bims-sicedi Biomed News
on Sickle cell disease
Issue of 2025–10–05
nine papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Sickle cell disease: doctors must listen and advocate.
  2. Enhanced PIEZO1 function contributes to the pathogenesis of sickle cell disease.
  3. Multiplex base editing of BCL11A regulatory elements to treat sickle cell disease.
  4. Intravenous immunoglobulins in the management of acute chest syndrome in two Jehovah's witnesses with sickle cell disease.
  5. Hydroxyurea pharmacokinetics in children with sickle cell anemia across different global populations.
  6. Altered cerebral blood flow and functional connectivity in sickle cell disease.
  7. The use of Eculizumab and Tocilizumab in the treatment of Hyperhemolysis syndrome, a comprehensive literature review.
  8. Severity patterns and predictors of sickle cell anaemia among Gambian children: A cross-sectional analysis.
  9. Association of Food Insecurity With Disease-Related Complications and Healthcare Utilization for Patients With Sickle Cell Disease.
  1. BMJ. 2025 Oct 03. 391 r2070
    Sickle cell disease: doctors must listen and advocate.
    Jennifer Darlow.
      
    DOI:  https://doi.org/10.1136/bmj.r2070
  2. Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2514863122
    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 F 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, leading to anemia and vaso-occlusion crises. In sickle erythrocytes, hemoglobin aggregation is followed by altered cation permeability and subsequent dehydration. Interventions that restore cation permeability can decrease hemolysis and ameliorate the symptoms associated with SCD. PIEZO1 is a nonselective 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 activity 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 activity in sickle erythrocytes, attenuates hemolysis, and reduces hypoxia-induced sickling. Furthermore, EPA 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 represents a promising therapeutic strategy to reestablishing normal cation permeability in SCD.
    Keywords:  PIEZO1; eicosapentaenoic acid (EPA); hemolysis; patch clamp electrophysiology; sickle cell disease
    DOI:  https://doi.org/10.1073/pnas.2514863122
  3. Cell Rep Med. 2025 Sep 26. pii: S2666-3791(25)00449-5. [Epub ahead of print] 102376
    Multiplex base editing of BCL11A regulatory elements to treat sickle cell disease.
    Letizia Fontana, Pierre Martinucci, Simone Amistadi, Tristan Felix, Margaux Mombled, Alexandra Tachtsidi, Guillaume Corre, Anne Chalumeau, Giulia Hardouin, Jeanne Martin, Oriana Romano, Mario Amendola, Panagiotis Antoniou, Annarita Miccio.
      Sickle cell disease (SCD) is a genetic anemia caused by the production of an abnormal adult hemoglobin. Elevated levels of fetal hemoglobin (HbF) in adulthood reduce disease severity. A promising therapy involves the treatment of hematopoietic stem/progenitor cells (HSPCs) with CRISPR-Cas9 to downregulate the HbF repressor BCL11A via generation of double-strand breaks (DSBs) in the +58-kb enhancer. To improve safety and HbF induction, we use base editors to target both the +58-kb and +55-kb enhancers without generating DSBs. We dissect key DNA motifs recognized by transcriptional activators and identify critical nucleotides. Multiplex base editing efficiently disrupts these sites, reactivating HbF to levels exceeding those achieved with CRISPR-Cas9-induced editing, while minimizing DSBs and genomic rearrangements. Base editing is effective in long-term repopulating HSPCs and results in robust HbF reactivation in vivo. These findings demonstrate that multiplex base editing of BCL11A enhancers is a safe, efficient, and durable strategy to treat SCD.
    Keywords:  BCL11A; base editing; fetal hemoglobin; gene editing; hematopoietic stem cells; sickle cell disease
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102376
  4. Haematologica. 2025 Oct 02.
    Intravenous immunoglobulins in the management of acute chest syndrome in two Jehovah's witnesses with sickle cell disease.
    Francesca Begali, Jacopo Ceolan, Silvia Vitale, Simone Villaboni, Matteo Merlo, Rachele Zamperini, Roberto Bertazzo, Soraia Ribeiro Luz, Filippo Mazzi, Lucia De Franceschi.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.287956
  5. Blood Adv. 2025 Sep 30. pii: bloodadvances.2025017254. [Epub ahead of print]
    Hydroxyurea pharmacokinetics in children with sickle cell anemia across different global populations.
    Alexandra Power-Hays, Kathryn E McElhinney, Thomas N Williams, George Mochamah, Peter Olupot-Olupot, George Paasi, Marvin E Reid, Angela E Rankine-Mullings, Robert O Opoka, Chandy C John, Patrick T McGann, Charles T Quinn, Nieko C Punt, Luke R Smart, Susan E Stuber, Teresa S Latham, Alexander A Vinks, Russell E Ware.
      Hydroxyurea provides effective disease-modifying treatment for people with sickle cell anemia (SCA), especially when escalated to maximum tolerated dose (MTD), but has wide interpatient dosing variability due to pharmacokinetic (PK) differences. Whether hydroxyurea PK parameters differ among children with SCA in different global regions is unknown. We compared hydroxyurea PK parameters among children with SCA from five clinical trials: HUSTLE (USA, NCT00305175), TREAT (USA, NCT02286154), NOHARM (Uganda, NCT01976416), REACH (Uganda and Kenya, NCT01966731), and EXTEND (Jamaica, NCT02556099). Key hydroxyurea PK parameters were determined using HdxSim™, a validated hydroxyurea PK-software program. The results were compared across regions by one way analysis of variance. The influence of laboratory and clinical variables on PK-guided doses were evaluated by linear regression. PK profiles from 451 children with SCA were included: 146 from the USA, 265 from Africa, and 40 from the Caribbean. Children from Africa had slightly lower volumes of distribution (p<0.001), but absorption rate (p=0.07) and clearance (p=0.2) were similar across regions. The PK-recommended doses to achieve MTD were statistically different but clinically similar: 26.6 ± 5.9, 27.6 ± 6.5, and 25.2 ± 4.7 mg/kg/day, respectively (p=0.04). In multivariable regression, younger age and increased reticulocyte counts were associated with higher PK-recommended doses. Hydroxyurea PK parameters in children with SCA differ minimally across global populations, predicting clinically similar doses to achieve MTD. Individualized hydroxyurea dosing based on a PK-population model derived from American children with SCA can be used broadly to maximize the benefits of this critical medication in other global populations.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017254
  6. J Sick Cell Dis. 2025 ;2(1): yoaf031
    Altered cerebral blood flow and functional connectivity in sickle cell disease.
    Daniel M Sop, Yue May Zhang, Wally R Smith.
       Background: Adults with sickle cell disease (SCD) often experience cognitive deficits and chronic pain, but the cerebral mechanisms underlying these symptoms remain unclear. Elevated cerebral blood flow (CBF) is a compensatory response to anemia, yet its impact on brain function and perception is not well understood.
    Objective: To examine alterations in cerebral perfusion and resting-state brain function in adults with SCD and their associations with cognition and pain sensitivity.
    Methods: Seven adults with SCD and 3 healthy controls underwent arterial spin labeling (ASL) and resting-state functional MRI (rs-fMRI). Metrics included global/regional CBF, resting-state functional connectivity (rsFC), and amplitude of low-frequency fluctuations (ALFF). Participants completed NIH Toolbox fluid cognition tests and the Pain Sensitivity Questionnaire (PSQ).
    Results: SCD patients exhibited significantly higher global CBF (72.1 vs. 47.2 mL/100g/min; P = .04), reduced cortical zALFF (P = .0013), and elevated white-matter zALFF (P = .0023). They also showed resting-state network hyperconnectivity, with diminished anti-correlations between the default mode and salience networks. SCD participants scored lower on processing speed (P = .02) and reported higher pain sensitivity (PSQ total, P = .0040). Higher CBF was associated with slower cognitive performance but not directly with pain sensitivity. Exploratory mediation models suggested that altered brain activity may partially mediate this relationship.
    Conclusions: Adults with SCD demonstrate cerebral hyperperfusion, disrupted functional connectivity, and altered spontaneous brain activity, which may contribute to cognitive slowing and heightened pain sensitivity. These findings highlight the need for further research into brain-targeted therapies in SCD.
    Keywords:  cerebral blood flow; cognitive impairment; functional connectivity; resting-state fMRI; sickle cell disease
    DOI:  https://doi.org/10.1093/jscdis/yoaf031
  7. Front Med (Lausanne). 2025 ;12 1651895
    The use of Eculizumab and Tocilizumab in the treatment of Hyperhemolysis syndrome, a comprehensive literature review.
    Ali Aqel, Yousef Al-Asa'd, Salam Al-Kindi, Jaafar Altouk, Abdullah Al Zayed, Abdulrahman Al-Abdulmalek, Mohamed A Yassin.
      Hyperhemolysis syndrome (HHS) is a rare but severe complication of red blood cell transfusion, characterized by the destruction of both the patient's and donor's red blood cells. This condition results in post-transfusion hemoglobin levels lower than pre-transfusion levels, often leading to profound anemia, tissue ischemia, and multiorgan failure. HHS predominantly affects individuals with hemoglobinopathies, particularly sickle cell disease. While the pathophysiology remains poorly understood, proposed mechanisms include bystander hemolysis via complement activation, suppression of erythropoiesis, macrophage-mediated RBC destruction. Refractory cases of HHS are managed with Eculizumab and Tocilizumab, targeting the complement pathway and macrophage activation, respectively. This review analyzed 22 reported cases of HHS identified through PubMed, Embase, and Google Scholar. Of these, 11 patients received Eculizumab, 10 received Tocilizumab, and 1 received both. The cohort had an mean age of 29.5 years, with 36.4% male and 63.6% female. Most patients had underlying hemoglobinopathies. Outcomes showed improvement in 18 patients without major side effects, while 1 patient showed no improvement, and 3 patients passed away. Despite promising results, concurrent use of other immune-modulating agents during treatment complicates attributing the observed efficacy to specific medications alone. Further studies are required to further evaluate the pathophysiology of HHS and assess the safety and effectiveness of these novel therapies.
    Keywords:  Eculizumab; HHS; Hyperhemolysis syndrome; Tocilizumab; monoclonal antibodies; transfusion reaction
    DOI:  https://doi.org/10.3389/fmed.2025.1651895
  8. Ann Hematol. 2025 Sep 29.
    Severity patterns and predictors of sickle cell anaemia among Gambian children: A cross-sectional analysis.
    Lamin Makalo, Muhammed Manka, Orlianys Ruiz Perez, Sheikh Joof, Fatoumatta Jitteh, Musa Touray, Cessare Medri.
      Sickle cell anemia (SCA) remains a significant cause of morbidity and mortality in sub-Saharan Africa. In The Gambia, limited data exist on the clinical severity and predictors of disease burden in affected children. This study aimed to assess severity patterns and identify factors associated with disease severity among children with SCA using a validated clinical scoring system. A hospital-based cross-sectional study was conducted at the Pediatric Hematology Clinic of Edward Francis Small Teaching Hospital, Banjul. One hundred sixty-four children aged 1-18 years with confirmed HbSS were enrolled. Clinical and demographic data were collected using a structured proforma, and disease severity was assessed using the Adegoke and Kuti scoring system. Data were analyzed with SPSS version 20. Associations between severity and clinical variables were explored using chi-square tests, t-tests, and correlation analysis. Among the 164 participants, 67.1% had mild disease, 31.7% moderate, and 1.2% severe. The mean age was 8.43 ± 4.19 years, and the male-to-female ratio was 1.34:1. Gender was significantly associated with disease severity (P = 0.028). Early age at diagnosis showed a non-significant trend toward higher severity. Painful crises, hospitalizations, and blood transfusions were significantly associated with greater severity (P < 0.001). Laboratory markers such as low packed cell volume and elevated white blood cell counts also correlated with higher severity. Acute chest syndrome was the most frequent complication (34%). Children on hydroxyurea tended to have higher severity scores, reflecting that the medication was typically initiated in those with more severe disease. Most Gambian children with SCA in this cohort exhibited mild to moderate disease. Clinical severity was significantly associated with gender, frequency of complications, and select hematologic parameters. The findings underscore the need for early diagnosis through neonatal screening and improved access to hydroxyurea and comprehensive care. Further research into genetic modifiers may enhance individualized disease management in this setting.
    Keywords:  Adegoke and kuti scoring system; Children; Complications; Disease severity; Hydroxyurea; Predictors; Sickle cell anemia; The gambia
    DOI:  https://doi.org/10.1007/s00277-025-06625-2
  9. Pediatr Blood Cancer. 2025 Oct 03. e32100
    Association of Food Insecurity With Disease-Related Complications and Healthcare Utilization for Patients With Sickle Cell Disease.
    Sharjeel Syed, Andrew Palmer, Austin Wesevich, Kristen Wroblewski, Gabrielle Lapping-Carr, Radhika Peddinti, Wendy S Darlington.
       BACKGROUND: Food insecurity is one of several household material hardships (HMH) recognized for their impact on disease severity and healthcare utilization in patients with chronic disease. Sickle cell disease (SCD) is a chronic disease, disproportionately affecting patients of lower socioeconomic status, that results in high rates of disease-related complications and high healthcare utilization. This study examines the relationship between food insecurity and SCD-related complications and healthcare utilization.
    METHODS: Patients (ages 2-24 years) and/or their parents were surveyed to assess food insecurity status during routine SCD clinic visits from July 2015 to July 2019. Food insecurity status was assessed using the United States Department of Agriculture (USDA) Food Security Short Form (six-item), with a lookback period of 12 months. Sociodemographic characteristics, disease-related complications, and healthcare utilization were abstracted from electronic health records.
    RESULTS: Overall, 22% (n = 25) of participant households were food insecure. Food insecurity was associated with significantly higher annual rates of acute chest syndrome (aOR = 3.12, 95% CI: 1.27-7.67), prevalence of cholecystectomy (aOR = 6.29, 95% CI: 1.66-23.80), and a higher number of hospitalizations (aOR = 2.40, 95% CI: 1.04-5.52).
    CONCLUSIONS: The rates of food insecurity among sampled households of pediatric and young adult patients with SCD were much higher than national (13.4%) and local county rates (13%). Food insecurity was independently associated with more disease-related complications and higher healthcare utilization even after adjusting for age, sex, and sickle cell type. These results suggest food insecurity may be a modifiable contributor impacting morbidity in patients with SCD and should prompt further study into these relationships.
    Keywords:  disease‐related complications; food insecurity; healthcare utilization; hemoglobin; pediatric; sickle; young adult
    DOI:  https://doi.org/10.1002/pbc.32100
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒09 at 22:16.