bims-sicedi Biomed News
on Sickle cell disease
Issue of 2025–04–06
twelve papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Maternal sleep-associated hypoxemia is common during pregnancy in sickle cell disease (SCD): a retrospective review.
  2. Osivelotor for the treatment of sickle cell disease.
  3. Enhanced PIEZO1 Function Contributes to the Pathogenesis of Sickle Cell Disease.
  4. Suspension physics govern the multiscale dynamics of blood flow in sickle cell disease.
  5. Hydroxyurea and Regression of Sickle Cell Nephropathy: Open Clinical Trial in a Pediatric Population in DR Congo.
  6. Genome Editing Strategies for Targeted Correction of β-globin Mutation in Sickle Cell Disease: From Bench to Bedside.
  7. Efficacy and safety of thalidomide with hydroxyurea in sickle cell anemia: a quasi-experimental clinical trial.
  8. Establishment of a haematopoietic cell transplantation programme for children with sickle cell disease in Tanzania.
  9. Efficacy of Hydroxyurea in Patients With Sickle Cell Anemia in a Low-Income Country (Côte d'Ivoire).
  10. Clinics and genetics of hyperhemolysis syndrome in patients with sickle cell disease.
  11. Epidemiological profile trends and cost of sickle cell disease in Brazil from 2008 to 2022.
  12. Comprehensive analysis of sickle β+-thalassemia genotypes and their associated HbA levels in France.
  1. Am J Obstet Gynecol MFM. 2025 Mar 26. pii: S2589-9333(25)00076-X. [Epub ahead of print] 101676
    Maternal sleep-associated hypoxemia is common during pregnancy in sickle cell disease (SCD): a retrospective review.
    Mofiyin A Obadina, Ada Chang, Iman Owens, Jane A Little.
      
    DOI:  https://doi.org/10.1016/j.ajogmf.2025.101676
  2. Expert Opin Pharmacother. 2025 Apr 03.
    Osivelotor for the treatment of sickle cell disease.
    Giovanna Cannas.
       INTRODUCTION: Despite advances in the treatment of sickle cell disease (SCD), an inherited disorder leading to abnormal sickle hemoglobin (HbS) polymerization, patients continue to have a shorter life expectancy comparatively to the general population. Increase in the concentration of oxygenated HbS in red blood cells (RBCs) has been considered as a novel approach to inhibit HbS polymerization and reduce RBC sickling and their complications, raising interest for novel oxygen affinity modulators.
    AREAS COVERED: This review summarizes characteristics and primary results obtained with osivelotor, a novel oxygen affinity modulator, for the treatment of SCD. Osivelotor is presented with improved pharmacokinetic properties comparatively to voxelotor. It may enable higher hemoglobin (Hb) occupancy at lower doses potentially leading to significant improvements of clinical outcomes.
    EXPERT OPINION: The first clinical phase 2/3 trial with osivelotor reported increases of Hb levels and RBC counts, and decrease of RBC sickling. The treatment was apparently well tolerated. However, osivelotor shares the same mechanism of action as voxelotor, and therefore similar limitations regarding its efficacy for which the improvement in Hb level appears misleading. Several issues remain to be resolved before considering any drug approval.
    Keywords:  Sickle cell disease; clinical trials; drug development; novel drug; osivelotor; oxygen affinity modulator
    DOI:  https://doi.org/10.1080/14656566.2025.2489123
  3. bioRxiv. 2025 Mar 19. pii: 2025.03.19.643952. [Epub ahead of print]
    Enhanced PIEZO1 Function Contributes to the Pathogenesis of Sickle Cell Disease.
    Luis O Romero, Manisha Bade, Laila Elsherif, Jada D Williams, Xiangmei Kong, Adebowale Adebiyi, Kenneth I Ataga, Shang Ma, Julio Cordero-Morales, Valeria Vásquez.
      Sickle cell disease (SCD), an inherited blood disorder caused by a mutation in the β-globin gene, is characterized by sickle erythrocytes that are prone to hemolysis, causing anemia and vaso-occlusion crises. In sickle erythrocytes, hemoglobin aggregation is followed by altered cation permeability and subsequent dehydration. Interventions to restore cation permeability can decrease hemolysis and ameliorate the symptoms associated with SCD. PIEZO1 is a non-selective mechanosensitive cation channel that regulates erythrocyte volume. Gain-of-function (GOF) mutations in PIEZO1 cause hemolytic anemia by increasing cation permeability, leading to erythrocyte dehydration in humans and mice. Although PIEZO1 plays a key role in erythrocyte homeostasis, its role in SCD remains unknown. Here, we demonstrate that the function of the PIEZO1 channel is upregulated in sickle erythrocytes of humans and mice, and this enhancement can be restored through a dietary intervention. We found that PIEZO1 function in sickle erythrocytes resembles that of the GOF mutation causing hemolytic anemia. A diet enriched in the ω -3 fatty acid eicosapentaenoic (EPA) acid decreases PIEZO1 function in sickle erythrocytes and hemolysis in a mouse model of SCD. Furthermore, EPA decreases hemolysis and reduces inflammatory markers. We propose that PIEZO1 contributes to the increase in nonselective cationic conductance (i.e., Psickle), which leads to dehydration downstream of hemoglobin polymerization. Our results suggest that reducing PIEZO1 function is a promising therapeutic approach to reestablishing normal cation permeability in SCD.
    DOI:  https://doi.org/10.1101/2025.03.19.643952
  4. bioRxiv. 2025 Mar 15. pii: 2025.03.13.642599. [Epub ahead of print]
    Suspension physics govern the multiscale dynamics of blood flow in sickle cell disease.
    Hannah M Szafraniec, Freya Bull, John M Higgins, Howard A Stone, Timm Krüger, Philip Pearce, David K Wood.
      In diseases from diabetes to malaria, blood dynamics are significantly altered, resulting in poor clinical outcomes. However, the multiscale mechanisms that determine blood flow in the microcirculation in health and disease are undefined, largely owing to the difficulty in directly linking cell properties to whole-blood rheology. Here, we overcome these difficulties by developing a microfluidic platform to measure red blood cell properties and flow dynamics in the same blood samples from donors. We focus on sickle cell disease (SCD), a genetic disorder that causes red blood cells to stiffen in deoxygenated conditions, with disease pathology driven by oxygen-dependent blood rheology. Our linked cell and whole-blood measurements establish that increases in effective resistances in heterogeneous suspensions are driven by increases in the proportion of stiff cells, similar macroscopically to the behavior of rigid-particle suspensions. Furthermore, by combining simulations with spatially resolved measurements of cell dynamics, we show how the spatio-temporal organization of stiff and deformable cells determines blood rheology and drives disease pathophysiology. In the presence of deformable cells, the stiffened cells marginate towards channel walls, increasing effective wall friction. In fully deoxygenated conditions in which all cells are stiffened, significant heterogeneity in cell volume fraction along the direction of flow causes localized jamming, drastically increasing effective viscous flow resistance. Our work defines the relevant suspension physics required to understand pathological blood rheology in SCD and other diseases affecting red blood cell properties. More broadly, we reveal the multiscale processes that determine emergent rheology in heterogeneous particle suspensions.
    DOI:  https://doi.org/10.1101/2025.03.13.642599
  5. Kidney360. 2025 Apr 03.
    Hydroxyurea and Regression of Sickle Cell Nephropathy: Open Clinical Trial in a Pediatric Population in DR Congo.
    Dieumerci Betukumesu Kabasele, Arriel Makembi Bunkete, Gloire Mbayabo, Paul Lumbala, Odio Matondo, Michel Aloni, Orly Kazadi, Tite Mikobi, Joseph Bodi Mabiala, François Kajingulu, Jean-Robert Makulo Rissassi, Ernest Sumaili, Prosper Lukusa, Jean-Lambert Gini Ehungu.
       BACKGROUND: Renal complications of sickle cell disease are becoming very common, and patients generally do not respond to conventional nephroprotective treatments. Among the drugs used, hydroxyurea (HU) seems to have produced good results according to some studies. This molecule has not yet been evaluated in the DR Congo for this purpose. To evaluate albuminuria and the glomerular filtration rate (GFR) after 9 months of HU treatment in a population of children with incipient sickle cell nephropathy.
    METHODS: This was an open clinical trial involving sickle cell syndrome children under 18 years of age followed by incipient sickle cell nephropathy (glomerular hyperfiltration =GHF and/or microalbuminuria). A mean HU dose of 20 mg/kg/d was administered to each child, with quarterly clinical and biological controls. GHF (new Schwartz formula) was defined as a rate > 130 ml/min/1.73 m2 for girls and > 140 ml/min/1.73 m2 for boys; albuminuria was defined as the albuminuria/creatinuria ratio (ACR) in mg/g. The Wilcoxon and McNemar tests were used to compare the results at admission and at the 9th month of treatment.
    RESULTS: In total, 30 children (mean age 8.9±4.1 years; 40% boys) whose mean fetal hemoglobin (HbF) level increased from 10±7.4 to 18.8±4.9% (p˂0.001), whose mean number of blood transfusions ranged from 7.4±6.7 to 0.1±0.3 bags/month (p˂0.001), and whose number of VOCs ranged from 1.8±1.1 to 0.2±0.4/month (p˂0.03) were included. The frequency of GHF decreased from 30% to 3.3% (p˂0.001). The mean albuminuria decreased from 122.5 ± 16.3 mg/g to 30 ± 2.4 mg/g.
    CONCLUSIONS: HU improved the course of sickle cell nephropathy. The mechanism of action behind this result appears to be an improvement in blood rheology.
    DOI:  https://doi.org/10.34067/KID.0000000805
  6. Mol Ther. 2025 Mar 30. pii: S1525-0016(25)00221-7. [Epub ahead of print]
    Genome Editing Strategies for Targeted Correction of β-globin Mutation in Sickle Cell Disease: From Bench to Bedside.
    Henna Butt, Shruti Sathish, Evan London, Taylor Lee Johnson, Khaled Essawi, Alexis Leonard, John F Tisdale, Selami Demirci.
      Sickle cell disease (SCD) includes a range of genotypes that result in a clinical syndrome, where abnormal red blood cell (RBC) physiology leads to widespread complications affecting nearly every organ system. Treatment strategies for SCD can be broadly categorized into disease-modifying therapies and those aimed toward a cure. Although several disease-modifying drugs have been approved, they do not fully address the complexity and severity of SCD. Recent advances in allogeneic transplantation and autologous gene therapy show promising outcomes in terms of efficacy and safety. While these approaches have improved the lives of many patients, achieving a durable and comprehensive cure for all remains challenging. To address this, gene-editing technologies, including zinc finger nucleases, TALENs, CRISPR-Cas, base editing, and prime editing, have been explored both ex vivo and in vivo for targeted correction of the β-globin gene (HBB) in SCD. However, direct correction of HBB and its translation from the laboratory to the clinic presents ongoing limitations, with challenges involved in achieving robust mutation correction efficiency, off-target effects, and high costs of therapies. The optimal strategy for curing SCD remains uncertain, but several promising approaches are emerging. This review will touch on past, present and future developments in HBB correction.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.03.047
  7. Blood Res. 2025 Apr 01. 60(1): 21
    Efficacy and safety of thalidomide with hydroxyurea in sickle cell anemia: a quasi-experimental clinical trial.
    Priyanka Samal, Anindita Paul, Harshwardhan Bahirat, Ajit Kumar Bishoyi, Venkatarao Epari.
       BACKGROUND: The clinical course of sickle cell anemia (SCA) is variable, with chronic hemolysis and end-organ damage caused by microvascular occlusion. We evaluated the efficacy and safety of thalidomide plus hydroxyurea (HU) compared with HU alone to determine whether the combination provides a superior clinical benefit and safety profile.
    METHODS: This was an open-label quasi-experimental clinical trial (Clinical Trials Registry of India, CTRI Registration Number 2023/04/065682). Patients with SCA aged > 12 years and postmenopausal females aged > 45 years were allocated 1:1 to receive either HU (20 mg/kg/day) and thalidomide (50 mg/day) in Group A or HU (20 mg/kg/day) only in Group B.
    RESULTS: The frequency of vaso-occlusive crises (VOCs), transfusion requirements, variations in hematological parameters (hemoglobin [Hb], fetal hemoglobin [HbF], and sickle hemoglobin [HbS]), and side effects between the groups were assessed over 12 months. Repeated-measures analysis of variance was used to determine changes across the observation period. The mean age of the 66 patients diagnosed with SCA (homozygous HbS mutation) was 32.9 (standard deviation ± 11.5) years, and 57.6% were males. Over the 12-month observation period, Group A had significantly fewer VOCs (3.48 ± 2.81) and packed red blood cell transfusions (3.61 ± 2.19) than Group B (11.36 ± 4.20 VOCs; 13.27 ± 3.70 transfusions) (p = 0.0001). There was a significant increase in Hb (8.2 ± 1.8 to 11.8 ± 1.2 g/dL), a decrease in HbS% (72.5 ± 5.5 to 64.5 ± 5.4), and a rise in HbF% (18.9 ± 5.1 to 28.4 ± 5.6) (p < 0.0001) in Group A.
    CONCLUSION: Combining thalidomide with HU significantly reduced VOCs and transfusion requirements, improved Hb and HbF%, and decreased HbS levels.
    Keywords:  Clinical trial; Hydroxyurea; Sickle cell anemia; Thalidomide
    DOI:  https://doi.org/10.1007/s44313-025-00068-4
  8. Lancet Haematol. 2025 Apr;pii: S2352-3026(24)00322-3. [Epub ahead of print]12(4): e244-e245
    Establishment of a haematopoietic cell transplantation programme for children with sickle cell disease in Tanzania.
    Fabio Giglio, Stella Malangahe, Shakilu Jumanne, Melikiard Mhozya, Alphonse Chandika, Cornelio Uderzo.
      
    DOI:  https://doi.org/10.1016/S2352-3026(24)00322-3
  9. Anemia. 2025 ;2025 3576890
    Efficacy of Hydroxyurea in Patients With Sickle Cell Anemia in a Low-Income Country (Côte d'Ivoire).
    Kouassi Gustave Koffi, Ruth Dieket, Emeraude N'dhatz, Nelly Eloise Abenan, Alexis Dohoma Silué, Ismael Kamara, Boidy Kouakou, Danho Clotaire Nanho.
      Background: Very few trials of hydroxyurea efficacy and safety have been conducted in sub-Saharan Africa. We aimed to evaluate the efficacy and safety of hydroxyurea and its utility in low-resource settings. Methods: We conducted a prospective comparative trial in patients with SCA. 128 patients were enrolled and divided into two groups. 68 patients were treated with hydroxyurea at a dose of 10-20 mg/kg/day and 62 patients in a control group without hydroxyurea. The endpoints evaluated were feasibility, safety, and benefit (laboratory variables, sickle cell-related events, transfusions). Results: The patients assigned to hydroxyurea treatment had a lower annual rate of crises than the control group (median 2.9 vs. 5.3 crises per year, p=0.001), a lower annual rate of hospitalizations (median 2.2 vs. 4.7, p=0.002), and a lower annual rate of transfusions (median 1.3 vs. 5.1, p=0.001). We observed a significant increase in Hb F from 11.77% to 14.6% (p=0.001) in patients treated with hydroxyurea. We also observed a significant increase in the mean Hb level from 7.3 g/dL to 9.2 g/dL in patients treated with hydroxyurea (p=0.004). Patients treated with hydroxyurea also have a beneficial effect on WBC and platelet levels by reducing leukocytosis and thrombocytosis. The annual number of infectious complications was significantly lower in the group of patients treated with hydroxyurea. Conclusion: Hydroxyurea has an important clinical benefit by reducing the incidence of vaso-occlusive events, infections, and transfusions, which translates into fewer hospitalizations. The main problem is that it is not accessible to most of our patients who live in poor socioeconomic conditions.
    DOI:  https://doi.org/10.1155/anem/3576890
  10. Transfusion. 2025 Apr 02.
    Clinics and genetics of hyperhemolysis syndrome in patients with sickle cell disease.
    International Component of the NHLBI Recipient Epidemiology and Donor Evaluation Study (REDS‐III) and for the TOPMed (NHLBI TransOmics for Precision Medicine) SCD working
       BACKGROUND: Hyperhemolysis syndrome (HHS) is a severe transfusion-related complication with a complex immune pathophysiology, primarily affecting individuals with sickle cell disease (SCD). Limited research has investigated the clinical and molecular risk factors for HHS, which could help identify at-risk patients. This study aimed to assess clinical factors associated with HHS and identify genetic variations that increase susceptibility using a candidate-gene approach.
    METHODS: Data were obtained from the REDS-III SCD cohort, comprising 2793 patients who underwent whole-genome sequencing as part of the Trans-Omics for Precision Medicine (TOPMed) program. Clinical and laboratory data were retrospectively collected. Patients with HHS were compared to matched controls (1:4) based on clinical variables and the frequency of single nucleotide variations (SNVs) associated with HHS, autoimmunity, and red blood cell (RBC) alloimmunization.
    RESULTS: HHS was identified in 13 patients (prevalence: 1.13%), the majority of whom had the HbSS genotype (69.2%). The most affected age group was 11-20 years (46.2%), and 61.5% of patients had RBC alloantibodies. Pain crisis was the most common indication for transfusion leading to HHS (41.7%). Three significant genetic variants were identified: rs10748663 (C > T) on chromosome 10 (BLNK gene), rs936469 (G > A) on chromosome 11 (PHRF1 gene), and rs6503691 (C > T) on chromosome 17 (STAT5B gene).
    CONCLUSION: HHS primarily affects adolescents and young adults with RBC alloantibodies, often following episodic transfusions. Genetic variations in STAT5B and the IRF7-PHRF1 region suggest that the B-cell receptor signaling pathway, which is essential for B-cell differentiation, may play a critical role in HHS pathophysiology.
    Keywords:  alloimmunization; blood transfusion; hemolysis; hemolytic reaction; sickle cell anemia; transfusion reaction
    DOI:  https://doi.org/10.1111/trf.18232
  11. Acta Cir Bras. 2025 ;pii: S0102-86502025000100901. [Epub ahead of print]40 e403025
    Epidemiological profile trends and cost of sickle cell disease in Brazil from 2008 to 2022.
    Luiza Telles, Paulo Henrique Moreira Melo, Gabriele Eckerdt Lech, Luana Baptistele Dornelas, Natália Zaneti Sampaio, Ayla Gerk, Madeleine Carroll, Cristina Camargo.
       PURPOSE: This study aimed to evaluate the epidemiological profile trends and economic impact of sickle cell disease (SCD) in Brazil from 2008 to 2022, focusing on incidence, mortality, and healthcare costs.
    METHODS: A cross-sectional analysis was conducted using data from the Fundação Oswaldo Cruz's platform, Plataforma de Ciência de Dados Aplicada à Saúde, encompassing hospitalizations related to SCD from January 2008 to December 2022. The International Classification of Diseases codes for SCD were used to retrieve data on incidence, mortality, procedures performed, and healthcare costs.
    RESULTS: The study included 151,535 hospitalizations for SCD, with 69.92% associated with SCD crises and 22.48% without crises. The mean annual hospitalizations were higher for crises (6,883.06) compared to those without crises (2,221.12). Mortality rates were significantly higher for patients hospitalized with crises compared to those without crises (p < 0.001). The economic impact of SCD was substantial, with annual costs exceeding 413 million USD.
    CONCLUSION: This study revealed a significant burden of SCD in Brazil, characterized by high hospitalization rates, particularly among younger patients, and elevated mortality rates associated with crises. Prospective studies and public health interventions are warranted to address SCD and mitigate its impact on public health.
    DOI:  https://doi.org/10.1590/acb403025
  12. Blood Cells Mol Dis. 2025 Mar 29. pii: S1079-9796(25)00015-4. [Epub ahead of print]112 102923
    Comprehensive analysis of sickle β+-thalassemia genotypes and their associated HbA levels in France.
    Cecilia Baltus, Stéphane Moutereau, Nathalie Couque, Bichr Allaf, Muriel Giansily-Blaizot, Julian Boutin, Ketty Lee, Emmanuelle Bernit, Estelle Cadet, Victor Bobee, Véronique Picard, Serge Pissard, Frédéric Galactéros, Céline Renoux, Philippe Connes, Patricia Aguilar-Martinez, Corinne Pondarre, Philippe Joly.
      We retrospectively reviewed the clinical records of 228 HbS/β+-thal patients. The different genotypes were distributed into three groups according to their mean residual HbA levels: <10 % (group 1; n = 22), between 10 and 20 % (group 2; n = 175) and > 20 % (group 3; n = 31). Routine red blood cells and hemoglobin parameters were compared between the three groups. Sixteen different sickle β+-thal genotypes were identified but only four of them were associated with a residual HbA level below 10 %. Patients of this group exhibited a more severe anemia (Hb < 10 g/dL; reticulocytes >200 G/L) compared to the two other groups. However, no difference could be observed on those parameters between patients of group 2 and 3, as well as for the main RBC parameters. According to our study, >80 % of the sickle β+-thalassemia patients in France have a residual HbA level beyond 10 % and a mild to moderate anemia. Only four β+-thal variations (all affecting the splicing process) would lead to a potentially severe SCD syndrome in association with HbS (HbA < 10 %) but this result should be confirmed in a prospective clinical study.
    Keywords:  Genotype-phenotype correlation; HbA levels; Sickle beta(+)-thalassemia
    DOI:  https://doi.org/10.1016/j.bcmd.2025.102923
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