bims-sicedi Biomed News
on Sickle cell disease
Issue of 2025–10–26
nine papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Evaluating anti-sickling therapies for sickle cell disease: a microfluidic assay for red blood cell-mediated microvascular occlusion under hypoxia.
  2. Protein S Enhances the Phagocytosis of Phosphatidylserine-Exposing Erythrocytes: Implications in Sickle Cell Disease.
  3. Evaluation of the podoplanin/C-type lectin-like receptor-2 (CLEC-2) pathway as a mediator of platelet and coagulation activation in sickle cell disease.
  4. How do I overcome apheresis collection challenges for sickle cell disease gene therapy.
  5. Thirty Years of Hydroxyurea for Sickle Cell Anemia - Scientific Progress, Global Health Gaps.
  6. Low bone mineral density and pain impact in adults with sickle cell disease.
  7. Involving Palliative Care to Improve Outcomes in Sickle Cell Disease.
  8. Utility of Placental Growth Factor (PlGF) for preeclampsia prediction in pregnancies complicated by Sickle Cell Disease.
  9. Sickle cell hepatopathy in Oman: An emerging burden demanding regional action.
  1. Lab Chip. 2025 Oct 20.
    Evaluating anti-sickling therapies for sickle cell disease: a microfluidic assay for red blood cell-mediated microvascular occlusion under hypoxia.
    Zoe Sekyonda, Yuxuan Du, Solomon Oshabaheebwa, Payam Fadaei, Yusang B Ley, Calvin Abonga, Michael A Suster, Pedram Mohseni, Umut A Gurkan.
      Sickle cell disease (SCD) is characterized by the polymerization of hemoglobin S (HbS) upon deoxygenation, leading to the formation of sickled red blood cells (RBCs) with reduced deformability. Under hypoxic conditions, the impaired RBC behavior significantly contributes to vaso-occlusive events, hemolysis, and end-organ damage. Consequently, RBC deformability serves as a pivotal hemorheological biomarker for evaluating disease severity and therapeutic response. The OcclusionChip, a microfluidic assay, measures RBCs deformability through microcapillary occlusion. However, its current hypoxic assay relies on a complex nitrogen gas setup, rendering it bulky, expensive, and unsuitable for point-of-care diagnostic use. Here, we optimized a chemically induced hypoxia assay using sodium metabisulfite (SMB) within the OcclusionChip platform and validated the hypoxia occlusion index (HOI) as a robust measure of RBC deformability in SCD. Optimal hypoxia conditions were established, replicating nitrogen-induced hypoxia without affecting RBC membrane integrity, reactive oxygen species (ROS) levels, or phosphatidylserine (PS) exposure. Under these conditions, RBCs from individuals with heterozygous (HbAS), HbSC, and HbSS genotypes showed significantly higher HOI compared to healthy controls (HbAA), correlating strongly with clinical biomarkers in SCD. Additionally, the HOI assay effectively assessed the efficacy of therapeutic agents, including hemoglobin-oxygen affinity modifiers (GBT021601, GBT440) and protein kinase R (PKR) activators (PKR-3, FT4202), which significantly reduced OI in SCD RBCs. Notably, combination therapies showed enhanced effectiveness, highlighting the assay's potential for optimizing treatment regimens. This study establishes the chemically induced hypoxia OcclusionChip assay as a reliable and clinically useful tool for evaluating RBC deformability in SCD, with significant potential to improve personalized treatment strategies and thus patient outcomes.
    DOI:  https://doi.org/10.1039/d5lc00264h
  2. Am J Hematol. 2025 Oct 25.
    Protein S Enhances the Phagocytosis of Phosphatidylserine-Exposing Erythrocytes: Implications in Sickle Cell Disease.
    Claire Auditeau, Aurélie Fricot, Raphaël Gauthier, Abdoulaye Sissoko, Zeynep Cacan, Céline Gounou, Laure Joseph, Sandra Manceau, Slimane Allali, Michael Dussiot, Mickael Marin, Alexis Lavergne, Mariem Khamari, Sophie Moog, Elsa Bianchini, Laetitia Claer, Sandrine Laurance, Valentine Brousse, Sébastien Eymieux, Philippe Roingeard, Pascal Amireault, Thiago Trovati Maciel, Alain Brisson, Pierre Buffet, François Saller, Delphine Borgel, Camille Roussel.
      The major anticoagulant Protein S (PROS1) also contributes to the phagocytosis of apoptotic cells by bridging exposed phosphatidylserine (PtdSer) to the MerTK receptor on macrophages (efferocytosis). Whether PROS1 is involved in the splenic clearance of PtdSer-positive senescent and altered erythrocytes such as erythrocyte ghosts (eryghosts) is unknown. Here, we investigate the contribution of PROS1 and MerTK to the phagocytosis of intact RBC and eryghosts in healthy subjects and patients with sickle cell disease (SCD). We show that PROS1 enhances the phagocytosis of ionomycin-treated PtdSer-positive erythrocytes and of eryghosts generated in vitro. We confirm that eryghosts circulate in patients with SCD at higher levels than in healthy subjects and observe increased hemolysis and decreased levels of plasmatic PROS1 in patients with the highest concentration of eryghosts. The proportion of circulating eryghosts is correlated with the intensity of hyposplenism, and eryghosts are less frequently observed in sections of SCD compared to control spleens. We demonstrate that circulating eryghosts are procoagulant and adhere to endothelial cells. In SCD, PROS1 enhances their phagocytosis in a MerTK-dependent manner but has no such effect on intact erythrocytes. PROS1 is therefore involved in erythrophagocytosis, a physiological process insufficient in patients with SCD due to intense intravascular hemolysis and hyposplenism, leading to PROS1 consumption and the abnormal persistence of eryghosts in circulation. PROS1 deficiency may in turn initiate a pathogenic loop, enhancing unregulated activation of coagulation and defective clearance of procoagulant and adherent eryghosts. This deeper understanding of physiological and pathological erythrophagocytosis opens new therapeutic approaches targeting PROS1 in SCD.
    Keywords:  PROS1; erythrocyte ghosts; phagocytosis; protein S; sickle cell disease
    DOI:  https://doi.org/10.1002/ajh.70117
  3. Res Pract Thromb Haemost. 2025 Aug;9(6): 103168
    Evaluation of the podoplanin/C-type lectin-like receptor-2 (CLEC-2) pathway as a mediator of platelet and coagulation activation in sickle cell disease.
    Ivanio Teixeira Borba-Junior, Mayck da Silva Barbosa, Carla Roberta Peachazepi Moraes, Letícia Queiroz Silva, Irene Santos, Bruno Benites, Joyce M Annichino-Bizzacchi, Fernando Ferreira Costa, Erich Vinicius De Paula.
       Background: Sickle cell disease (SCD) is a condition characterized by a prothrombotic state attributed to the simultaneous activation of hemostasis and innate immunity, referred to as thromboinflammation. Previous studies have demonstrated that the podoplanin (PDPN)/C-type lectin-like receptor-2 (CLEC-2) pathway is an emerging and important element of the pathogenesis of conditions in which inflammation and thrombosis coexist, but no data is available regarding its role in SCD.
    Objectives: To explore the PDPN/CLEC-2 pathway in SCD and correlate it with parameters of disease severity.
    Methods: Fifty SCD patients (35 with SS genotype; 15 with SC genotype) and 25 healthy individuals were recruited. PDPN and CLEC-2 were assessed for both soluble and surface expression on cells and cell aggregates, along with other classical parameters of hemostasis and platelet activation. An in vitro study was performed to analyze the effect of anti-PDPN antibody on the formation of monocyte-platelet aggregates.
    Results: Circulating levels and expression of PDPN and CLEC-2 were higher in patients with SCD, particularly in those with genotype SS. The number of CD41+CLEC+ monocytes correlated with hemoglobin, D-dimer, von Willebrand factor, and PDPN+ monocytes. In vitro, PDPN blockade reduced both monocyte-platelet aggregate formation and platelet activation. Finally, patients with a history of vaso-occlusive crises presented a trend toward increased PDPN expression in monocytes (P = .06).
    Conclusion: Our findings suggest that the PDPN/CLEC-2 pathway may play an important role in the pathogenesis of thromboinflammation in SCD, especially in patients with the SS genotype.
    Keywords:  CLEC-2; leukocyte–platelet aggregate; podoplanin; sickle cell disease; thromboinflammation
    DOI:  https://doi.org/10.1016/j.rpth.2025.103168
  4. Transfusion. 2025 Oct 19.
    How do I overcome apheresis collection challenges for sickle cell disease gene therapy.
    Yvette C Tanhehco, Gaurav K Gupta, Nirupama Singh, Patricia Shi, Nicole Aqui, Elizabeth A Godbey, Jan C Hofmann, Jennifer Schneiderman, Suzanne Thibodeaux, Abba Zubair, Yanyun Wu, Hien D Liu.
       BACKGROUND: Sickle cell disease (SCD) is a hemoglobinopathy with limited treatment options. Genetic modification of the patient's own hematopoietic stem cells (HSCs) offers an avenue to curative therapy using the patient's own cells. Many challenges exist in collecting sufficient numbers of starting material for manufacturing, beginning with the pre-mobilization optimization of the patient to the mobilization, collection, and post-collection phases.
    STUDY DESIGN AND METHODS: A working group within the Cellular Therapy Subcommittee of the American Society for Apheresis Clinical Applications Committee describes the challenges associated with apheresis collection of the starting material for gene therapy (GT) product manufacturing for patients with SCD and discusses potential strategies for overcoming these challenges.
    RESULTS AND DISCUSSION: Patients must undergo automated red blood cell exchange (RCE) to lower hemoglobin S in a relatively short window of time before apheresis collection of HSCs. The risks and benefits of transfusion as well as the logistics of providing adequate and appropriate blood products must be considered. Limited agents are available for mobilization of HSCs into the peripheral blood for collection and the timing of administration is short. Each collection cycle consists of RCE followed by at least three mobilization and apheresis collection events in addition to collecting backup cells. More than one cycle is typically needed to collect enough cells for GT drug product manufacturing. Optimization of patient factors and apheresis instrument parameters leads to better collection yields. Early and frequent ongoing coordination with all stakeholders involved is critical to developing personalized treatment plans for patients.
    Keywords:  apheresis; gene therapy; mobilization; red cell exchange; stem cell collection
    DOI:  https://doi.org/10.1111/trf.18461
  5. N Engl J Med. 2025 Oct 23. 393(16): 1556-1559
    Thirty Years of Hydroxyurea for Sickle Cell Anemia - Scientific Progress, Global Health Gaps.
    Enrico Costa, Russell Ware, Leon Tshilolo, Lucio Luzzatto.
      
    DOI:  https://doi.org/10.1056/NEJMp2511272
  6. Blood Adv. 2025 Oct 24. pii: bloodadvances.2025015957. [Epub ahead of print]
    Low bone mineral density and pain impact in adults with sickle cell disease.
    Oyebimpe Adesina, Jenna M Voutsinas, Qian Vicky Wu, Leyla Y Teos, Mehrad Rokni, Hande Nalbant, Lorenzo Nardo, Ted Wun, Babette S Zemel.
      Low bone mineral density (BMD) is prevalent skeletal finding in people with sickle cell disease (SCD), but its clinical consequences are poorly understood. We hypothesized that low BMD, independent of osteonecrosis (ON), would associate with worse pain in SCD adults. In the SCD Bone Pain study, 53 ambulatory adults (64% females, mean age 38±11years, 66% Hb SS/Sβ0 thalassemia) underwent dual-energy X-ray absorptiometry (DXA) scans of the lumbar spine, hip, forearm, and whole body. They also completed the Adult Sickle Cell Quality of Life Measurement Information System pain impact questionnaire. Twenty-three participants (43%) had low bone mass, defined as lumbar spine, total hip, or femoral neck BMD Z-scores ≤ -2. In multivariate linear regression, lumbar spine BMD Z-scores significantly changed by +0.31, -0.29, -0.14, and -1.3 for every unit increase in hemoglobin, indirect bilirubin, and white blood cell count, and with Crizanlizumab use, respectively. Pain impact T-scores significantly decreased (worsened) by 6.0 and 6.5 with reduced estimated glomerular filtration rate and chronic opioid therapy, respectively, but increased (improved) by 3.8 for every unit increase in serum phosphate. Median [interquartile range] pain impact T-scores were significantly lower in participants with low BMD and ON (38.3 [37.4, 40.1]), compared to those with either low BMD (49.5 [43.6, 54.4), p=3x10-5 or ON (52.7 [45.3, 57]), p=2x10-4 alone. Whether sickle cell-related low BMD results from impaired bone formation and/or accelerated bone loss remains unclear. Understanding how low bone density, with or without osteonecrosis, mediates SCD pain warrants further investigation. NCT05283148.
    DOI:  https://doi.org/10.1182/bloodadvances.2025015957
  7. N Engl J Med. 2025 Oct 23. 393(16): 1553-1556
    Involving Palliative Care to Improve Outcomes in Sickle Cell Disease.
    Eberechi Nwogu-Onyemkpa, Griffin Collins, Mgbechi Erondu, Erica C Kaye.
      
    DOI:  https://doi.org/10.1056/NEJMp2505493
  8. Blood Adv. 2025 Oct 21. pii: bloodadvances.2025016821. [Epub ahead of print]
    Utility of Placental Growth Factor (PlGF) for preeclampsia prediction in pregnancies complicated by Sickle Cell Disease.
    Evangelia Vlachodimitropoulou, Tharshini Balasubramaniam, Nadine Shehata, Richard Ward, Kevin H M Kuo, John Charles Kingdom, Kinga Malinowski.
      Outside of pregnancy, Placental Growth Factor (PlGF), is produced by erythroid cells in typically undetectable levels. In pregnancy, PlGF is strongly expressed by the trophoblast layer covering the placental villi. PlGF levels rise progressively due to placental growth, peak at 28-30 weeks' gestation, then slowly decline towards term. Low PlGF has emerged as a powerful diagnostic test for preterm preeclampsia. However its interpretation in context of sickle cell disease (SCD) is potentially confounded by: upregulation of cellular PlGF expression in non-pregnant SCD individuals, and higher 3rdtrimester circulating PlGF levels documented in healthy Black compared with Caucasian individuals. Primary objectives were to determine the distribution of PlGF at mid-trimester in pregnant individuals with SCD compared to unaffected Black controls and to explore the diagnostic accuracy of PlGF in the context of suspected preeclampsia in SCD pregnancies. Secondary objective was to examine the relationship between low PlGF and placental disease in SCD pregnancies. Pregnant individuals with SCD at Mount Sinai Hospital in Canada (Jan. 2017-Sept. 2021) with at least one PlGF measurement 20+0 - 35+6 weeks' gestation and pregnant Black controls without SCD, with suspected preeclampsia or growth restriction, were included in this retrospective study. Maternal and neonatal outcomes were extracted from medical records. For early-onset, but not late-onset, preeclampsia, a PlGF cut-off <100 pg/mL demonstrated 100% sensitivity and specificity at 20-24 weeks' gestation. This study is the first to demonstrate the utility of PlGF in predicting early-onset preeclampsia in SCD pregnancies, allowing clinicians to anticipate and mitigate adverse pregnancy outcomes.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016821
  9. Saudi J Gastroenterol. 2025 Oct 24.
    Sickle cell hepatopathy in Oman: An emerging burden demanding regional action.
    Bandar Al-Judaibi, Ibrahim Alrajhi, Shaykhah Alotaibi.
      
    DOI:  https://doi.org/10.4103/sjg.sjg_360_25
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