bims-sicedi Biomed News
on Sickle cell disease
Issue of 2025–12–14
eleven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Chronic Hydroxyurea Therapy in Children with Sickle Cell Anemia: Mechanisms of Action, Systemic Effects, and Long-Term Safety.
  2. Cellular therapies for sickle cell disease: Should we be calling them a cure?
  3. Hemorphins, atypical endogenous opiate peptides, in sickle cell disease and their association with pain.
  4. The correlation of lupus anticoagulant and anticardiolipin antibodies with hematological parameters and clinical findings in sickle cell disease at steady state phase.
  5. Thrombomodulin protects against acute vascular and multiorgan injury in Sickle Cell disease.
  6. Histopathological Features of Sickle Cell Nephropathy in the Arab-Indian Haplotype.
  7. Hydroxyurea Therapy in Sickle Cell Disease: Evaluating Healthcare Costs and Utilization in a Brazilian Tertiary Setting.
  8. Increased Prevalence of Clonal Hematopoiesis in Children with Sickle Cell Disease.
  9. When Blood Disorders Meet Cancer: Uncovering the Oncogenic Landscape of Sickle Cell Disease.
  10. HLA-haploidentical hematopoietic stem cell transplantation in patients with sickle cell disease: results from the phase II DREP-HAPLO trial.
  11. Shoulder complications in sickle cell disease: Challenges, management strategies, and future directions.
  1. J Clin Med. 2025 Dec 04. pii: 8599. [Epub ahead of print]14(23):
    Chronic Hydroxyurea Therapy in Children with Sickle Cell Anemia: Mechanisms of Action, Systemic Effects, and Long-Term Safety.
    Federica Fogliazza, Martina Berzieri, Giulia Carbone, Davide Ciriaco, Susanna Esposito.
      Sickle cell disease (SCD) is the most common monogenic disorder worldwide and remains a major cause of morbidity and mortality. Sickle cell anemia (SCA), the homozygous HbSS genotype, represents the most severe and frequent form within the spectrum of SCD. Hydroxyurea (HU), a ribonucleotide reductase inhibitor, represents the first and most widely used disease-modifying therapy for SCA. This review summarizes current evidence on the mechanisms of action, clinical efficacy, systemic effects, and long-term safety of chronic HU therapy in patients with SCA. A comprehensive literature search was conducted in PubMed up to 2025 using the terms "sickle cell disease," "sickle cell anemia", "hydroxyurea," and "children" or "paediatric." Eligible studies included randomized controlled trials, cohort studies, and systematic reviews evaluating HU therapy in SCA. Literature analysis showed that HU exerts pleiotropic effects by inducing fetal hemoglobin (HbF) synthesis, improving red blood cell deformability, reducing leukocyte and platelet counts, and enhancing nitric oxide bioavailability. These mechanisms lead to decreased vaso-occlusive crises, acute chest syndrome, transfusion requirements, and overall mortality. Beyond hematologic improvement, HU confers neuroprotective benefits, modulates inflammatory and immune pathways, and supports normal growth and endocrine development in children. Adverse events, primarily mild bone marrow suppression, are dose-dependent and reversible with appropriate monitoring. No evidence supports an increased risk of malignancy with long-term use. In conclusion, chronic HU therapy is a safe, effective, and multifaceted treatment that substantially improves survival and quality of life in patients with SCA. Early initiation and individualized dosing maximize its therapeutic benefits and help prevent irreversible organ damage.
    Keywords:  fetal hemoglobin; hydroxyurea; inflammation; long-term safety; neuroprotection; sickle cell anemia; sickle cell disease
    DOI:  https://doi.org/10.3390/jcm14238599
  2. Hemasphere. 2025 Dec;9(12): e70283
    Cellular therapies for sickle cell disease: Should we be calling them a cure?
    Lydia O Okoibhole, Funmi Dasaolu, Zainab Garba-Sani, Stephen P Hibbs.
      
    DOI:  https://doi.org/10.1002/hem3.70283
  3. Pain. 2025 Nov 19.
    Hemorphins, atypical endogenous opiate peptides, in sickle cell disease and their association with pain.
    Yanqi Tan, Yavnika Kashyap, Eduardo De La Toba, Seth W Croslow, Meghna Gill, Xiao Guo, Giokdjen Ilktach, Erin Davy, Robert Molokie, Zaijie Jim Wang, Jonathan V Sweedler.
       ABSTRACT: Sickle cell disease (SCD) is a genetic disorder caused by a mutation in the beta hemoglobin gene, resulting in red blood cell (RBC) distortion, hemolysis, and severe pain episodes. Despite advancements in understanding acute crisis pain that is caused by vaso-occlusion, the neurobiological mechanisms underlying chronic pain in SCD remain poorly studied. Hemorphins, atypical endogenous opioid peptides derived from the hemoglobin beta chain in RBCs have analgesic effects and may contribute to SCD-related pain mechanisms, as their formation occurs when hemoglobin in RBCs is exposed to proteases in plasma. In this study, we investigated the levels of hemorphins in both plasma and nervous system of humanized transgenic SCD mice using liquid chromatography mass spectrometry. Our results show a significant elevation of hemorphins in SCD mice compared with wild-type controls, with a strong correlation with individual pain levels. These findings suggest that altered hemorphin processing in SCD may contribute to chronic pain by modulating the opioid signaling pathways, offering insights into the neurobiology of pain in SCD.
    Keywords:  Cathepsin D; Endogenous opioid peptide; Hemoglobin; Hemorphins; Peptide hormone; Sickle cell disease
    DOI:  https://doi.org/10.1097/j.pain.0000000000003859
  4. Thromb J. 2025 Dec 08. 23(1): 117
    The correlation of lupus anticoagulant and anticardiolipin antibodies with hematological parameters and clinical findings in sickle cell disease at steady state phase.
    Mohammed Aw Almorish, Ahmed M E Elkhalifa, Moataz Mohamedalhasan Ali, Isameldin Mohamed Abdalla Hamad, Omer M Aburaida, Rabei M Elbadry, Yasir S Kaloda, Elfatih Mirghani M Salih, Khaled Mohammed Al-Sayaghi, Mohammed A Hameed Albalawi, Maher M Aljohani, Burhanudin Saha.
       BACKGROUND: Current therapeutic interventions for Sickle Cell Disease (SCD) have improved patient survival; however, the clinical determinants of elevated autoantibody prevalence and related complications in patients with SCD remain insufficiently elucidated.
    OBJECTIVE: This study aimed to examine the frequency of lupus anticoagulant (LA), anticardiolipin antibody (aCL), and anti-beta2 glycoprotein I antibodies (anti- β2GPI) in patients with SCD at steady state phase to evaluate their possible correlations with hematological factors and clinical complications.
    METHODS: This cross-sectional study involving 92 SCD patients in a steady state phase was conducted. Blood specimens were obtained for complete blood count (CBC), in conjunction with the identification of IgG for aCL and anti-β2GPI utilizing enzyme-linked immunosorbent assay (ELISA) and the assessment of LA through the Diluted Russell Viper Venom Time (dRVVT).
    RESULTS: The prevalence of LA, aCL, and anti-β2GPI (IgG) in SCD patients at steady state was 29.4%, 16.3%, and 5.4%, respectively. A correlation was found between LA and chronic leg ulcers, history of thrombosis, decreased platelet counts (PLT), and increased mean platelet volume (MPV) in SCD patients. Furthermore, aCL (IgG) exhibited a significant association with chronic leg ulcers, history of thrombosis, elevated Hemoglobin (Hb) levels, increased red blood cell count (RBC), and higher red cell distribution width (RDW) in SCD patients at steady state phase.
    CONCLUSION: This research elucidates the incidence of LA and aCL in SCD patients during steady state, linking these autoantibodies to hematological parameters and clinical complications; thus, prospective assessments of aPL in SCD patients are essential.
    Keywords:  Anticardiolipin antibodies; Chronic leg ulcers; Lupus anticoagulant; Sickle cell disease; Thrombosis; anti-beta2 glycoprotein I antibodies
    DOI:  https://doi.org/10.1186/s12959-025-00813-w
  5. JCI Insight. 2025 Dec 09. pii: e193884. [Epub ahead of print]
    Thrombomodulin protects against acute vascular and multiorgan injury in Sickle Cell disease.
    Guohui Ren, Dustin R Fraidenburg, Suman Setty, Jiwang Chen, Janae Gonzales, Maria Armila Ruiz, Zalaya Ivy, Najmeh Eskandari, Richard D Minshall, James P Lash, Victor R Gordeuk, Santosh L Saraf.
      Vaso-occlusive episodes (VOEs) in the setting of hyperhemolysis can rapidly evolve into multiorgan failure in sickle cell disease (SCD). Although the mechanisms for rapid progression to multiorgan failure are unclear, a systemic vasculopathy with thrombotic microangiopathy-type features has been described. Reduced thrombomodulin (TM) function is implicated in some thrombotic microangiopathy syndromes. We observed a greater decline in platelet count and hemoglobin concentration and increase in vascular injury biomarkers within 24-hours of admission for a VOE in 12 SCD patients with versus 12 without multiorgan failure. We observed decreased TM expression on the lung and kidney vasculature of three additional SCD patients with multiorgan failure and an autopsy performed compared to a non-SCD control. Transgenic SCD mice challenged with cell-free hemoglobin had reduced TM function, increased vascular injury biomarkers, and reduced renal cortical blood flow. Infusion of recombinant TM 2- or 24-hours after the challenge restored cortical blood flow, mitigated increases in vascular injury, complement activation, and tubular injury biomarkers, and protected against acute kidney and lung injury. We demonstrated that impaired TM function may be involved in the systemic vasculopathy of SCD-related multiorgan failure and infusion of recombinant TM may restore vascular function and protect against acute organ damage.
    Keywords:  Hematology; Nephrology; Thrombomodulin
    DOI:  https://doi.org/10.1172/jci.insight.193884
  6. Glomerular Dis. 2025 Jan-Dec;5(1):5(1): 438-447
    Histopathological Features of Sickle Cell Nephropathy in the Arab-Indian Haplotype.
    Basil Alnasrallah, Manaf Aljishi, Shatha Alfaraj, Abduallah Alqawain, Zainab Alkhuraidah, Eman Alabbad, Mohammad M Aljishi, Ahmed Ali Alnasser, Jafar Alrebh, Amein K Al-Ali, Husam Alzayer.
       Introduction: Sickle cell disease (SCD), an autosomal recessive disorder caused by hemoglobin S, leads to red blood cell sickling and multiorgan damage, including sickle cell nephropathy (SCN). While SCN histopathological changes are well described, data from the Middle East region, where the Arab-Indian (AI) haplotype is common, are limited. We hypothesized that SCN in patients in Saudi Arabia shows histopathological features similar to those in other regions, reflecting a shared renal injury mechanism.
    Methods: This single-center retrospective study analyzed kidney biopsies from adults with SCD in the Eastern Province of Saudi Arabia from 2012 to 2023. Histological specimens were examined using hematoxylin and eosin, periodic acid-Schiff stain, Masson trichrome stain, Jones silver stain, and immunofluorescence. Haplotype genotyping was performed using a nuclease allelic discrimination assay with target-specific primers and TaqMan probes labeled with VIC and FAM. Clinical and biochemical data were collected at the time of biopsy and at the last follow-up.
    Results: Twelve biopsies were included in the study (median age 44 years, 50% female). Median serum creatinine was 91.5 µmol/L (interquartile range [IQR] 59-130), and 24-h urinary protein was 3,300 mg (IQR 1,181-5,725). Of 9 patients tested, seven had homozygous AI haplotype, one had heterozygous AI, and one had BEN/CAR/CAM. Histopathology showed tubular hemosiderosis (92%), global sclerosis (75%), glomerular hypertrophy (75%), sickled red blood cells (58%), focal segmental glomerulosclerosis (42%), and glomerular basement membrane duplication (33%). These findings mirror SCN patterns in other haplotypes.
    Conclusions: In Saudi patients with SCD with predominant AI haplotype, SCN histopathological features align with those reported globally, suggesting a consistent renal pathogenesis across haplotypes. This study improves our understanding of SCN in the AI haplotype, supporting standardized treatment methods and further research into preventing progression.
    Keywords:  Arab-Indian haplotype; Chronic kidney disease; Pathology; Renal biopsy; Sickle cell disease; Sickle cell nephropathy
    DOI:  https://doi.org/10.1159/000549367
  7. Blood Glob Hematol. 2025 Oct 28. pii: 100040. [Epub ahead of print]
    Hydroxyurea Therapy in Sickle Cell Disease: Evaluating Healthcare Costs and Utilization in a Brazilian Tertiary Setting.
    La'Ron L A Browne, Emilia Matos do Nascimento, Patricia Moura, Delaine Fidlarczyk, Jane Duran, Roberto Barbosa, Thais Oliveira, George Goshua, Jane S Hankins, Clarisse Lobo.
      Patients with sickle cell disease (SCD) treated with hydroxyurea, a disease-modifying agent, experience reduced hospitalizations, blood utilization, opioid use, and mortality, but how the reduced acute care utilization translates to cost-savings is understudied. This study aimed to test whether hydroxyurea reduces overall care costs for SCD patients in Brazil. Healthcare costs in Brazilian Reais (R$) were collected from patients with SCD who had at least one encounter between January 1, 2018, and June 30, 2018. The total median healthcare resource utilization included ambulatory clinic, emergency department (ED), and inpatient care. Patients were stratified by hydroxyurea use and medication adherence (MPR >50% vs. ≤50%). A total of 3331 active patients were included in the analysis, with 3032 having at least one encounter. 51% were female, and the median age was 15 years (range 0-76). 2212 (73.0%), had HbSS/Sβ°thalassemia, followed by HbSC (n=610, 20%) and HbSβ+thalassemia (n=148, 5%). 614 (20.2%) were prescribed hydroxyurea. Hydroxyurea-treated patients had higher median ambulatory visits, fewer ED visits, and fewer hospitalizations than those not on hydroxyurea. While hydroxyurea reduced acute care utilization, costs remained comparable to those of patients not using hydroxyurea suggesting that disease severity, use of expensive drugs, and chronic conditions are key factors driving costs requiring further analysis.
    Keywords:  acute complications; admission; cost analysis; emergency department; emergency room; financial analysis; hospitalization; hydroxycarbamide; medication possession ratio; micro-costing; sickle cell anemia
    DOI:  https://doi.org/10.1016/j.bglo.2025.100040
  8. Blood. 2025 Dec 08. pii: blood.2025030898. [Epub ahead of print]
    Increased Prevalence of Clonal Hematopoiesis in Children with Sickle Cell Disease.
    Jessica Ulloa, Kristin Wuichet, Sara R Rashkin, Yash Pershad, Connor Shore, Caitlyn Vlasschaert, Mark J Rodeghier, Yu Yao, Victor R Gordeuk, Binal N Shah, Clifford M Takemoto, Santosh L Saraf, Michael R DeBaun, Mitchell J Weiss, Alexander G Bick.
      Recent studies have reached opposing conclusions about whether clonal hematopoiesis (CH) is increased or decreased in patients with sickle cell disease (SCD). Given that CH is typically age-related, its presence in children with SCD could offer unique insights into early-life mutagenesis and disease-related stressors. We tested the primary and secondary hypotheses, that children with SCD would have a higher prevalence of CH when compared to age, sex, and race matched children without SCD; and children with hydroxyurea would have a higher CH prevalence than children not treated with hydroxyurea. To address this, we conducted a cross-sectional study in two independent cohorts of children, ages 0-18 years, with SCD (n=1,025 and n=1,293, respectively) and a 2,957-person matched comparison group. Using a highly sensitive, error-corrected sequencing assay capable of detecting CH at a variant allele frequency ≥ 0.5%, we found that children with SCD have a significantly higher prevalence of CH in relation to the comparison group (odds ratio (OR)=4.2, p=7.4x10-13). Additionally, CH was not associated with exposure to hydroxyurea therapy (OR=0.76, p=0.44).
    DOI:  https://doi.org/10.1182/blood.2025030898
  9. J Clin Med. 2025 Nov 30. pii: 8509. [Epub ahead of print]14(23):
    When Blood Disorders Meet Cancer: Uncovering the Oncogenic Landscape of Sickle Cell Disease.
    Elise Casadessus, Manon Saby, Stéphanie Forté, Yves Pastore, Vincent-Philippe Lavallée, Thomas Pincez.
      Sickle cell disease (SCD) is a hemoglobinopathy characterized by hemolysis, vaso-occlusion, and systemic inflammation. Epidemiological studies identified an increased risk of leukemia, especially acute myeloid leukemia (AML), in individuals with SCD, whereas data regarding other tumors are conflicting. SCD-associated AMLs frequently display high-risk features with unfavorable karyotypes and a dismal prognosis. SCD is associated with multiple phenomena linked to carcinogenesis in other contexts, including chronic inflammation, oxidative stress, ineffective erythropoiesis, accelerated hematopoietic aging, impaired tumor immunosurveillance, and increased clonal hematopoiesis. The role and respective contribution of these disease-intrinsic mechanisms in SCD remain to be studied. Although therapies used in SCD could theoretically modulate the risk of malignancies, no data exist to support an increased or reduced risk associated with their use. The most notable exception is hematopoietic stem cell transplantation and, to a lesser extent, gene therapy, for which the conditioning and/or procedure itself is known to increase the risk of leukemia. In sum, the effect of SCD on carcinogenesis is an emerging area of investigation with data supporting specificities in SCD-associated AML. Future research is required to determine the role of treatments to mitigate the increased risk and improve the outcome of SCD-associated AML.
    Keywords:  clonal hematopoiesis; hematopoietic stem cell transplantation; hydroxyurea; leukemia; malignancy; sickle cell disease
    DOI:  https://doi.org/10.3390/jcm14238509
  10. Haematologica. 2025 Dec 11.
    HLA-haploidentical hematopoietic stem cell transplantation in patients with sickle cell disease: results from the phase II DREP-HAPLO trial.
    Nathalie Dhedin, Benedicte Bruno, Catherine Paillard, Erasti Gounfle, Nimnrod Buchbinder, Marie Ouachee Chardin, Mabel Gaba, Jean-Benoit Arlet, Cecile Arnaud, Camille Jung, Corinne Pondarre.
      We report the final analysis of the Drep-Haplo multicenter phase 2 protocol, which evaluated haploidentical transplantation after reduced-intensity conditioning regimen incorporating thiotepa, in children and adults with severe sickle cell disease (SCD). Twenty-two patients (median age: 17 years; range: 12-40) received a conditioning regimen consisting of 2 Gy total body irradiation, thymoglobulin, cyclophosphamide, fludarabine, and thiotepa, followed by T cell-replete bone marrow infusion and graft-versus-host disease (GVHD) prophylaxis based on post-transplant cyclophosphamide. The primary endpoint, event-free survival, defined as survival without graft failure and without moderate-to-severe chronic GVHD, was 68.18% (95% CI: 51.25%-90.70%) and 61.98% (95% CI: 44.07%-87.19%) at 1 and 4 years, respectively. Overall survival and rejection-free survival at 4 years were 90.15% (95% CI: 78.03%-100%) and 85.56% (95% CI: 71.63%-100%), respectively. Six patients (27%) developed moderate-to-severe GVHD. In most cases (4/6), GVHD resolved, leaving only two patients (9%) with persistent moderate to severe GVHD at last follow-up. Eighty-five grade 2 to 4 infectious episodes were reported in 21 patients during the 24 months of follow-up, most of which were bacterial (38 cases). These data strengthen existing evidence supporting the feasibility of haploidentical transplantation in both pediatric and adult patients with severe SCD, demonstrating a very low rejection rate when thiotepa is incorporated into the conditioning regimen. Future efforts should focus on reducing chronic GVHD and infection rates.
    DOI:  https://doi.org/10.3324/haematol.2025.300013
  11. World J Orthop. 2025 Nov 18. 16(11): 112198
    Shoulder complications in sickle cell disease: Challenges, management strategies, and future directions.
    Emad Anam.
      Sickle cell disease (SCD) is a genetic disorder characterized by chronic hemolysis and vaso-occlusive crises (VOCs), leading to musculoskeletal complications that significantly affect quality of life. Among these, shoulder complications are a concern, with humeral head avascular necrosis (AVN) being the second most common site of involvement after the femoral head. Other shoulder pathologies, including osteomyelitis and septic arthritis, further contribute to morbidity. However, these conditions remain underdiagnosed and understudied, often due to overlapping symptoms with VOC-related bone infarctions. Imaging, particularly magnetic resonance imaging, is crucial for early diagnosis and accurate differentiation. Management strategies range from conservative pain control to surgical interventions, including core decompression for early-stage AVN and arthroplasty for advanced joint destruction. Surgical outcomes in SCD, however, remain inconsistent due to higher complication rates and a lack of standardized guidelines. Despite advancements in diagnosis and treatment, shoulder pathology in SCD remains an area of limited research. This review highlights the need for larger, long-term studies with a homogeneous etiology to support and refine current treatment strategies and improve patient outcomes.
    Keywords:  Arthroplasty; Avascular necrosis; Core decompression; Osteomyelitis; Shoulder; Sickle cell disease
    DOI:  https://doi.org/10.5312/wjo.v16.i11.112198
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