bims-sicedi Biomed News
on Sickle cell disease
Issue of 2025–04–20
ten papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. "Learn and Know" in the era of gene addition/gene editing based approaches for sickle cell disease: The EHA-EBMT consensus paper.
  2. Thrombotic microangiopathic anemia in patients with sickle cell disease and its variants during a vaso-occlusive crisis.
  3. The feasibility of pharmacokinetic-based dosing of hydroxyurea for children with sickle cell anaemia in Uganda: Baseline results of the alternative dosing and prevention of transfusions trial.
  4. The vaso-occlusive pain crisis in sickle cell patients: A focus on pathogenesis.
  5. Exploration of Leucine Rich Alpha-2-Glycoprotein 1 (LRG1) and its Association with Proangiogenic Mediators in Sickle Cell Disease: A Potential Player in the Pathogenesis of the Disease.
  6. Molecular inflammatory expression profiles associated with the frequency of pain in individuals with sickle cell disease.
  7. Estradiol is Pro-Nociceptive and Associated with a Small-Fiber Neuropathy Among Premenopausal Women with Sickle Cell Disease.
  8. Evaluating the Long-Term Benefits of Hydroxyurea in Pediatric Sickle Cell Anemia.
  9. Outcomes of Hematopoietic Stem Cell Transplantation in children with Sickle Cell Disease: Does donor Sickle cell trait status matter?
  10. Oxidation of low-density lipoprotein by hemoglobin causes pulmonary microvascular endothelial barrier dysfunction through lectin-like oxidized LDL receptor 1.
  1. Bone Marrow Transplant. 2025 Apr 16.
    "Learn and Know" in the era of gene addition/gene editing based approaches for sickle cell disease: The EHA-EBMT consensus paper.
    Lucia De Franceschi, Emanuele Angelucci.
      
    DOI:  https://doi.org/10.1038/s41409-025-02561-x
  2. Res Pract Thromb Haemost. 2025 Feb;9(2): 102734
    Thrombotic microangiopathic anemia in patients with sickle cell disease and its variants during a vaso-occlusive crisis.
    Wouhabe Bancheno, Donna Alexander, Mekdem Melaku, Bary Malik.
      
    DOI:  https://doi.org/10.1016/j.rpth.2025.102734
  3. Br J Clin Pharmacol. 2025 Apr 13.
    The feasibility of pharmacokinetic-based dosing of hydroxyurea for children with sickle cell anaemia in Uganda: Baseline results of the alternative dosing and prevention of transfusions trial.
    Alexandra Power-Hays, Ruth Namazzi, Min Dong, Caroline Kazinga, Charles Kato, Sadat Aliwuya, Kathryn McElhinney, Andrea L Conroy, Adam Lane, Chandy John, Alexander A Vinks, Teresa Latham, Robert O Opoka, Russell E Ware.
      Pharmacokinetic (PK)-guided dosing of hydroxyurea for children with sickle cell anaemia (SCA) could optimize dosing and improve outcomes, but its feasibility has not been demonstrated in low-resource settings where the majority of affected children live. Alternative Dosing And Prevention of Transfusions (ADAPT) is a prospective trial evaluating blood transfusions and the feasibility of determining PK-guided, hydroxyurea maximum tolerated doses (MTD) for children with SCA in Uganda, using portable high-performance liquid chromatography (HPLC) and a novel PK software programme (HdxSim). ADAPT enrolled 106 participants, and 100% completed PK testing. PK-guided doses were generated for 78%, of which 38% were within the protocol-defined range. Accurately, measuring serum hydroxyurea concentrations via HPLC and the potential for hydroxyurea degradation impacted the feasibility. Ensuring that people with SCA globally have access to hydroxyurea is imperative, and improving treatment strategies requires ongoing innovation including PK-guided dosing. ADAPT is registered at ClinicalTrials.gov (NCT05662098).
    Keywords:  HPLC < drug analysis; clinical pharmacology; haematology; paediatrics; pharmacokinetics
    DOI:  https://doi.org/10.1002/bcp.70071
  4. Curr Res Transl Med. 2025 Mar 29. pii: S2452-3186(25)00021-2. [Epub ahead of print]73(3): 103512
    The vaso-occlusive pain crisis in sickle cell patients: A focus on pathogenesis.
    Fatemeh Javaherforoosh Zadeh, Azadeh Fateh, Hamed Saffari, Mohammadtaghi Khodadadi, Mohammadamin Eslami Samarian, Nasim Nikoubakht, Fatemeh Dadgar, Vahid Goodarzi.
      Vaso-occlusive pain crisis (VOC) is recognized as a prominent complication of sickle cell disease, accompanied by debilitating pain and serious consequences for patients, making it the primary cause of visits to hospital emergency departments. In the etiology of VOC, the intricate interaction of endothelial cells, hypoxia, inflammation, and the coagulation system is pivotal. Hemoglobin S polymerization under hypoxic conditions leads to the formation of rigid and adhesive red blood cells that interact with vascular endothelial cells and other blood cells, causing occlusion and subsequent inflammation. Hemolysis of red blood cells results in anemia and heightened inflammation, whereas oxidative stress and involvement of the coagulation system further complicate matters. In this review, we strive to examine the pathophysiology of VOC from these mentioned aspects by consolidating findings from various studies, as a comprehensive understanding of the causes of VOC is essential for the development of targeted therapeutic interventions and the prevention and management of pain, ultimately improving the quality of life for patients.
    Keywords:  Endothelial dysfunction; Pathogenesis; Sickle cells; Vaso-occlusive pain crisis
    DOI:  https://doi.org/10.1016/j.retram.2025.103512
  5. Turk J Haematol. 2025 Apr 15.
    Exploration of Leucine Rich Alpha-2-Glycoprotein 1 (LRG1) and its Association with Proangiogenic Mediators in Sickle Cell Disease: A Potential Player in the Pathogenesis of the Disease.
    Oğuzhan Özcan, Murat Kaçmaz, Fatma Hazal Erdoğan, Lütfiye Seçil Deniz Balyen, Hamdi Oğuzman, Hasan Kaya, Abdullah Arpacı.
       Objective: Leucine rich alpha-2-glycoprotein 1 (LRG1) is a novel mediator involved in the abnormal angiogenesis. We aimed to investigate circulating LRG1 levels and their relationship with proangiogenic mediators in sickle cell disease (SCD).
    Methods: A total of 50 patients with SCD, 25 in steady-state conditions (SCD-SS), 25 in painful VOC periods (SCD-VOC), and 25 healthy controls were included in the study. Demographical and clinical data were collected from hospital records. Serum LRG1, VEGFA, and HIF1A levels were measured by ELISA, and CRP by the nephelometric method. Routine biochemical parameters were assessed using an auto analyzer. Multinomial logistic regression was used to analyze ELISA parameters, and ROC curves were constructed to determine the optimal cut-off point for HIF1A to estimate VOC in SCD patients.
    Results: LRG1 and VEGFA levels were significantly higher in SCD patients than controls (p<0.001), with no difference between SCD-SS and SCD-VOC groups. HIF1A, CRP, and LDH levels differed significantly across all groups, highest in SCD-VOC (p<0.001). After adjusting for age and gender, LRG1, HIF1A, and VEGFA remained elevated in SCD groups. HIF1A correlated with CRP (r = 0.351, p = 0.024), but LRG1 showed no correlation with proangiogenic mediators in SCD-VOC group. The area under the curve (AUC) was calculated as 0.694 (95% CI, 0.542-0.845, p=0.021) and the optimal cut-off point were 494.5 pg/ml for HIF1A parameter to estimate VOC in patients with SCD.
    Conclusion: Circulating LRG1 levels may reflect neutrophil activation and contribute to the cross-talk between proangiogenic mediators released in SCD.
    Keywords:  Angiogenesis; HIF1A; LRG1; Sickle cell disease; VEGF
    DOI:  https://doi.org/10.4274/tjh.galenos.2025.2025.0441
  6. Blood Adv. 2025 Apr 16. pii: bloodadvances.2024015085. [Epub ahead of print]
    Molecular inflammatory expression profiles associated with the frequency of pain in individuals with sickle cell disease.
    Lana Mucalo Katunaric, Shuang Jia, Ashima Singh, Mark F Roethle, Julie A Panepinto, David Brousseau, Martin Hessner, Amanda M Brandow.
      Pain is the most common complication of sickle cell disease (SCD). The underlying biology of SCD pain is not well understood, which is a barrier to novel, effective analgesic and preventative therapies. A wide variability in the phenotypic expression of pain exists among individuals with SCD, despite the inheritance of a similar defective hemoglobin gene. This interindividual pain variability further complicates the ability to understand the biology and effectively treat pain. We sought to discover a biological signature comprised of differentially expressed genes unique to SCD that could differentiate between individuals with varied pain frequency. We conducted plasma-induced transcription analysis from 149 individuals with SCD and 60 Black individuals without SCD from multiple sites. We discovered 3028 differentially expressed genes that underwent Weighted Gene Co-Expression Network Analysis (WGCNA) to distinguish gene modules significantly associated with pain frequency. We identified 524 genes, significantly associated with pain frequency (≥|0.3| and p<0.05), that were further analyzed using The Database for Annotation, Visualization and Integrated Discovery (DAVID) tool to delineate the biological pathways associated with these genes. The highest ranked gene ontology process from DAVID was inflammatory response (p=1.67E-12) and many related pathways were enriched (e.g., response to lipopolysaccharide, chemokine and cytokine signaling). The top 10 hub genes identified within our biologic signature were TNF, CCL2, ITGAM, ITGAX, ICAM1, CCR5, CXCL2, IFNG, CCR1, CXCL3. Future work should focus on further validating this signature and investigating the potential targets uncovered for their mechanistic and potentially therapeutic role in SCD pain.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015085
  7. Hemoglobin. 2025 Apr 14. 1-11
    Estradiol is Pro-Nociceptive and Associated with a Small-Fiber Neuropathy Among Premenopausal Women with Sickle Cell Disease.
    Zachary Ramsay, Deva Sharma, Margaret Wisdom-Phipps, Nicki Chin, Leroy Campbell, Jennifer Knight-Madden, Monika Asnani.
      Vaso-occlusive crisis (VOC) pain episodes often occur with menses and concurrent hormonal contraceptive use may reduce their frequency. This study tested the hypothesis that among women with sickle cell disease (SCD), sex hormones are associated with pain detection thresholds. Women with SCD aged minimum 18 years with regular menses, and without acute illnesses, pregnancy, oophorectomy, or hormonal contraceptive use within three months prior were included. Pain detection thresholds for heat (HPT) and pressure (PPT), and serum estradiol, progesterone and testosterone were measured at follicular and luteal phases. The Adult Sickle Cell Quality-of-Life Measurement Information System assessed quality-of-life and VOC frequency and severity scores. Generalized linear mixed models were performed, including the day of the cycle standardized by cycle length. Among 125 participants, neither the day nor phase of the menstrual cycle was associated with PPT or HPT. In multivariate analyses, worse VOC scores (β = 1.7) and severe genotype (β = -46.0) were associated with higher and lower trapezius PPT, respectively. Older age was associated with lower forearm HPT (β = -0.1). Among leg measurements, ovulatory cycles (β = -1.1) and hydroxyurea use (β = -1.2) were associated with lower HPT, while worse VOC scores (β = 0.1) were associated with higher HPT. Higher estradiol was associated with lower HPT at the leg (β = -0.02), with an interaction with the cycle day (β = 0.001) predicting lower thresholds earlier in the cycle for the same estradiol level. Estradiol is associated with a time-varying, length-dependent small-fiber neuropathy among SCD women; and may be a potential therapeutic target and biomarker for SCD pain.
    Keywords:  Neuropathy; estrogen; nociception; pain; sickle cell disease
    DOI:  https://doi.org/10.1080/03630269.2025.2489634
  8. Blood Adv. 2025 Apr 16. pii: bloodadvances.2024015564. [Epub ahead of print]
    Evaluating the Long-Term Benefits of Hydroxyurea in Pediatric Sickle Cell Anemia.
    Paul E George, Grace Gardiner Kalmus, Peter A Lane, Wilbur A Lam, Joseph Lipscomb, David Howard.
      Hydroxyurea is the primary disease-modifying medication for sickle cell anemia (SCA), but its long-term effects, particularly how these effects change over time, are not well understood. This study aimed to quantify the effects of hydroxyurea on clinical and laboratory outcomes in children with SCA over a prolonged period of use. We conducted a quasi-experimental study using contemporary difference-in-differences and dynamic event study analyses on a longitudinal cohort of 2,147 children with SCA (HbSS/HbSβ0) from 2010-2021. Primary outcomes included emergency department (ED) visits per year, hospital days per year, and annual average hemoglobin concentration. Hydroxyurea use was associated with fewer ED visits per year (average treatment effect on the treated [ATT] -0.36 visits/year, 95% CI -0.57, -0.16) and fewer hospital days per year (ATT -0.84 days/year, 95% CI -1.51, -0.17), with sustained effects over time. On average, hemoglobin concentration increased with hydroxyurea use (ATT 0.56 g/dL, 95% CI 0.39, 0.73) but the sustained effect was observed only among the subgroup with laboratory markers of good adherence. This study demonstrates that hydroxyurea has sustained clinical benefits in reducing ED visits and hospital days across years of use in children with SCA. These findings provide perspective for clinicians and families regarding the long-term efficacy of hydroxyurea in pediatric SCA management and underscore the importance of ongoing adherence counseling to optimize clinical benefit. Furthermore, this study design provides a methodological framework for rigorously and causally evaluating other SCA-specific treatments, such as stem cell transplant and gene therapy, in real-world settings.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015564
  9. Bone Marrow Transplant. 2025 Apr 18.
    Outcomes of Hematopoietic Stem Cell Transplantation in children with Sickle Cell Disease: Does donor Sickle cell trait status matter?
    Mohamed Bayoumy, Enass H Raffa, Amal Alseraihy Alharbi, Ibraheem Abosoudah, Amany Orabe, Hassan Altrabolsi, Abdulatef Ahmed, Marwa Elhadidy, Lamis Alkhateeb, Wasil Jastaniah.
      
    DOI:  https://doi.org/10.1038/s41409-025-02572-8
  10. Am J Physiol Lung Cell Mol Physiol. 2025 Apr 18.
    Oxidation of low-density lipoprotein by hemoglobin causes pulmonary microvascular endothelial barrier dysfunction through lectin-like oxidized LDL receptor 1.
    Jamie E Meegan, Kyle J Riedmann, Samantha Gonski, Joel S Douglas, Avery M Bogart, Lorraine B Ware, Julie A Bastarache.
      Elevated circulating cell-free hemoglobin (Hb) is a pathological driver of endothelial injury and contributes to disease severity and organ dysfunction during several pathologies, including sickle cell disease, pulmonary hypertension, primary graft dysfunction after lung transplantation, and sepsis. However, the signaling mechanisms involved in Hb-mediated pulmonary microvascular endothelial barrier dysfunction are not well understood. One mechanism by which Hb may contribute to microvascular endothelial barrier dysfunction is through its ability to oxidize circulating lipids and lipoproteins, including low-density lipoproteins (LDL). In this study, we hypothesized that oxidation of LDL (oxLDL) by Hb (Hb-oxLDL) disrupts the pulmonary microvascular endothelial barrier via the scavenger receptor for oxLDL, lectin-like oxidized LDL receptor 1 (LOX-1). We stimulated primary human pulmonary microvascular endothelial cells (HPMEC) with Hb-oxLDL and found significant disruption to the endothelial barrier. Barrier dysfunction by Hb-oxLDL was partially prevented by haptoglobin or LOX-1 inhibitor. We also found that oxidation of LDL by heme was sufficient to disrupt the endothelial barrier. Together, these data demonstrate that oxidation of LDL by Hb disrupts the pulmonary microvascular endothelial barrier through the LOX-1 receptor, indicating a potential mechanism for Hb-mediated microvascular injury during inflammatory and hemolytic conditions.
    Keywords:  LOX-1; barrier dysfunction; endothelial; hemoglobin; lipoprotein
    DOI:  https://doi.org/10.1152/ajplung.00026.2025
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