bims-conane Biomed News
on Congenital anemias
Issue of 2025–08–03
nine papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Association between hereditary spherocytosis and gallstone disease: Pathophysiology, diagnosis, and management.
  2. When Unstable Hemoglobin Lansing Interacts with Alpha Thalassemia Along with HbS: An Interesting Case with Unique Clinical Presentation.
  3. Impact of lifetime anaemia and iron control on outcomes in β-thalassaemia: Data from the longitudinal de-LIGHT study.
  4. Diagnosis and Management of Prenatal Hereditary Pyropoikilocytosis.
  5. Increased Prevalence of Thromboembolic Events in Patients with Congenital Dyserythropoietic Anemia Type I.
  6. Removal of promoter CpG methylation by epigenome editing reverses HBG silencing.
  7. Red Blood Cell Extracellular Vesicles as Key Players in Thromboinflammation.
  8. Incidence of hepatocellular carcinoma in beta thalassemia: a systematic review and meta-analysis.
  9. Transfusion-dependent thalassemia and venous thromboembolism: Position Statement from the Steering Committees of Hemostasis and Erythrocyte & Hemoglobinopathies study groups -Hellenic Society.
  1. World J Gastrointest Surg. 2025 Jul 27. 17(7): 105033
    Association between hereditary spherocytosis and gallstone disease: Pathophysiology, diagnosis, and management.
    Shan Cong, Yu-Ning Wang, Jun-Rong Wang, Rui-Heng Duan.
      Hereditary spherocytosis (HS), a common inherited hemolytic anemia, is characterized by red blood cell membrane protein defects leading to chronic hemolysis. This condition significantly predisposes patients to gallstone disease, including both gallbladder and bile duct stones, due to excessive bilirubin production from hemolysis. Gallstones in HS patients, primarily composed of bilirubin, can lead to complications such as cholecystitis, cholangitis, and obstructive jaundice. This review provides a comprehensive landscape of the pathophysiological mechanisms linking HS to gallstone formation, emphasizing the roles of hemolysis, bile composition, and genetic factors. It also discusses the clinical manifestations of gallstone disease in HS, including recurrent jaundice and biliary obstruction, and highlights the diagnostic value of imaging modalities such as ultrasonography and magnetic resonance cholangiopancreatography. Furthermore, current management strategies, including splenectomy, cholecystectomy, and endoscopic approaches for bile duct stones, are examined in the context of HS. By synthesizing existing knowledge, this review aims to provide insights into improving the diagnosis, prevention, and treatment of gallstone disease in patients with HS, while identifying gaps for future research.
    Keywords:  Bilirubin metabolism; Gallstone disease; Hemolysis; Hereditary spherocytosis; Multidisciplinary management
    DOI:  https://doi.org/10.4240/wjgs.v17.i7.105033
  2. Hemoglobin. 2025 Jul 27. 1-4
    When Unstable Hemoglobin Lansing Interacts with Alpha Thalassemia Along with HbS: An Interesting Case with Unique Clinical Presentation.
    Adwait Marhatta, Jui Choudhuri, Joseph J Mulvey, Sean Campbell, Yanan Fang.
      Hemoglobin (Hb) Lansing is a rare mildly unstable variant of α globin. Here, we report the first case of compound Hb Lansing/HbS coinherited with a single α thalassemia deletion (-alpha3.7) in a 27-year-old woman. The patient exhibited moderate hemolytic anemia and low oxygen saturation by pulse oximetry, which failed to improve with supplemental oxygen. Notably, her oxygen saturation levels were normal by arterial blood gas. Capillary electrophoresis and high-performance liquid chromatography showed an HbS peak along with other abnormal peaks. Subsequent α globin gene sequencing revealed one copy of the -alpha3.7 α-globin deletion and one copy of Hb Lansing variant in the alpha2-globin gene. Hemoglobin Lansing is known to cause spuriously low pulse oximetry. Additionally, the co-inheritance of the Hb Lansing and a single α thalassemia deletion may contribute to her moderate hemolytic anemia. The timely identification of hemoglobin variants is crucial for understanding the underlying cause when encountering unexpectedly low pulse oximetry, facilitating genetic counseling, and preventing unnecessary investigations and treatments. Further research is also needed to enhance our comprehension of the interactions among various hemoglobin variants; especially those associated with single a α thalassemia deletion.
    Keywords:  Hemoglobin Lansing; Hemoglobin S; falsely low pulse oximetry; hemolytic anemia; single alpha thalassemia deletion; unstable hemoglobin
    DOI:  https://doi.org/10.1080/03630269.2025.2533221
  3. Br J Haematol. 2025 Jul 31.
    Impact of lifetime anaemia and iron control on outcomes in β-thalassaemia: Data from the longitudinal de-LIGHT study.
    Khaled M Musallam, Angela Vitrano, Alessandro Inzerillo, Rosario Di Maggio, Rita Barone, Antonino Giangreco, Maria Concetta Renda, Emanuela Fecarotta, Antonio Troia, Antonino Giambona, Giovan Battista Ruffo, Efthymia Vlachaki, Theodora M Venou, Paolo Ricchi, Brunella Ziello, Marilena Serra, Elena Colizzi, Filomena Longo, Martina Culcasi, Aurelio Maggio.
      Evidence on the impact of anaemia and iron control on morbidity and mortality in β-thalassaemia is limited to short-term studies assessing spot measures. We conducted a retrospective longitudinal cohort study of 557 patients with β-thalassaemia followed from diagnosis for a median of 38 years. There was a significant association between the lifetime proportion spent on transfusion and thalassaemia-related mortality (adjusted hazard ratios (HR) 0.987 for each 1-percent increase, p = 0.014). In both patients with non-transfusion-dependent β-thalassaemia (NTDT) and transfusion-dependent β-thalassaemia (TDT) (lifetime proportion on transfusion ≤70% and >70%, respectively), there was a significant association between a lifetime anaemia and iron control index (LAICI) and mortality (NTDT: adjusted HR 0.916 for each 1-point increase, p = 0.017; TDT: adjusted HR 0.672, p = 0.027). Survival was significantly lower in patients with suboptimal than optimal LAICI, defined based on international NTDT and TDT guidelines for anaemia and iron overload management (NTDT: adjusted HR 0.395, p = 0.046; TDT: adjusted HR 0.205, p = 0.020 for optimal vs. suboptimal LAICI). Patients with optimal LAICI had significantly lower odds of cardiac (NTDT, TDT), vascular (TDT), hepatic (NTDT), endocrine morbidity (NTDT, TDT) and osteoporosis (NTDT). Optimal anaemia and iron control throughout the entire disease course are essential to reduce morbidity and mortality in patients with β-thalassaemia.
    Keywords:  haemoglobin; morbidity; mortality; serum ferritin; transfusion
    DOI:  https://doi.org/10.1111/bjh.70047
  4. Prenat Diagn. 2025 Jul 26.
    Diagnosis and Management of Prenatal Hereditary Pyropoikilocytosis.
    Connor Hartzell, Samantha Stover, Nora Gibson, Timothy Olson, James Connelly, Matthew Grace, Jennifer Andrews.
      Hereditary pyropoikilocytosis (HPP) is a severe hemolytic anemia caused by variants in SPTA1, SPTB, and EPB41. These weaken horizontal interactions in the erythrocyte cytoskeleton, causing membrane fragmentation and splenic sequestration. It will readily cause fetal anemia and often hydrops fetalis. Prenatal diagnosis requires first ruling out immune and other non-immune causes of fetal anemia. Diagnosis is made using characteristic blood smear morphology, ideally examined on a native blood sample, paired with exome sequencing. When these are inconclusive, laboratory tests such as ektacytometry and eosin-5-maleimide flow cytometry can help distinguish HPP from other membranopathies. Prenatal disease almost always requires intrauterine transfusion. In the neonatal period, HPP will continue to cause severe anemia, and patients usually remain transfusion dependent until definitive intervention. For some patients, splenectomy relieves or reduces their transfusion requirements while others continue to be transfusion dependent. This response may be related to a patient's genotype. Allogeneic stem cell transplant (SCT) is an emerging therapy that has been performed in a few patients with good outcomes. We report three additional patients with membranopathy who have undergone SCT. All were diagnosed prenatally and required transfusion support pre- and post-natally. Following SCT, all patients became transfusion independent and are doing well.
    DOI:  https://doi.org/10.1002/pd.6867
  5. Acta Haematol. 2025 Jul 30. 1-13
    Increased Prevalence of Thromboembolic Events in Patients with Congenital Dyserythropoietic Anemia Type I.
    Mahdi Asleh, Aya Khalaila, Yotam Eshel, Kayed Al-Athamen, Joseph Kapelushnik, Hagit Miskin.
       BACKGROUND: Congenital Dyserythropoietic Anemia Type I (CDA-I) is a rare disorder of erythropoiesis. All CDA-I patients are expected to have iron overload and chronic hemolysis. Patients with severe anemia may undergo splenectomy. Hemochromatosis, chronic hemolysis and splenectomy are all found to increase risk for thromboembolism in thalassemic patients. As CDA-I patients have similar findings, we sought to evaluate prevalence of thromboembolic events in these patients.
    MATERIALS AND METHODS: A retrospective case-control study was conducted, including 110 CDA-I patients (study group) and 326 age and sex-matched iron deficiency anemia patients of the same ethnicity (control group). Patients were risk-stratified using Risk Assessment Models for thromboembolism.
    RESULTS: We identified three cases (2.7%) with thromboembolic events in the CDA group and one case (0.3%) in the control group. All patients were females. VTE risk scores were low to moderate for CDA patients and higher for IDA patient. When compared to control group, CDA-I patients were nine times more likely to develop thromboembolic event (OR 9.11, 95% CI=1.15-185.27, p=0.057). All three CDA patients had a history of remarkable hemolysis and iron overload. Two underwent splenectomy.
    DISCUSSION: These findings show that CDA patients appear to be at increased risk for thromboembolic events.
    DOI:  https://doi.org/10.1159/000547577
  6. Nat Commun. 2025 Jul 27. 16(1): 6919
    Removal of promoter CpG methylation by epigenome editing reverses HBG silencing.
    Henry W Bell, Ruopeng Feng, Manan Shah, Yu Yao, James Douglas, Phillip A Doerfler, Thiyagaraj Mayuranathan, Michael F O'Dea, Yichao Li, Yong-Dong Wang, Jingjing Zhang, Joel P Mackay, Yong Cheng, Kate G R Quinlan, Mitchell J Weiss, Merlin Crossley.
      β-hemoglobinopathies caused by mutations in adult-expressed HBB can be treated by re-activating the adjacent paralogous genes HBG1 and HBG2 (HBG), which are normally silenced perinatally. Although HBG expression is induced by global demethylating drugs, their mechanism is poorly understood, and toxicity limits their use. We identify the DNMT1-associated maintenance methylation protein UHRF1 as a mediator of HBG repression through a CRISPR/Cas9 screen. Loss of UHRF1 in the adult-type erythroid cell line HUDEP2 causes global demethylation and HBG activation that is reversed upon localized promoter re-methylation. Conversely, targeted demethylation of the HBG promoters activates their genes in HUDEP2 or primary CD34+ cell-derived erythroblasts. Mutation of MBD2, a CpG-methylation reading component of the NuRD co-repressor complex, recapitulates the effects of promoter demethylation. Our findings demonstrate that localized CpGmethylation at the HBG promoters facilitates gene silencing and identify a potential therapeutic approach for β-hemoglobinopathies via epigenomic editing.
    DOI:  https://doi.org/10.1038/s41467-025-62177-z
  7. Semin Thromb Hemost. 2025 Jul 24.
    Red Blood Cell Extracellular Vesicles as Key Players in Thromboinflammation.
    Denis F Noubouossie, Nigel S Key.
      Thromboinflammation is an emerging concept which highlights the interactions between coagulation and inflammation in various disease states. Activation of coagulation and inflammation are both hallmarks of hemolytic diseases. However, the mechanisms by which they cause adverse outcomes in hemolytic disorders is incompletely understood. The existing literature suggests that red blood cells (RBCs) play a role in thrombosis and in immune regulation. RBCs release extracellular vesicles (RBC-EVs) with increased numbers found in the circulation of patients with hemolytic disorders. In this review, we summarize the existing literature addressing the interaction of RBC-EVs with coagulation and inflammatory pathways in vitro and in vivo. Additionally, we discuss the potential contribution of RBC-EV-induced thromboinflammation in the pathogenesis of certain complications of sickle cell disease as a model of a severe hemolytic disorder.
    DOI:  https://doi.org/10.1055/a-2664-0871
  8. Hematol Transfus Cell Ther. 2025 Jul 30. pii: S2531-1379(25)00202-0. [Epub ahead of print]47(3): 103934
    Incidence of hepatocellular carcinoma in beta thalassemia: a systematic review and meta-analysis.
    Marcella Adisuhanto, Alver Prasetya, Alius Cahyadi, Amaylia Oehadian.
       BACKGROUND: Current evidence indicates that iron overload increases the risk of hepatocellular carcinoma. However, the incidence of hepatocellular carcinoma in thalassemia is still unclear. This review aims to summarize the current evidence regarding the incidence of hepatocellular carcinoma in thalassemia patients.
    METHODS: Detailed searches were conducted in several databases, including PubMed, Europe PMC, EBSCOHost, and ProQuest. Keywords such as "thalassemia" and "hepatocellular carcinoma," along with other relevant synonyms, were used. Articles investigating the incidence of hepatocellular carcinoma in thalassemia patients were included. Pooled estimates were calculated using the DerSimonian Laird inverse-variance random effect model and presented as incidence (%) along with their 95 % confidence intervals and 95 % prediction intervals.
    RESULTS: From a total of 318 articles, five studies encompassing a total of 9592 thalassemia patients were included in this study. The cumulative incidence of hepatocellular carcinoma in thalassemia patients was 1.96 % (95 % confidence interval: 0.88 %-4.27 %; prediction interval: 0.12 %-24.74 %; I2 = 86.8 %). Of the 139 hepatocellular carcinoma patients, 121 were reported positive for anti-HCV, 78 for HCV RNA, three for HbsAg, and 50 positive for anti-HBV or had past infections. The liver iron concentration and ferritin level ranges in all studies were 2.95-10.5 mg/g and 3.1-2950 µg/L, respectively.
    CONCLUSIONS: The present meta-analysis demonstrates that the incidence of hepatocellular carcinoma in thalassemia patients was high (1.96 %). It might be caused by liver infection, iron overload, or something else.
    Keywords:  Hepatocellular carcinoma; Thalassemia
    DOI:  https://doi.org/10.1016/j.htct.2025.103934
  9. Semin Thromb Hemost. 2025 Jul 29.
    Transfusion-dependent thalassemia and venous thromboembolism: Position Statement from the Steering Committees of Hemostasis and Erythrocyte & Hemoglobinopathies study groups -Hellenic Society.
    Vasiliki Danilatou, Emmanouil Papadakis, Elias Kyriakou, Efrosyni Nomikou, Sophia Delicou, Fotios Girtovitis.
      Venous thromboembolism is often under-estimated in transfusion dependent thalassemia (TDT) patients, as arterial thrombotic events are more commonly observed. Although therapeutic advancements have transformed this disease from a once-fatal childhood disease into a manageable chronic condition, some treatments may contribute to an increased risk of thrombosis. Additionally, the prolonged life expectancy of these patients further contributes to the overall thrombotic risk. Patients with thalassemia major present multiple challenges when considering anticoagulation therapy. The decision-making process is complicated by a delicate balance between thrombotic risk-driven by disease-related and treatment-associated factors-and potential bleeding tendencies, particularly in the presence of comorbid conditions such as liver dysfunction, hypersplenism, or thrombocytopenia. Therefore, ongoing assessment of both thrombotic and bleeding risk and the implementation of appropriate preventive strategies are essential to optimize patient outcomes. This document presents a consensus statement from the Steering Committee of the Hemostasis Working Group of the Hellenic Society of Hematology, offering guidance on thromboprophylaxis and anticoagulation management in adult TDT patients.
    DOI:  https://doi.org/10.1055/a-2669-7739
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