bims-sicedi Biomed News
on Sickle cell disease
Issue of 2025–10–19
nine papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Circulating Erythrocyte- and Endothelial-Derived Microvesicles as Biomarkers of Hemolysis and Clinical Severity in Sickle Cell Disease.
  2. Higher aged neutrophils and differential inflammatory profiles in sickle cell disease patients on chronic transfusion therapy versus those on hydroxyurea.
  3. Association Between Steady-State Lactate Dehydrogenase Levels and Sickle Cell Complications: A Systematic Review.
  4. Early Biomarkers of Nephropathy in Patients with Sickle Cell Disease.
  5. Tebapivat Improves Red Cell Deformability and Decreases Sickling in Patients With Sickle Cell Disease: A Phase 1 Trial Substudy.
  6. Cerebral Blood Flow Decline in Adults With Sickle Cell Anemia: What Does It Mean and Is Treatment Required?
  7. Unexpected absence of fetal hemoglobin induction by lenalidomide in a patient with sickle cell anemia with concurrent multiple myeloma.
  8. Association of depression and hydroxyurea use with neuropathic pain in hemoglobinopathies.
  9. Cerebral Blood Flow in Children and Adults With Sickle Cell Anemia.
  1. J Cell Mol Med. 2025 Oct;29(19): e70827
    Circulating Erythrocyte- and Endothelial-Derived Microvesicles as Biomarkers of Hemolysis and Clinical Severity in Sickle Cell Disease.
    Khouloud Khalfaoui, Mariem Chebbi, Oussema Souiai, Ilhem Ben Fraj, Monia Ben Khaled, Amine Hableni, Mbarka Barmate, Dorra Chaouachi, Fethi Mellouli, Monia Ouederni, Ines Safra, Samia Menif, Imen Moumni.
      Sickle cell disease (SCD) is a monogenic disorder caused by the presence of hemoglobin S (Hb S) and is associated with a wide range of clinical complications, including hemolytic anemia, vaso-occlusive crises (VOC), and acute chest syndrome (ACS). This variability is largely driven by Hb S polymerisation and abnormal cell adhesion, which promote the release of circulating microvesicles (MVs). MVs are small vesicles (0.1-1.0 μm) released from various cell types in response to oxidative stress, cellular activation, or apoptosis. They possess pro-coagulant and pro-inflammatory properties and are increasingly recognised as potential modulators of disease processes. In this study, homozygous SCD patients and healthy controls were recruited to characterise their MVs profiles using flow cytometry and to explore associations with clinical and biological parameters. SCD patients exhibited significantly elevated levels of MVs compared to controls. Notably, red cell-derived MVs (RMVs) and phosphatidylserine-positive MVs (AMVs) were strongly associated with elevated lactate dehydrogenase (LDH) levels and clinical severity. A negative correlation was observed between fetal hemoglobin (Hb F) and endothelial MVs (EMVs), suggesting a protective role of Hb F against endothelial injury. These findings support the potential of MVs as diagnostic and prognostic biomarkers for identifying SCD patients at higher risk of complications.
    Keywords:  LDH; circulating microvesicles; fetal hemoglobin; flow cytometry; sickle cell disease
    DOI:  https://doi.org/10.1111/jcmm.70827
  2. Front Immunol. 2025 ;16 1671061
    Higher aged neutrophils and differential inflammatory profiles in sickle cell disease patients on chronic transfusion therapy versus those on hydroxyurea.
    Katrina Terrigno, Zachary N Flamholz, Aakash Mahant Mahant, Ilir Agalliu, Jennifer De Los Santos, Karen Ireland, Janine Keenan, Jacob S Kazmi, Anayeli Correa, Paul S Frenette, Libusha Kelly, Betsy C Herold, Deepa Manwani.
       Background: Sickle cell disease (SCD) is characterized by a point mutation in the β globin molecule, causing the sickling of red blood cells, and leading to hemolytic anemia, pain, and end-organ damage. Hydroxyurea (HU) is a cornerstone of SCD patient treatment, while chronic transfusions (CT) are used as part of treatment for more severe SCD. Increases in aged neutrophils and inflammation have been linked to more severe SCD and contribute to vaso-occlusive crises. The current study was designed to test the hypothesis that HU reduces inflammation and aged neutrophils.
    Study design: We compared clinical characteristics, aged neutrophils, levels of select cytokines, chemokines, and cell adhesion molecules in the blood and the Shannon diversity index (SDI) and ratio of Firmicutes/Bacteroides (F:B) in stool samples from pediatric SCD patients treated with HU (n=40) versus CT (n=14).
    Results: Patients in the HU group had significantly lower total and aged neutrophils (p<0.0001) compared to the CT group and also had lower levels of several chemokines including CXCL10 (IP-10), CCL2 (MCP-1) and CCL4 (MIP-1β) as well as IFN-γ and IL10. Conversely, HU was associated with higher levels of IL-1α, IL-6 and IL-8. There were no significant differences in cell adhesion markers or in markers of gut microbial dysbiosis between treatment groups. In a multivariable linear regression model, only being on CT was associated with increased number of aged neutrophils (p<0.001) whereas being on CT and having a lower SDI were associated with higher total neutrophil count.
    Discussion: Lower numbers of total and aged neutrophils and lower levels of several cytokines and chemokines in the HU group highlight the drug's potential to modulate leukocyte activation and recruitment. These findings suggest that adding or maintaining HU therapy in SCD patients undergoing CT could potentially enhance immunologic regulation and warrants further study.
    Keywords:  aged neutrophils; chronic transfusion; gut microbiome; hydroxyurea; inflammation; inflammatory cytokines; sickle cell disease
    DOI:  https://doi.org/10.3389/fimmu.2025.1671061
  3. Avicenna J Med. 2025 Jul;15(3): 100-108
    Association Between Steady-State Lactate Dehydrogenase Levels and Sickle Cell Complications: A Systematic Review.
    Sagad O O Mohamed, Amged Mohammed, Fatima S K Salih, Hozifa A M Elgadal, Ayman A A Elsamany, Mohamed S K Salih, Huda M A Mustafa, Israa Elawad, Mona G A Ahmedkaroum, Safaa G A Saeed, Rowa E A Ibrahim, Esraa A Mohamedien, Aya A H Babiker, Esraa T Suliman, Eman O E Mohamed.
      Sickle cell disease (SCD) is a hereditary hemoglobin disorder characterized by vaso-occlusion and chronic hemolysis, leading to severe complications. Finding cost-effective and reliable biomarkers for predicting disease severity and identifying high-risk patients remains challenging, especially in resource-limited settings. This systematic review evaluates the association between lactate dehydrogenase (LDH) levels measured during clinical steady-state and various complications of SCD to assess its prognostic value. A systematic literature search, adhering to PRISMA guidelines, was conducted across Medline/PubMed, Web of Science, Embase, and ScienceDirect. Eligible studies included all observational studies examining the relationship between LDH levels and subsequent SCD complications. The statistical analyses were performed to calculate the pooled standardized mean difference (SMD) and its 95% confidence interval (CI). A total of 34 studies were included, highlighting significant associations between elevated LDH levels and various SCD-related complications. These included pulmonary arterial hypertension (SMD = 0.454, 95% CI: 0.032-0.875, p  = 0.035), stroke risk through transcranial Doppler velocities (SMD = 0.651, 95% CI: 0.459-0.843, p  < 0.001), and kidney involvement (SMD = 0.399, 95% CI: 0.014-0.785, p  = 0.042). This systematic review reveals a consistent association between elevated steady-state LDH levels and major complications of SCD. The findings suggest a potential role for LDH as a readily available biomarker for SCD severity, underlining its potential for inclusion in clinical assessments of SCD severity, risk stratification, and tailored interventions for high-risk patients.
    Keywords:  complications; lactate dehydrogenase; sickle cell disease; systematic review
    DOI:  https://doi.org/10.1055/s-0045-1811706
  4. Indian J Pediatr. 2025 Oct 13.
    Early Biomarkers of Nephropathy in Patients with Sickle Cell Disease.
    Vineeta Gupta, Luv Kumar, Ragini Srivastava, Priyanka Aggarwal.
      
    DOI:  https://doi.org/10.1007/s12098-025-05810-5
  5. Eur J Haematol. 2025 Oct 13.
    Tebapivat Improves Red Cell Deformability and Decreases Sickling in Patients With Sickle Cell Disease: A Phase 1 Trial Substudy.
    Julia Z Xu, Brian J Philips, Nelly K Kiriza, Selma K Bendtsen, Jesper B Petersen, Jens Helby, Manzoor Mohideen, Enrico M Novelli, Andreas Glenthøj.
      
    DOI:  https://doi.org/10.1111/ejh.70048
  6. Neurology. 2025 Nov 11. 105(9): e214331
    Cerebral Blood Flow Decline in Adults With Sickle Cell Anemia: What Does It Mean and Is Treatment Required?
    Fenella J Kirkham, Nomazulu Dlamini.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000214331
  7. Orphanet J Rare Dis. 2025 Oct 17. 20(1): 522
    Unexpected absence of fetal hemoglobin induction by lenalidomide in a patient with sickle cell anemia with concurrent multiple myeloma.
    Rasmus Rønnemoes, Jens Helby, Amina Nardo-Marino, Morten Hanefeld Dziegiel, Jesper Petersen, Agoston Gyula Szabo, Nina Toft, Andreas Glenthøj.
      Sickle cell anemia (SCA) and multiple myeloma (MM) are debilitating hematologic diseases impacting hemoglobin and plasma cells, respectively. Despite differing origins, they share overlapping clinical features including bone pain and anemia. A cornerstone of SCA is to induce fetal hemoglobin through hydroxyurea treatment. Lenalidomide, a central treatment of MM, has also been shown to induce fetal hemoglobin in vitro. Here we present a case of a young woman with SCA and subsequently multiple myeloma. When lenalidomide was used as part of multiple myeloma treatment, we investigated the proposed induction of fetal hemoglobin, using high-pressure liquid chromatography. Over a treatment period of 114 days, we did not observe lenalidomide-induced increases in fetal hemoglobin and were thereby unable to replicate in vitro findings. Moreover, the case highlights many difficulties of diagnosing and treating patients with SCA and concurrent malignancies.
    DOI:  https://doi.org/10.1186/s13023-025-04052-0
  8. Sci Rep. 2025 Oct 13. 15(1): 35750
    Association of depression and hydroxyurea use with neuropathic pain in hemoglobinopathies.
    Derya Yavuz Demiray, Gönül Oktay.
      This study aimed to investigate the presence of neuropathic pain and its associated factors in patients diagnosed with the hemoglobinopathies thalassemia major (TM) and sickle cell disease (SCD). This study included 27 patients with TM and 30 patients with SCD who presented to the neurology clinic between 2022 and 2023. All participants had normal electromyography (EMG) findings and nerve conduction studies. Patients aged between 20 and 50 years were evaluated for neuropathic pain using the Neuropathic Pain Scale (DNET-4). Data were analyzed in relation to age, sex, smoking status, hemoglobin levels, platelet count, ferritin levels, presence of depression, use of hydroxyurea and chelation therapy, and splenectomy status. Depression was assessed using the Beck Depression Inventory. Patients with neuropathy due to anatomical pathology, lumbar disc herniation, diabetes mellitus, prior use of neurotoxic drugs, or clinical signs of peripheral nerve involvement were excluded from the study. The mean age was 29.22 years in the TM group and 32.03 years in the SCD group (p = 0.010). Neuropathic pain was reported by 37.1% of patients with TM and 46.7% of those with SCD, with higher pain scores tending to occur in the sickle cell group (p = 0.069). A statistically significant difference and moderate positive correlation were found between neuropathic pain and hydroxyurea treatment (p < 0.01). No significant difference was observed between the groups in terms of depression levels (p = 0.63); however, a strong positive correlation was found between depression severity and neuropathic pain scores (p < 0.001). As depression levels increased, neuropathic pain severity also increased. The TM group had significantly lower hemoglobin levels (8.21 ± 0.92 g/dL) compared to the SCD group (10.03 ± 1.45 g/dL) (p < 0.001). Ferritin levels were significantly higher in the TM group (2678 ± 1689 ng/mL) than in the sickle cell group (580 ± 689 ng/mL) (p < 0.001). No statistically significant associations were observed between neuropathic pain and chelation therapy, splenectomy, or smoking status. Neuropathic pain in patients with TM and SCD was significantly associated with depression severity. Hydroxyurea treatment showed a moderate association with neuropathic pain in patients with SCD, potentially reflecting greater disease burden. These findings underscored the importance of comprehensive clinical evaluation, including both neurological and psychological assessments, in the management of these patients.
    Keywords:  Depression; Neurologic complications; Neuropathic pain; Sickle cell disease; Thalassemia major
    DOI:  https://doi.org/10.1038/s41598-025-20590-w
  9. Neurology. 2025 Nov 11. 105(9): e214227
    Cerebral Blood Flow in Children and Adults With Sickle Cell Anemia.
    Lori C Jordan, Wesley Richerson, Megan Aumann, Alexander K Song, Spencer Waddle, Meher R Juttukonda, R Sky Jones, L Taylor Davis, Sumit Pruthi, Dann Martin, Mark Rodeghier, Samantha M Davis, Adetola A Kassim, Michael R DeBaun, Manus J Donahue.
       BACKGROUND AND OBJECTIVES: Understanding age-related changes in cerebral blood flow (CBF, rate of blood delivery to brain tissue) in sickle cell anemia (SCA) is a prerequisite to incorporating CBF as a marker of brain health. CBF decreases from school-age through adulthood in nonanemic people. In SCA, CBF is generally increased to compensate for anemia, but knowledge of age-related norms is limited. We hypothesized that age-related CBF trajectories differ for SCA vs nonanemic healthy persons: CBF increases from childhood to early adulthood in SCA to compensate for reduced blood oxygen content and then plateaus because of reduced vasodilatory capacity with older age.
    METHODS: Children and adults with SCA and race-matched controls (hemoglobin [Hb] AA) aged 6-45 years were enrolled in an observational cross-sectional study from 2014 to 2023 at an academic and community health center. History of overt stroke or arterial stenosis >50% were exclusions. Brain MRIs were performed at 3T with arterial-spin-labeling measurements of gray matter CBF. Regression analyses assessed how age, imaging markers of ischemia, Hb, and arterial oxygen saturation (SpO2) related to CBF.
    RESULTS: In 192 Black participants with SCA (N = 126; mean age = 18.7 ± 9.0 years, 52.4% female) or without SCA (N = 66; mean age = 22.4 ± 9.7 years, 54.5% female), total Hb was lower in SCA (mean Hb = 8.9 ± 1.3 g/dL) vs control (mean Hb = 13.4 ± 1.5 g/dL) participants (p < 0.001) and did not differ with age in the SCA group. SpO2 was reduced in SCA (median SpO2 = 96%; interquartile range [IQR] = 94-97.4%) vs controls (median SpO2 = 98%, IQR = 97-99%, p < 0.001). In SCA participants, SpO2 was lower in adults (median SpO2 = 95%, IQR = 94%-97%, p = 0.001) compared with children (SpO2 = 96.5%, IQR = 95%-98.2%). Regression analyses, including an interaction between age and group (SCA vs control), showed that CBF increases in SCA by 5.03 mL/100 g/min per decade (95% CI 1.70-8.37) and plateaus at approximately age 30-35 years. In controls, CBF decreased by -5.20 mL/100 g/min per decade (95% CI -8.96 to -1.94).
    DISCUSSION: The divergent age dependency of CBF between SCA and non-anemic persons may be explained by a gradient of increasing CBF with age required to compensate for reductions in blood oxygen content in SCA, with possible exhaustion of cerebral vasodilatory abilities in the fourth decade of life. Longitudinal studies are needed.
    DOI:  https://doi.org/10.1212/WNL.0000000000214227
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