, Zafer Başlar, Tuğrul Elverdi.

  The development of pulmonary hypertension (PH) after splenectomy is one of the recently controversial issues. This study aims to investigate whether splenectomy itself is an independent risk factor for the development of PH or if the primary contributor to PH development is the underlying condition that necessitated splenectomy. This study was conducted prospectively. We included 21 patients with immune thrombocytopenia (ITP) and 22 with hemolytic anemia. The patients' symptoms were assessed according to a questionnaire form. Blood tests, including N-terminal pro-B type natriuretic peptide (NT-proBNP) and D-dimer levels were done and the 6-minute walk test (6MWT) was performed. PH risk was evaluated using echocardiography (ECHO) and according to the study algorithm, Q-SPECT/CT (perfusion single-photon emission computed tomography/computed tomography) and right heart catheterization (RHC) were performed on selected patients for further assessment. Only one patient in the ITP group was diagnosed as group 2 PH based on ECHO findings and 3 patients with beta thalassemia in the hemolytic anemia group were diagnosed with group 4-5 PH by RHC. There was no statistically significant difference between ECHO-assessed risk for PH in splenectomized patients with hemolytic anemia and ITP (p > 0.05). ECHO risk for PH in the hemolytic anemia patients was found to be low in patients whose hemolysis decreased and transfusion needs disappeared after splenectomy. The results of the study suggest that the development of PH after splenectomy appears to be related to the underlying condition rather than the absence of the spleen.

Keywords:  Hemolytic anemia; Immune thrombocytopenia; Pulmonary hypertension; Splenectomy

DOI:  https://doi.org/10.1007/s00277-025-06583-9
Blood Adv. 2025 Sep 12. pii: bloodadvances.2025017197. [Epub ahead of print]

Abatacept Improves Post-Transplant Survival and Reduces Endothelial Injury Syndromes in Beta-Thalassemia major.

Pooja Khandelwal, Azada Ibrahimova, Adam Lane, Michael Grimley, Stella M Davies, Sonata Jodele.

Iron overload in transfusion-dependent beta thalassemia (TDT) generates reactive oxygen species, predisposing to post hematopoietic stem cell transplant (HSCT) endothelial activation. Abatacept prevents acute graft versus host disease (GVHD) by inhibiting CD80/CD86 on T-cells, but CD80 is also expressed on neutrophils. Elevated neutrophil extracellular traps (NETs) at day+14 are associated with thrombotic microangiopathy (TMA) after HSCT, mechanistically linking endothelial activation to complement activation. We wanted to compare post HSCT survival and incidence of endothelial injury syndromes in children with TDT with and without addition of abatacept to standard acuteGVHDprophylaxis. We performed a retrospective review of children with TDT who underwent HSCT at our center. All received intravenous busulfan, fludarabine and thiotepa for conditioning and calcineurin inhibitor-based acute GVHD prophylaxis. Patients without abatacept served as controls. Abatacept was administered intravenously at 10 mg/kg on days -1, +5, +14 and +28 after HSCT. Sixty-four children underwent HSCT for TDT. Fifty received abatacept while 14 did not. No differences were observed between rates of neutrophil or platelet engraftment, rates of bacteremia or viral reactivation. Acute grade II-IV GVHD was lower in the abatacept cohort (0%) compared to no abatacept cohort (35%) p=0.0003. Incidence of any endothelial injury syndromes (TA-TMA, SOS, PRES, DAH) was lower in the abatacept cohort (16%) compared to no abatacept (64%) p=0.0009. Day+14 dsDNA( surrogate of NETs) and sC5b-9 values were lower in the abatacept cohort compared to no abatacept cohort (p=0.04 and p<0.001 respectively). All patients in the abatacept cohort had full donor myeloid chimerism and remained transfusion-independent at a median last follow up of 1915 days (range 266-3464 days) post HSCT. Thalassemia-free survival was 100% in the abatacept cohort and 71% in the no abatacept cohort. Addition of abatacept to calcineurin inhibitor based acute GVHD prophylaxis resulted in excellent thalassemia-free survival and lower endothelial injury syndromes.

DOI: https://doi.org/10.1182/bloodadvances.2025017197