bims-sicedi Biomed News
on Sickle cell disease
Issue of 2025–05–04
nine papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Hydroxyurea reduces the levels of the fetal globin gene repressors ZBTB7A/LRF and BCL11A in erythroid cells in vitro.
  2. Use of the Microfluidic Impedance Red Cell Assay (MIRCA) in Sickle Cell Disease.
  3. Evidence and gaps in clinical outcomes of novel pharmacologic therapies for sickle cell disease: A systematic literature review highlighting insights from clinical trials and real-world studies.
  4. Optimization of hydroxyurea in sickle cell disease in Brazil.
  5. Inflammation and Iron Profile in Children With Sickle Cell Disease in Cameroon: Frequency and Associated Factors, an Analytical Cross-Sectional Study.
  6. The role of red blood cell characteristics and viscosity in sickle cell retinopathy and maculopathy.
  7. Comprehensive management of sickle cell disease in rural Uganda: a model of integrated care.
  8. Hepatobiliary complications in patients with sickle cell disease: A 30-year review of 1009 patients.
  9. Management of severe acute chest syndrome in a patient with a history of severe delayed haemolytic transfusion reaction.
  1. J Sick Cell Dis. 2024 ;1(1): yoae008
    Hydroxyurea reduces the levels of the fetal globin gene repressors ZBTB7A/LRF and BCL11A in erythroid cells in vitro.
    Gabriella E Martyn, Phillip A Doerfler, Yu Yao, Kate G R Quinlan, Mitchell J Weiss, Merlin Crossley.
       Objectives: Hydroxyurea (HU) is the most widely used therapy for adults and children with sickle cell disease (SCD). It is believed to act largely by inducing the transcription of fetal γ-globin genes to generate fetal hemoglobin (HbF), which inhibits the pathological polymerization of sickle hemoglobin (HbS). The mechanisms by which hydroxyurea elevates HbF are unclear. We explored the hypothesis that hydroxyurea induces HbF expression by inhibiting the expression of 2 γ-globin gene repressors, BCL11A and ZBTB7A (also known as LRF), which normally bind the γ-globin gene promoters to inhibit their expression after birth.
    Methods: We treated immortalized murine erythroleukemia cells and normal human donor CD34+ hematopoietic stem and progenitor cell-derived erythroblasts with hydroxyurea and measured the effects on globin, BCL11A and ZBTB7A protein and mRNA expression.
    Results: Treating murine erythroleukemia cells or human CD34+ hematopoietic stem and progenitor cell-derived erythroblasts with hydroxyurea reduced the protein levels of BCL11A and ZBTB7A compared to the vehicle-treated control. BCL11A mRNA levels were reduced in both cell types upon hydroxyurea treatment. However, ZBTB7A mRNA levels were only reduced in human CD34+ hematopoietic stem and progenitor cell-derived erythroblasts.
    Conclusions: Hydroxyurea can act in erythroid cells to reduce the levels and activity of two direct fetal γ-globin transcriptional repressors with accompanying de-repression of the γ-globin genes and induction of HbF, which may explain the mechanism of action leading to amelioration of symptoms in SCD patients treated with this drug.
    Keywords:  BCL11A; SCD; ZBTB7A; fetal globin; hydroxyurea
    DOI:  https://doi.org/10.1093/jscdis/yoae008
  2. Blood Adv. 2025 May 01. pii: bloodadvances.2024015590. [Epub ahead of print]
    Use of the Microfluidic Impedance Red Cell Assay (MIRCA) in Sickle Cell Disease.
    Akshay Amit Patwardhan, Ashwin P Patel, Abhinav K Pasupuleti, Solomon Oshabaheebwa, Christopher A Delianides, Zoe Sekyonda, Justin J Yoo, Jonathan W Wade, Erica N Evans, Michael A Suster, Pedram Mohseni, Umut A Gurkan, Vivien A Sheehan.
      In sickle cell disease (SCD), red blood cells (RBC) are poorly deformable, even under normoxia. With deoxygenation, deformability of sickle RBCs is further reduced due to polymerization of hemoglobin S (HbS). Rigid, poorly deformable sickle RBCs block microvasculature, causing ischemia, pain, and organ damage. The Microfluidic Impedance Red Cell Assay (MIRCA) can mechanically measure RBC deformability, providing occlusion index under normoxia (NOI) or hypoxia (HOI) as readouts. We analyzed RBCs from 68 adult and 34 pediatric SCD patients using the MIRCA. Higher HOI and NOI were positively associated with markers of inflammation, hemolysis, RBC density, older age, and severe SCD genotypes (HbSS/ Sβ0). Each 1% higher NOI across individuals was associated with a 6.3% higher incidence of acute complications per year. Individuals with chronic complications in the past year had a 3.1% higher median NOI than those without chronic complications. Individuals on chronic transfusion therapy (CTF) exhibit a subpopulation of poorly deformable RBC that is captured by the MIRCA, but not by a commercially available device that also measures RBC deformability, the LoRRca. In vitro addition of voxelotor or osivelotor to samples from individuals on CTF improved the deformability of these endogenous RBC. Longitudinally collected NOI and HOI values in HbSS individuals were stable, with a median percent point change of 13.3% and 15.7%, respectively. MIRCA can be used in combination with clinical laboratory tests to monitor RBC deformability as a biomarker of clinical status at routine clinic visits and included in clinical trials of disease modifying agents.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015590
  3. Blood Rev. 2025 Apr 25. pii: S0268-960X(25)00043-8. [Epub ahead of print] 101298
    Evidence and gaps in clinical outcomes of novel pharmacologic therapies for sickle cell disease: A systematic literature review highlighting insights from clinical trials and real-world studies.
    Mohamed Yassin, Caterina Minniti, Nirmish Shah, Salam Alkindi, Fateen Ata, Mohammed Qari, Abdullah Al Zayed, Jaffer Altooq, Mona Al Rasheed, Maria Domenica Capellini.
      This systematic review aims to summarise the clinical outcomes of l-glutamine, crizanlizumab, and voxelotor in the treatment of sickle cell disease (SCD) based on clinical trials and real-world data and to identify any gaps in the observations. The review identified 97 studies reporting data until 31 May 2024. A pivotal phase III study of l-glutamine showed that patients treated with l-glutamine had a 25 % reduction in pain crises and 33 % fewer hospital days compared to placebo. l-glutamine was generally well tolerated with minimal side effects. Real-world studies of l-glutamine emphasize patient adherence and obstacles to medication accessibility and approval as key concerns. In the SUSTAIN study, a 5-mg/kg dose of crizanlizumab reduced the occurrence of vaso-occlusive crises (VOCs) and hospitalizations by 45 % and 41 %, respectively. Real-world studies of crizanlizumab showed a reduction in complicated VOC events. The high discontinuation rate and results of the STAND trial led to a significant decrease in the use of crizanlizumab. The HOPE trial demonstrated a 51 % improvement in hemoglobin response and a reduction in hemolytic markers in patients treated with voxelotor. While some real-world studies have reported a decrease in VOCs and hospitalizations, the results are inconsistent and not conclusive. Further studies are needed to assess the impact of these novel therapies on end-organ-specific complications of SCD.
    Keywords:  Clinical trials; Crizanlizumab; Sickle cell disease; Vaso-occlusive crisis; Voxelotor, real-world studies; l-glutamine
    DOI:  https://doi.org/10.1016/j.blre.2025.101298
  4. Hematol Transfus Cell Ther. 2025 May 01. pii: S2531-1379(25)00094-X. [Epub ahead of print]47(2): 103826
    Optimization of hydroxyurea in sickle cell disease in Brazil.
    Clarisse Lobo, Ana Cristina Silva-Pinto, Rodolfo Delfini Cançado.
      Despite sickle cell disease (SCD) being a well-recognized and highly prevalent condition identified early through neonatal screening programs, it represents a substantial public health challenge due to high morbidity and premature mortality rates. Hydroxyurea (HU) is the only available disease-modifying therapy for SCD approved in Brazil. Indeed, its underutilization highlights the need for improved therapeutic strategies to enhance adherence and management of SCD. Innovative formulations of HU might favor treatment adherence and precise dosing. Thus, we aimed to describe HU's pharmacological characteristics, clinical efficacy, and tolerability, including dose escalation. Recent interventional and observational studies revealed the efficacy and safety of an innovative formulation: dispersible scored tablets of 100 mg and 1000 mg, allowing easier dose adjustments and, consequently, more precise dosing. The 100 mg tablets scored can be cut into two parts of 50 mg, and the 1000 mg tablets can be cut into four parts of 250 mg. The fractionating dose is possible due to the formulation technology that allows the tablet to be cut with a uniform amount of drug in each part. This new formulation of HU, suitable for children, may influence the prognosis of SDC, regardless of associated symptoms.
    Keywords:  Hydroxyurea therapy; Innovative drug development; Prognosis; Sickle cell disease
    DOI:  https://doi.org/10.1016/j.htct.2025.103826
  5. Health Sci Rep. 2025 May;8(5): e70773
    Inflammation and Iron Profile in Children With Sickle Cell Disease in Cameroon: Frequency and Associated Factors, an Analytical Cross-Sectional Study.
    Romaric De Manfouo Tuono, Josué Louokdom Simo, Prosper Cabral Biapa Nya, Claude Tagny Tayou, Constant Anatole Pieme.
       Background and Aims: Sickle Cell Disease is a chronic inflammatory disease that could be aggravated by exposure to variable factors such as infections, hemolysis, oxidative stress and so forth. that could preciptate variable acute or end-organ manifestation. However, the degree of inflammation could vary in individuals. Thus this study evaluates the inflammatory state (hs-CRP, IL6, ferritin) of children living with SCD and the associated factors.
    Methods: We conducted an analytical cross-sectional study for 03 months. The patients included were those from the Central Hospital of Yaounde and the Regional Hospital of Bafoussam in which they are regularly monitored and/or interned in the Hematology department. The exploration of inflammation was made by determining hs-CRP, IL6, and ferritin concentrations. The hematological parameters and iron profile were evaluated using standard methods. Statistical analyses of the data were carried out using the statistical software R version 4.1.1. from which logistic regression analyses according to univariate and multivariate models made it possible to identify factors associated with inflammation in patients.
    Results: Hundred and forty-nine SCD patients were included in the study. The frequency of inflammation in the population was 42.3%. Hyperferritinemia was significantly greater (p < 0.001) in patients with inflammation compared to the noninflammatory patients (96.8% and 76.7% respectively). Patients with inflammation showed a significant elevation of iron parameters (p < 0.05). In addition, ferritin and IL6 elevation were associated with inflammation during sickle cell disease, respectively (OR = 4.96; 95% CI [1.15-36.42]; p = 0.056) and (OR = 6.23; 95% CI [1.43-45.96]; p = 0.030).
    Conclusion: The elevated iron in plasma is an effect of inflammation in sickle cell patients. Thus, inflammation constitutes a significant and significant factor in worsening the pathophysiology of sickle cell disease. Hence the need of controlling inflammation and iron in the latter is necessary.
    Keywords:  associated factors; inflammation; iron profile; sickle cell anemia
    DOI:  https://doi.org/10.1002/hsr2.70773
  6. Br J Haematol. 2025 Apr 29.
    The role of red blood cell characteristics and viscosity in sickle cell retinopathy and maculopathy.
    Rajani P Brandsen, Roselie M H Diederen, Ingeborg Klaassen, Martijn Veldthuis, Herbert Korsten, Rob van Zwieten, Reinier O Schlingemann, Erfan Nur, Bart J Biemond.
      Sickle cell disease (SCD), encompassing genotypes such as HbSS and HbSC, causes chronic haemolysis and microvascular occlusion, leading to organ damage. The retina is particularly vulnerable, often resulting in sickle cell retinopathy (SCR) or sickle cell maculopathy (SCM). The precise underlying mechanisms are unclear, though various factors are suggested to contribute. This study explored the role of whole blood viscosity and red blood cell (RBC) deformability in SCR and SCM. Adult HbSS (n = 34) and HbSC patients (n = 34) were offered an ophthalmic examination to determine SCR stage. A venous ethylenediaminetetraacetic acid (EDTA) sample was collected from each participant. Whole blood viscosity was measured using a Brookfield viscometer and RBC deformability was assessed using the Oxygenscan feature of the Laser Optical Rotational Red Cell Analyser as a function of the (varying) partial oxygen pressure. HbSC patients with proliferative sickle cell retinopathy (PSCR) had a lower delta elongation index (p = 0.012) and point of sickling (p = 0.002) than those without PSCR, suggesting that RBC sickling might not play a central role in the pathogenesis of PSCR in HbSC patients. Despite hyperviscosity being a commonly proposed mechanism, no associations were found between blood viscosity, SCR and SCM. These results point to alternative mechanisms contributing to SCR and SCM, highlighting the complexity and need for further research to fully understand the underlying factors.
    Keywords:  erythrocyte deformability; sickle cell disease; sickle cell maculopathy; sickle cell retinopathy; viscosity
    DOI:  https://doi.org/10.1111/bjh.20124
  7. Lancet Haematol. 2025 May;pii: S2352-3026(25)00104-8. [Epub ahead of print]12(5): e331-e332
    Comprehensive management of sickle cell disease in rural Uganda: a model of integrated care.
    Jon Salmanton-García, Samanya Mohamed Ali, Renata Horáková, Barbora Šilharová, Ivan Kiríynia, Immaculate Mussímenta, Zdeněk Ráčil.
      
    DOI:  https://doi.org/10.1016/S2352-3026(25)00104-8
  8. Hepatol Commun. 2025 May 01. pii: e0712. [Epub ahead of print]9(5):
    Hepatobiliary complications in patients with sickle cell disease: A 30-year review of 1009 patients.
    Maya Deeb, Kristel K Leung, Richard Ward, Jordan J Feld, Kevin H M Kuo, Gideon M Hirschfield.
       BACKGROUND: Sickle cell disease (SCD) is the most common hemoglobinopathy. We aimed to identify the prevalence of hepatobiliary injury and its association with mortality in SCD.
    METHODS: Patients with SCD followed at a dedicated clinic at our tertiary center were retrospectively evaluated with descriptive statistics. Correlations between hepatobiliary complications and SCD complications were expressed as ORs. To evaluate mortality predictors, log-rank testing was used for univariate analysis and Cox proportional hazards for multivariable analysis, with time-dependent covariates for biochemistry.
    RESULTS: Between January 1990 and December 2020, 1009 patients with SCD were identified; 63.2% were HbSS. The median age at first clinic visit was 26.4 years (IQR: 18.9-37.1), 44.3% were male, and 62.6% were ever treated with hydroxyurea. The median follow-up was 4.8 years (IQR: 1.9-8.5); mortality was 8.9%. The most frequent hepatobiliary manifestations were cholelithiasis (n=431 [42.7%]) and iron overload (n=121; 12%). Chronic viral hepatitis was reported in only 18 patients. Twenty-nine patients (2.1%) had peak ALT> 2× upper limit of normal, 15 (2.3%) had peak ALP> 2× upper limit of normal, 97 (10.3%) had peak total bilirubin >103 μmol/L, (6.02 mg/dL), and 184 (18.2%) patients had elevated peak direct bilirubin. Hepatomegaly was reported in 37 patients (3.7%), while 24 patients (2.4%) were clinically cirrhotic. Five patients received a liver transplant. In an exploratory multivariate model, age (HR 1.08 [95% CI: 1.05-1.11]), ALT elevation (HR 1.52 [95% CI: 1.29-1.78]), and total bilirubin >103 μmol/L (HR 9.3 [95% CI: 3.95-21.9]) predicted mortality independently.
    CONCLUSIONS: Hepatobiliary complications are common in patients with SCD and require vigilance for identification.
    Keywords:  cirrhosis; hemosiderosis; sickle cell hepatopathy
    DOI:  https://doi.org/10.1097/HC9.0000000000000712
  9. BMJ Case Rep. 2025 Apr 29. pii: e258680. [Epub ahead of print]18(4):
    Management of severe acute chest syndrome in a patient with a history of severe delayed haemolytic transfusion reaction.
    Omar B Taha, Tianshi Liu, Molly W Mandernach.
      A case of a patient in her 30s with sickle cell anaemia who developed multiorgan failure and Acute Respiratory Distress Syndrome(ARDS) from acute chest syndrome (ACS) despite a simple red blood cell transfusion is presented in this report. She was treated with plasma exchange (PLEX) due to a history of severe delayed haemolytic transfusion reaction and a lack of available compatible units of packed red blood cells. Following one session of PLEX with half plasma/half albumin, she had rapid clinical improvement from mechanical ventilation to room air in 5 days. This finding is consistent with existing case reports of rapid improvement in pain, oxygenation and organ function following PLEX. Proposed mechanisms include the modulation of rheological properties of red blood cells by plasma, as well as the removal of the cytotoxic effects of haptoglobin and haemopexin. This case demonstrates the effectiveness and safety of an alternative upfront approach to managing complications related to ACS in those who are heavily alloimmunised.
    Keywords:  Haematology (incl blood transfusion); Sickle cell disease
    DOI:  https://doi.org/10.1136/bcr-2023-258680
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