bims-sicedi 2025-04-27 papers

bims-sicedi

Biomed News

on Sickle cell disease

Issue of 2025–04–27
seven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Effect of dalcetrapib, voxelotor and their combination on red blood cell deformability and sickling in sickle cell disease.
Exploring pharmacogenetic factors influencing hydroxyurea response in tanzanian sickle cell disease patients: a genomic medicine approach.
Decoding HbF reactivation by hydroxyurea in hemoglobinopathy patients through microRNA signatures.
Impact of protein-energy malnutrition on outcomes of patients with sickle cell disease: an analysis of the National inpatient sample.
Arginine Therapy for Pain in Sickle Cell Disease: A Phase-2 Randomized, Placebo-Controlled Trial.
Prostacyclin-analog therapy for pulmonary vascular dysfunction during severe acute chest syndrome in sickle cell disease.
Prophylactic versus on-demand transfusion in pregnant women with sickle cell disease: A systematic review and meta-analysis of randomised controlled trials.

Clin Hemorheol Microcirc. 2025 Apr 21. 13860291251320332

Effect of dalcetrapib, voxelotor and their combination on red blood cell deformability and sickling in sickle cell disease.

Claire Bordat, Elie Nader, Philippe Connes, Philippe Joly, Solene Poutrel, Anne Perez, Eric Niesor.

  The aim of the present study was to test the effects of dalcetrapib and voxelotor on red blood cells (RBC) of sickle cell patients. Oxygen gradient ektacytometry was performed to measure RBC deformability in normoxia and hypoxia, as well as the propensity of RBC to sickle. Voxelotor and dalcetrapib reduced the propensity of RBC to sickle under deoxygenation and increased RBC deformability in hypoxia. Dalcetrapib did not affect the affinity of hemoglobin S (HbS) to oxygen. Combining the two molecules caused greater RBC rheological improvement. Our findings suggest that dalcetrapib could block HbS polymerization without affecting HbS oxygen affinity.

Keywords:  dalcetrapib; red blood cell rheology; sickle cell disease; sickling

DOI:  https://doi.org/10.1177/13860291251320332
Pharmacogenomics J. 2025 Apr 23. 25(3): 11

Exploring pharmacogenetic factors influencing hydroxyurea response in tanzanian sickle cell disease patients: a genomic medicine approach.

Siana Nkya, Collin Nzunda, Emmanuel Saukiwa, Frida Kaywanga, Eliud Buchard, David Solomon, Heavenlight Christopher, Doreen Ngowi, Julieth Johansen, Florence Urio, Josephine Mgaya, Christina Kindole, Mbonea Yonazi, Salman Karim, Mohamed Zahir Alimohamed, Raphael Z Sangeda, Clara Chamba, Collet Dandara, Enrico Novelli, Emile R Chimusa, Julie Makani.

In sub-Saharan Africa, sickle cell disease (SCD) remains a significant public health challenge. Despite the discovery of SCD over a century ago, progress in developing and accessing effective treatments has been limited. Hydroxyurea is the primary drug used for managing SCD and associated with improving clinical outcomes. However, up to 30% of patients do not respond to hydroxyurea, likely due to genetic factors. This study involved 148 individuals with SCD investigated the association of hydroxyurea response with genetic variants across 13 loci associated with HbF synthesis and drug metabolism, focusing on MYB, HBB, HBG1, HBG2, BCL11A, KLF10, HAO2, NOS1, ARG2, SAR1A, CYP2C9, and CYP2E1. Significant associations with hydroxyurea response were identified in CYP2C9, CYP2E1, KLF10, BCL11A, ARG2, HBG1, SAR1A, MYB, and NOS1 loci. Furthermore, pathway enrichment and gene-gene interaction analyses provide deeper insights into the genetic mechanisms underlying hydroxyurea treatment response, highlighting potential avenues for personalized therapy in SCD management.

DOI: https://doi.org/10.1038/s41397-025-00372-3
Ann Hematol. 2025 Apr 25.

Decoding HbF reactivation by hydroxyurea in hemoglobinopathy patients through microRNA signatures.

Neha Kargutkar, Anita Nadkarni.

  Hydroxyurea promotes HbF elevation in b-thalassemia and sickle cell anemia patients however, its mechanism is not completely elucidated. Previous studies have associated microRNAs with the regulation of HBG2, prompting this study to investigate specific microRNAs linked to HbF regulation in patients treated with hydroxyurea. 150 patients were recruited in the study. miRNA microarray panel of 754 miRNAs was used, and a further customised microarray card was designed. In silico tools predicted target genes of miRNAs and in vitro transfection functionally validated miRNAs in erythroblast cells from patients and K562 cells. Global microarray revealed 59 differentially expressed miRNAs, with 42 upregulated and 17 downregulated significantly following 3/6 months of hydroxyurea treatment (p < 0.001). Further, the customised miRNA panel of these 59 miRNAs confirmed the results. Among 59 miRNAs, 12 upregulated and 3 downregulated miRNAs correlated with HBG2 expression and HbF levels. In silico predictions and in vitro cells study identified miR-150, miR-155, miR-374, miR-486-3p (BCL11A, MYB); miR-190, miR-26a, miR-30b, miR-362, miR-411 (BCL11A); miR-192, miR-454 (MYB); miR-326 (KLF1); miR-150 (GATA1) and miR-15a, miR-484, miR-105 commonly share BCL11A, MYB, KLF1 and GATA1. Our study uncovers how microRNAs influence fetal hemoglobin induction in patients with hydroxyurea treatment, thus offering insights for developing treatment strategies and alleviating clinical severity.

Keywords:  HbF; Hydroxyurea; Sickle cell anemia; Thalassemia; miRNA

DOI:  https://doi.org/10.1007/s00277-025-06252-x
Ann Hematol. 2025 Apr 21.

Impact of protein-energy malnutrition on outcomes of patients with sickle cell disease: an analysis of the National inpatient sample.

Mrinalini Ramesh, Yasmin Fakhari-Tehrani, Vaishali Deenadayalan, Parikshit Padhi.

  Patients with sickle cell disease (SCD) are often malnourished, leading to complications such as increased vaso-occlusive crises, infections, prolonged hospital stays, and decreased quality of life. This study examines the impact of protein-energy malnutrition (PEM) on clinical outcomes in hospitalized SCD patients. A retrospective cohort study using National Inpatient Sample data (2016-2020) was performed. Adult SCD patients were stratified by PEM status. Primary outcomes included mortality, length of stay, and hospital charges. Multivariate regression analyses were performed in STATA 17. Among 771,175 SCD patients, 25.9% (20,030) had PEM. More PEM patients were female (57.3%), and PEM was more prevalent in males compared to those without (42.7% vs. 34.3%, p < 0.001). Patients with PEM had higher Charlson Comorbidity Index scores (≥ 3: 42.6% vs. 12.8%, p < 0.001). PEM was associated with increased mortality (aOR 2.66, p < 0.001), longer hospital stays (9.56 vs. 4.79 days, p < 0.001), and higher costs ($100,209 vs. $41,412, p < 0.001). PEM also raised the odds of intubation, pressor support, acute kidney injury, sepsis, blood transfusion, pneumonia, and urinary tract infections (all p < 0.001). PEM is associated with worse outcomes in hospitalized SCD patients, leading to higher mortality, extended stays, and increased costs due to intensive interventions. Early nutritional consultation may improve patient outcomes.

Keywords:  Adverse inpatient outcomes; Disparities; Hematology; Sickle cell disease

DOI:  https://doi.org/10.1007/s00277-025-06358-2
Am J Hematol. 2025 Apr 24.

Arginine Therapy for Pain in Sickle Cell Disease: A Phase-2 Randomized, Placebo-Controlled Trial.

Claudia R Morris, Dunia Hatabah, Rawan Korman, Scott Gillespie, Nitya Bakshi, Lou Ann Brown, Frank Harris, Deborah Leake, Chris A Rees, Kirshma Khemani, Elliott P Vichinsky, Alexus Locke, Bridget Wynn, Mark A Griffiths, Hagar Wilkinson, Polly Kumari, Lisa Sudmeier, Sruti Shiva, Carlton D Dampier.

  We present a prospective randomized, placebo-controlled trial of intravenous arginine in patients 3-21 years hospitalized with sickle cell disease vaso-occlusive pain episodes (SCD-VOE) at two tertiary-care children's hospitals. Participants were randomized into 1 of 3 arms: Standard-dose (SD; 100 mg/kg/dose) every 8 h, Loading-dose (200 mg/kg followed by SD), or Placebo. The primary outcome was total parenteral opioid use (TPO). Secondary outcomes included time-to-crisis-resolution, pain scores, patient-reported outcomes (PROs), arginine bioavailability, and biomarkers of oxidative stress/mitochondrial function. Of 1548 patients screened, 108 were randomized (36 per study-arm; mean 12.6 ± 3.8 years, 52% female, and 65% hemoglobin-SS). This study did not meet its primary endpoint. TPO, time-to-crisis-resolution, pain scores, and PROs at discharge were similar across arms. Post hoc sensitivity analyses of children 5-16 years old demonstrated nearly double TPO utilization in those receiving placebo versus arginine (n = 87, p = 0.056), achieving significance in patients with plasma arginine < 60 μM. Arginine was low at presentation in 79% of patients (mean 50 ± 28 μM), and increased with arginine therapy (p < 0.001). Arginine bioavailability at VOE presentation inversely correlated with time-to-crisis-resolution (r = -0.39, p = 0.01) after placebo, an association eliminated by arginine supplementation (r = -0.04, p = 0.70). A dose-dependent increase in platelet-mitochondrial activity occurred after arginine versus no change after placebo (p < 0.001); plasma protein-carbonyl levels, a measure of oxidative stress, decreased after arginine therapy (p < 0.001) but increased in the placebo group (p = 0.02). SCD-VOE is associated with an acquired arginine deficiency that correlates with worse clinical outcomes. Arginine improved mitochondrial function and decreased oxidative stress compared to placebo, with clinically relevant opioid-sparing becoming significant in children with the lowest arginine concentration. TRIAL REGISTRATION: Registered with ClinicalTrials.gov (NCT02536170) in August 2015.

Keywords:  arginine; mitochondrial function; sickle cell disease; vaso‐occlusive pain episodes

DOI:  https://doi.org/10.1002/ajh.27692
Shock. 2025 Apr 23.

Prostacyclin-analog therapy for pulmonary vascular dysfunction during severe acute chest syndrome in sickle cell disease.

Julien Lopinto, Elsa Moncomble, Ségolène Gendreau, Guillaume Carteaux, François Bagate, Nicolas de Prost, Pablo Bartolucci, Anoosha Habibi, Keyvan Razazi, Armand Mekontso Dessap.

   BACKGROUND: The purpose of this study is to evaluate the impact of parenteral epoprostenol in sickle cell adults patients presenting acute cor pulmonale (ACP) complicating severe acute chest syndrome (ACS).
METHODS: Retrospective single-center analysis of sickle cell patients in ICU with ACP complicating severe ACS receiving Epoprostenol in addition to usual care (prostacyclin group) or usual care alone (control group). Primary outcome: relative change in pulmonary artery systolic pressure over 1 day.
RESULTS: 45 patients were included in the study, including 21 who received usual care and 24 who received Epoprostenol. There was a significant reduction in PASP during the first 24 hours in the prostacyclin group (from 69 [60-77] to 52 [42-61] mmHg, p < 0.001) but not in the control group (from 50 [40-56] to 50 [35-55] mmHg, p = 0.285). The median decrease in PASP was greater in the prostacyclin group than in the control group (-25% [-33;-13] vs -2 % [-8; 0], p < 0.001).
CONCLUSION: Parenteral prostacyclin analogue therapy is associated with a significant reduction in PASP in patients with SCD admitted in ICU with ACS-related ACP.

Keywords:  Acute Chest Syndrome, Acute cor pulmonale; Epoprostenol; Sickle cell disease; pulmonary vascular dysfunction

DOI:  https://doi.org/10.1097/SHK.0000000000002593
EJHaem. 2025 Apr;6(2): e21086

Prophylactic versus on-demand transfusion in pregnant women with sickle cell disease: A systematic review and meta-analysis of randomised controlled trials.

Denise Menezes Brunetta, Evangelia Vlachodimitropoulou, Nita Prasannan, Paul T Seed, Eugene Oteng-Ntim.

   Introduction: Sickle cell disease (SCD) poses significant risks during pregnancy. Transfusions are the only recommended treatment, but there is no strong evidence of its efficacy. The aim of this study was to evaluate prophylactic transfusion on pregnancy outcomes.
Methods: We performed a systematic review and meta-analysis (PROSPERO-CRD42024510511), using MEDLINE, EMBASE, Cochrane, Web of Science, and Maternity and Infant Care. No date or language restrictions were applied. Inclusion criteria comprised randomised-controlled trials (RCTs) involving SCD pregnancy, comparing maternal and foetal outcomes for prophylactic versus on-demand transfusions. Two independent reviewers performed screening, selection, and data extraction, following PRISMA. Two authors independently assessed certainty and risk-of-bias. Data were pooled using random-effects model. Primary outcomes included mortality, vaso-occlusive crisis (VOC), acute chest syndrome, venous thromboembolism and preterm delivery. The measure of the effect was the unadjusted odds ratio (OR), calculated from numbers of events.
Results: Ninety-one studies were identified and two RCTs (106 patients) were included, with uncertain and low risk of bias. Prophylactic transfusions reduced VOC, OR of 0.197 (95% CI 0.08-0.49). However, due to the small number of patients, this meta-analysis was underpowered to evaluate other outcomes.
Conclusion: A larger RCT is needed to comprehensively assess the impact of prophylactic transfusion in SCD pregnancy.

Keywords:  pregnancy; randomised controlled trials; sickle cell disease; systematic review; transfusion

DOI:  https://doi.org/10.1002/jha2.1086