bims-sicedi Biomed News
on Sickle cell disease
Issue of 2025–04–13
seven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. MicroRNAs in sickle cell disease: A comprehensive review.
  2. MLL1 complex is a critical regulator of fetal hemoglobin repression.
  3. Procedures under tourniquet in sickle cell disease: safety evaluated in two hundred and thirty three sickle-cell disease anaemia adult patients in comparison with outcomes in five hundred and seventy four sickle cell anaemia patients with procedures without tourniquet.
  4. Key-Role of Long-Duration Cardiac Rhythm Monitoring in Sickle Cell Disease Patients with Atrial Hyperexcitability.
  5. HIF-Prolyl Hydroxylase Inhibitor Desidustat Increases Pyruvate Kinase Activity and Reduces Oxidative Stress in Red Blood Cells, Causes Erythrocytosis in Thalassaemic Mice, and Reduces Sickling in Sickle Cell Patient's Blood.
  6. Development of Polygenic Risk Score for Persistent Albuminuria in Children and Adults With Sickle Cell Anemia.
  7. Comparison of Prophylactic and Therapeutic Doses of Anticoagulation for Acute Chest Syndrome in Sickle Cell Disease: The TASC Randomized Clinical Trial.
  1. Gene. 2025 Apr 03. pii: S0378-1119(25)00258-6. [Epub ahead of print] 149470
    MicroRNAs in sickle cell disease: A comprehensive review.
    Parul Gupta, Ravindra Kumar.
      Sickle cell disease (SCD) is a multifactorial disease characterized by a high incidence of morbidity and mortality due to chronic hemolysis, inflammation and oxidative stress. Recent studies have highlighted the crucial role of microRNAs (miRNAs) in regulating key pathophysiological processes in SCD, including high levels of fetal hemoglobin production, and reduction in inflammation and cellular adhesion. This comprehensive review discusses the current understanding of miRNAs in SCD, including their potential as biomarkers and therapeutic targets. Furthermore, despite substantial evidences indicating that malaria exacerbates SCD, the review will explore the complex interplay between miRNAs and SCD, with a focus on the exacerbating effects of malaria on SCD severity. Understanding the complex interplay between miRNAs and SCD may lead to the development of novel therapeutic interventions aimed at ameliorating disease severity and improving patient outcomes. Future prospects, challenges and safety concerns related to miRNA-based therapies, highlighting the need for further research.
    Keywords:  Fetal hemoglobin; Malaria; Sickle cell disease; Vaso-occlusive crisis; miRNA
    DOI:  https://doi.org/10.1016/j.gene.2025.149470
  2. bioRxiv. 2025 Mar 25. pii: 2025.03.24.645036. [Epub ahead of print]
    MLL1 complex is a critical regulator of fetal hemoglobin repression.
    Yufen Han, Bjorg Gudmundsdottir, Kristbjorn O Gudmundsson, Kartik R Roy, John Tisdale, Yang Du.
      Increasing fetal-type hemoglobin (HbF) expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and β-thalassemia. We have identified MLL1 complex as a critical regulator of fetal and embryonic hemoglobin repression. Knockdowns of MEN1 and KMT2A, encoding essential components of the complex, caused a significant downregulation of BCL11A expression and a substantial increase in γ- and ε-globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A were readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34 + hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their γ- and ε-globin expression and the production of F cells in the culture. Treatment of these cells with MENIN inhibitors yielded similar results and promoted erythroid differentiation with minimal effects on their growth. These findings underscore a critical role of MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for sickle cell disease and β-thalassemia.
    DOI:  https://doi.org/10.1101/2025.03.24.645036
  3. Int Orthop. 2025 Apr 07.
    Procedures under tourniquet in sickle cell disease: safety evaluated in two hundred and thirty three sickle-cell disease anaemia adult patients in comparison with outcomes in five hundred and seventy four sickle cell anaemia patients with procedures without tourniquet.
    Philippe Hernigou.
       PURPOSE: There is a lack of data evaluating the impact of tourniquet versus no tourniquet surgery in patients with sickle cell disease (SCD).
    METHODS: The records of 233 sickle cell patients who underwent orthopaedic surgery with a tourniquet between 1978 and 2018 were retrospectively reviewed. This study group (233 patients) was compared to a control group of 574 SCD patients followed by the same surgical team in the same hospital undergoing the same procedures in the same period between 1978 and 2018 but without a tourniquet. Outcomes assessed skin complications, thrombophlebitis, bone necrosis, muscle necrosis or abnormal muscle function, peripheral nerve impairment, elevated blood pressure, post-operative sickle cell crises, and blood loss under a tourniquet.
    RESULTS: The pneumatic tourniquet was primarily applied proximally in both lower and upper limbs. The median tourniquet duration was 65 minutes, with most procedures lasting between 30 and 90 minutes . Postoperative medical complications occurred in both groups, with no significant difference in hospital stay (6.7 vs. 7.1 days). Painful sickling crises affected 86 patients, with a lower prevalence in transfused patients (p = 0.04). Blood loss was significantly lower in the tourniquet group during knee surgeries (438 ml vs. 731 ml, p = 0.031), resulting in fewer transfusions. Skin complications did not affect wound healing. The 90-day incidence of venous thromboembolism (VTE) was 0.4%, with no significant difference between groups. Muscle biopsies showed no necrosis immediately post-surgery, but some necrosis appeared after 12 weeks in the tourniquet group. New bone osteonecrosis cases and infection rates were similar between groups.
    CONCLUSION: this study provides valuable insights into the use of tourniquets in sickle cell disease.
    Keywords:  Blood loss; Sickle cell disease; Tourniquet; Transfusion
    DOI:  https://doi.org/10.1007/s00264-025-06510-7
  4. Blood Adv. 2025 Mar 06. pii: bloodadvances.2024015307. [Epub ahead of print]
    Key-Role of Long-Duration Cardiac Rhythm Monitoring in Sickle Cell Disease Patients with Atrial Hyperexcitability.
    Thuy Linh Dang, Thibaut Moulin, Gonzalo De Luna, Sihem Iles, Anaïs Lamadieu, David Calvet, Geneviève Derumeaux, Pablo Bartolucci, Nicolas Lellouche, Thomas d'Humières.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024015307
  5. Drug Dev Res. 2025 Apr;86(2): e70086
    HIF-Prolyl Hydroxylase Inhibitor Desidustat Increases Pyruvate Kinase Activity and Reduces Oxidative Stress in Red Blood Cells, Causes Erythrocytosis in Thalassaemic Mice, and Reduces Sickling in Sickle Cell Patient's Blood.
    Vishal J Patel, Amit A Joharapurkar, Samadhan G Kshirsagar, Maulik S Patel, Hardikkumar H Savsani, Milan H Rakhasiya, Harshad S Dodiya, Mukul R Jain.
      Sickle cell anemia and beta-thalassemia are the major hemoglobinopathies associated with anemia. Bone marrow transplants or blood transfusion are frequently employed as treatment for these diseases, and erythropoietin analogues are sometimes used to boost erythropoiesis to compensate the destruction of RBCs. RBCs of hemoglobinopathy patients have reduced pyruvate kinase activity and increased oxidative stress, which makes the RBCs prone to destruction and precipitate vaso-occlusive crises and pain. The objective of this study was to evaluate desidustat, a hypoxia inducible factor (HIF) stabilizer in beta thalassemic mice (B6.D2-Hbbd3th/BrkJ) model, phenylhydrazine-induced acute hemolysis in C57 mice model, and sodium metabisulfite-induced sickling in sickle cell disease patient's blood. Desidustat treatment increased hemoglobin, RBCs, and hematocrit in both mice models. Desidustat treatment decreased iron overload, splenomegaly, and oxidative stress in phenylhydrazine-induced hemolytic anemia in mice. Desidustat treatment increased pyruvate kinase activity in RBCs of human, mice, and rats in a dose-dependent manner, and reduced sickling in SCD patients' RBCs. These data indicate that desidustat stimulates pyruvate kinase and attenuates oxidative stress in red blood cells, causes erythrocytosis in thalassemic mice, and reduces sickling in sickle cell patient's blood.
    Keywords:  beta‐thalassemia; desidustat; sickle cell anemia
    DOI:  https://doi.org/10.1002/ddr.70086
  6. Am J Hematol. 2025 Apr 05.
    Development of Polygenic Risk Score for Persistent Albuminuria in Children and Adults With Sickle Cell Anemia.
    Rima S Zahr, Guolian Kang, Xu Zhang, Sara R Rashkin, Csaba P Kovesdy, Clifford Takemoto, Mitch Weiss, Jeffrey Lebensburger, Kenneth I Ataga, Santosh L Saraf.
      Albuminuria is associated with high-risk apolipoprotein-L1 variants (APOL1 G1/G2) in patients with sickle cell anemia (SCA). However, this gene variant does not account for all chronic kidney disease (CKD) risk. We hypothesized that we could develop a polygenic risk score (PRS) for CKD in SCA, combining APOL1 G1/G2 with other candidate genes that modify SCA severity and further stratify patients into risk categories based on this risk score. Variants in APOL1, HMOX1 (rs743811), BCL11A (rs1424407), and α-thalassemia (α-3.7) were identified in children with SCA enrolled in the Sickle Cell Clinical Research and Intervention Program longitudinal cohort (SCCRIP). We individually tested the association of these variants with persistent albuminuria, tested a three-variant PRS (PRS-3) (APOL1, BCL11A (rs1424407), and α-3.7), and developed a four-variant PRS (PRS-4) after adding HMOX1 (rs743811) to PRS-3 using the summation of high-risk alleles. An adult SCA cohort from the University of Illinois, Chicago (UIC), was used for validation. Persistent albuminuria was defined as having a urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g on at least 2 of 3 consecutive measurements. In both cohorts, APOL1 risk variants increased the risk while α-thalassemia protected against persistent albuminuria. PRS-4 was significantly associated with persistent albuminuria (SCCRIP: p = 0.004; UIC: p = 0.00016). When stratifying patients into three and four risk categories based on the PRS, 58% and 86% of the high-risk (PRS-3) and 54% and 89% of very high-risk (PRS-4) categories developed persistent albuminuria cases in the SCCRIP and UIC cohorts, respectively. A PRS may identify high-risk SCA patients for albuminuria. Applying this PRS to guide the early implementation of disease modifiers and renoprotective therapies may help reduce the burden of SCA-related CKD. Trial Registration: NCT02098863.
    Keywords:  CKD; albuminuria; genetic risk score; sickle cell anemia
    DOI:  https://doi.org/10.1002/ajh.27678
  7. Am J Respir Crit Care Med. 2025 Apr 10.
    Comparison of Prophylactic and Therapeutic Doses of Anticoagulation for Acute Chest Syndrome in Sickle Cell Disease: The TASC Randomized Clinical Trial.
    Armand Mekontso Dessap, Anoosha Habibi, Jean-Benoît Arlet, Muriel Fartoukh, Laurent Guerin, Constance Guillaud, Damien Roux, Johanna Oziel, Stéphanie Ngo, Benjamin Carpentier, Marilucy Lopez-Sublet, Louis Affo, Giovanna Melica, Maryse Etienne-Julan, Isabelle Delacroix, François Lionnet, Gylna Loko, Daniel Da Silva, Marc Michel, Keyvan Razazi, Anaïs Charles-Nelson, Pablo Bartolucci, Ségolène Gendreau, Sandrine Katsahian, Bernard Maitre.
       BACKGROUND: Patients with sickle cell disease hospitalised for acute chest syndrome (ACS) are at high risk of in situ pulmonary microthrombosis. We evaluated whether therapeutic anticoagulation could shorten ACS duration.
    METHODS: TASC is a randomized, controlled, double-blind trial conducted in 12 French hospitals (December 2016-April 2021) in adult ACS patients with no initial thrombosis on chest computerised tomography with pulmonary angiogram. We randomised 172 patients (1:1) to receive either prophylactic or therapeutic doses of low-molecular-weight tinzaparin for 7 days. The primary efficacy outcome was time to ACS resolution. The primary safety outcome was major bleeding. Main secondary outcomes included parenteral opioids consumption, transfusion, mortality at hospital discharge, and hospital readmissions at 6 months.
    FINDINGS: The primary efficacy outcome, time to ACS resolution, analysed using a Cox model, was shorter with therapeutic anticoagulation than with prophylactic doses (hazard ratio 0.71; 95% CI: [0.51-0.99]; p=0.044). As a supplemental estimate, the restricted mean time to ACS resolution (over a 15-day horizon or discharge) was shorter with therapeutic doses (4.8±0.4 vs 6.1±0.5 days). The primary safety outcome (major bleeding) did not occur in either group. The cumulative dose of parenteral opioids was lower with therapeutic anticoagulation: (124 [80;272] vs 219 [65;378] mg morphine equivalent, difference: -96, 95%CI: -202 to -46, p=0.02). Other short- and long-term secondary outcomes were similar between groups.
    INTERPRETATION: In adult patients with ACS, a therapeutic anticoagulation shortened ACS duration and reduced opioids consumption compared with prophylactic doses, without increasing bleeding risk. Clinical trial registration available at www.
    CLINICALTRIALS: gov, ID: NCT02580773.
    Keywords:  acute chest; anticoagulation; sickle cell
    DOI:  https://doi.org/10.1164/rccm.202409-1727OC
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