bims-sicedi 2025-03-30 papers

bims-sicedi

Biomed News

on Sickle cell disease

Issue of 2025–03–30
nine papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Sticking together: Polymerization of sickle hemoglobin drives the multiscale pathophysiology of sickle cell disease.
The wider perspective: Barriers and recommendations for transfusion support for patients with sickle cell disease in low- and middle-income countries.
Kidney function after nonmyeloablative hematopoietic cell transplant for sickle cell disease.
Impact of Different Definitions of Vaso-Occlusion on Efficacy Assessments in Sickle Cell Disease Clinical Trials.
Unraveling the Complex Genomic Interplay of Sickle Cell Disease Among the Saudi Population: A Case-Control GWAS Analysis.
Prevalence of Duffy Null and Its Impact on Hydroxyurea Dosing in Children With Sickle Cell Disease.
Outcomes on the use of hyperhemolysis prophylaxis in pediatric sickle cell disease patients with history of hyperhemolysis syndrome.
Factors associated with the occurrence of leg ulcers in people with sickle cell disease: A case-control study.
Historical View and Some Unsolved Problems in Red Blood Cell Membrane Research.

Biophys Rev (Melville). 2025 Mar;6(1): 011309

Sticking together: Polymerization of sickle hemoglobin drives the multiscale pathophysiology of sickle cell disease.

Dillon C Williams, Hannah M Szafraniec, David K Wood.

Sickle cell disease is a hereditary disorder in which the pathophysiology is driven by the aggregation of a mutant (sickle) hemoglobin (HbS). The self-assembly of deoxygenated sickle hemoglobin molecules into ordered fiber structures has consequences extending to the cellular and rheological levels, stiffening red blood cells and inducing pathological flow behavior. This review explores the current understanding of the molecular processes involved in the polymerization of hemoglobin in sickle cell disease and how the molecular phase transition creates quantifiable changes at the cellular and rheological scale, as well as, identifying knowledge gaps in the field that would improve our understanding of the disease and further improve treatment and management of the disease.

DOI: https://doi.org/10.1063/5.0238698
Br J Haematol. 2025 Mar 27.

The wider perspective: Barriers and recommendations for transfusion support for patients with sickle cell disease in low- and middle-income countries.

Jeremy W Jacobs, Luiz Amorim, France Pirenne, Claude Tayou, Ijele Adimora, Lydia H Pecker, Aaron A R Tobian, Jeannie Callum, Julie Makani, Mark T Gladwin, Meghan Delaney, Darrell J Triulzi, Isaac Odame, Evan M Bloch.

  Globally, sickle cell disease (SCD) is the most common inherited haemoglobinopathy. The highest burden of SCD is encountered in low- and middle-income countries (LMICs), most of which lack the resources to contend with the disease. There is a marked divide between care for individuals with SCD in high-income countries (HICs) versus LMICs, whereby the few disease-modifying therapies and curative regimens are only accessible to those in HICs. As such, blood transfusion remains central to the emergent treatment and prevention of complications of SCD. However, there are a myriad of related challenges in LMICs, which have impeded efforts to treat patients with SCD effectively. In addition to blood safety and availability, examples that impact SCD specifically include capabilities to detect and/or manage red blood cell alloimmunization, capacity for automated red cell exchange, limited immunohematology, suboptimal quality oversight with a lack of safeguards to prevent transfusion of incompatible blood and limited or absent post-transfusion surveillance to detect and/or manage transfusion-associated adverse events. Consequently, clinical practices that are otherwise regarded as standard of care in HICs remain the exception in LMICs, highlighting disparities in care. A multifaceted approach that prioritizes transfusion support in LMICs is needed to improve care for patients with SCD.

Keywords:  alloimmunization; haematology; red blood cells; sickle cell disease; transfusion medicine; transfusion support; transfusion‐transmitted infection

DOI:  https://doi.org/10.1111/bjh.20055
Bone Marrow Transplant. 2025 Mar 22.

Kidney function after nonmyeloablative hematopoietic cell transplant for sickle cell disease.

Emily Limerick, Matthew M Hsieh, Mauricio Barretto, Neal Jeffries, Clarissa Diamantidis, Yuliya Lokhnygina, Ritika Menon, Santosh L Saraf, Courtney D Fitzhugh.

Hematopoietic cell transplantation (HCT) is potentially curative for patients with sickle cell disease (SCD). Both SCD and HCT cause kidney damage. This study analyzed data from 160 patients who received nonmyelablative HCT for SCD. Renal function was assessed at baseline and annually for 3years. The rate of new-onset eGFR <60 ml/min/1.73m2 was low (2.8%). Rapid kidney function decline in the first year post-HCT was noted in 7.5% of patients but was not associated with subsequently worse renal function. The eGFR decreased post-HCT (1 year: -7.19 p < 0.0001, 2 year: -11.32 p < 0.0001, 3 year: -12.37 ml/min/1.73m2 p < 0.0001). Mean eGFR remained within normal limits throughout the follow-up period (1 year:119, 2 year:115, 3 year:113 ml/min/1.73m2). Hyperfiltration rates decreased with a corresponding increase in patients with normal eGFR post-HCT. Therefore, the decline in eGFR after HCT may represent preservation of renal function. The prevalence of kidney damage increased transiently but, by 3 years post-HCT, was not significantly changed from baseline. Most cases of kidney damage were due to albuminuria. AKI, noted early post-HCT in 39% of patients, was most commonly stage 1 and was associated with decreased survival (p = 0.03). Larger studies with longer follow-up are required to explore the effects of HCT on renal function in patients with SCD.

DOI: https://doi.org/10.1038/s41409-025-02550-0
Adv Ther. 2025 Mar 27.

Impact of Different Definitions of Vaso-Occlusion on Efficacy Assessments in Sickle Cell Disease Clinical Trials.

Haydar Frangoul, Franco Locatelli, Michael J Eckrich, Suzan Imren, Nanxin Li, Fengjuan Xuan, Stephan A Grupp.

   INTRODUCTION: Patients with sickle cell disease (SCD) experience recurrent, severe pain events due to vaso-occlusion. Eliminating these acute pain events is a key outcome in SCD clinical trials; however, the definition of a vaso-occlusive crisis (VOC) or a vaso-occlusive event (VOE) has not been consistently applied, hampering comparisons of treatment efficacy between different therapeutic approaches. We have examined the degree to which differing definitions of vaso-occlusion in clinical trial endpoints impact efficacy outcomes.
METHODS: Descriptions of clinical endpoints related to vaso-occlusion and pain events were reviewed from trials of exagamglogene autotemcel (exa-cel), lovotibeglogene autotemcel (lovo-cel), renizgamglogene autogedtemcel (reni-cel), hydroxyurea, L-glutamine, voxelotor, and crizanlizumab. Patient-level data from the published exa-cel Phase 3 pivotal trial (CLIMB SCD-121; data cut 14 Jun 2023) was used to evaluate efficacy outcomes based on differing endpoint definitions of vaso-occlusion.
RESULTS: In the seven clinical trials reviewed, definitions of vaso-occlusion and/or pain events varied by care setting, duration of care, treatments used, and associated complications, with the frequency and duration of medical facility visits for acute pain events being most dissimilar between trials. Definitions of severe VOCs (exa-cel), VOC (voxelotor), and sickle cell-related pain crises (SCPCs; crizanlizumab and L-glutamine) included pain events requiring a medical facility visit of any duration, whereas the definition of painful crises (hydroxyurea) required a medical facility visit of > 4 h and the definition of severe vaso-occlusive events (VOEs; lovo-cel and reni-cel) required a hospital or emergency room (ER) observation unit visit lasting ≥ 24 h or ≥ 2 visits to a day unit or ER over a 72-h period. Based on the definition of severe VOCs, 29/30 patients [96.7%; 95% confidence interval (CI): 82.8, 99.9] in the CLIMB SCD-121 trial were considered free from severe VOCs for ≥ 12 consecutive months, whereas when the severe VOEs definition was applied to the same data, all patients (30/30; 100.0%; 95% CI: 88.4, 100.0) were considered free from severe VOEs for ≥ 12 consecutive months.
CONCLUSION: Differences exist in definitions of vaso-occlusion and pain events used in SCD clinical trials. Severe VOCs (exa-cel), VOC (voxelotor), and SCPCs (crizanlizumab and L-glutamine) were more broadly inclusive than severe VOEs (lovo-cel and reni-cel) or painful crisis (hydroxyurea). Clinically, these differences resulted in differing numbers of patients being considered free from vaso-occlusion pain events, underscoring the challenge in comparing frequencies of pain events across SCD clinical trials.

Keywords:  Clinical trials; Sickle cell disease; Vaso-occlusion

DOI:  https://doi.org/10.1007/s12325-025-03162-2
Int J Mol Sci. 2025 Mar 20. pii: 2817. [Epub ahead of print]26(6):

Unraveling the Complex Genomic Interplay of Sickle Cell Disease Among the Saudi Population: A Case-Control GWAS Analysis.

Ali Alghubayshi, Dayanjan Wijesinghe, Deemah Alwadaani, Farjah H Algahtani, Salah Abohelaika, Mohsen Alzahrani, Hussain H Al Saeed, Abdullah Al Zayed, Suad Alshammari, Yaseen Alhendi, Barrak Alsomaie, Abdulmonem Alsaleh, Mohammad A Alshabeeb.

  Sickle cell disease (SCD) is a severe inherited blood disorder characterized by abnormal hemoglobin (HbS) that leads to varying degrees of severity, including chronic hemolysis, episodic vaso-occlusion, and damage to multiple organs, causing significant morbidity and mortality. While SCD is a monogenic disease, its complications are influenced by polygenic factors. SCD prevalence is notably high in regions including the Middle East, with Saudi Arabia reporting significant cases, particularly in the Eastern Province. Most genetic factors associated with SCD outcomes have been identified in populations predominantly from Africa or of African ancestry. This study aims to identify genetic variants that characterize Saudi SCD patients with the potential to influence disease outcomes in this population. A multicenter case-control genome-wide association study (GWAS) was conducted involving 350 adult Saudi SCD patients and 202 healthy controls. Participants were genotyped using the Affymetrix Axiom array, covering 683,030 markers. Rigorous quality control measures were applied to ensure data integrity. Fisher's exact was used to identify genetic variants with a significant difference in allele frequency (p < 5 × 10-8). Functional annotations and regulatory functions of variants were determined using the Ensembl Variant Effect Predictor (VEP) and RegulomeDB databases. The GWAS identified numerous significant genetic variants characterizing SCD cases in the Saudi population. These variants, distributed across multiple chromosomes, were found in genes with known functional consequences. A substantial proportion of the markers were detected in the olfactory receptor cluster, TRIM family, and HBB locus genes. Many of the identified genes were reported in previous studies showing significant associations with various SCD outcomes, including hemoglobin regulation, inflammation, immune response, and vascular function. The findings highlight the genetic complexity underlying SCD and its clinical manifestations. The identified variants suggest potential molecular biomarkers and therapeutic targets, enhancing our understanding of the molecular basis of SCD in the Saudi population. This is the first genetic analysis characterizing SCD patients compared to healthy individuals, uncovering genetic markers that could serve as diagnostic biomarkers and therapeutic targets. Given the known molecular mechanisms of the detected genetic loci, these provide a foundation for precision medicine in SCD management, highlighting the need for further studies to validate these results and explore their clinical implications.

Keywords:  Saudis; genome-wide association study (GWAS); hemoglobin S (HbS); olfactory receptor clusters (ORs); sickle cell disease (SCD); β-globin subunit

DOI:  https://doi.org/10.3390/ijms26062817
Pediatr Blood Cancer. 2025 Mar 28. e31693

Prevalence of Duffy Null and Its Impact on Hydroxyurea Dosing in Children With Sickle Cell Disease.

Jill S Menell, S Raelle Jackson, Alissa R Kahn, William C Woolbright, Leya Y Schwartz, John Norko.

Duffy null phenotype is common in people of African ancestry and is associated with lower baseline white blood cell (WBC) and neutrophil counts. We evaluated whether the presence of the Duffy null phenotype had any association with neutropenia in our patients with sickle cell disease on hydroxyurea (HU). We found a statistically significant difference (p = 0.006) in HU maximum tolerated dose (MTD) in patients with Duffy null phenotype compared with Duffy-positive individuals. Our study suggests that careful dose escalation is warranted in Duffy-null individuals.

DOI: https://doi.org/10.1002/pbc.31693
Transfusion. 2025 Mar 26.

Outcomes on the use of hyperhemolysis prophylaxis in pediatric sickle cell disease patients with history of hyperhemolysis syndrome.

HyoJeong Han, Lisa Hensch, In Lei, Titilope Fasipe, Jun Teruya, Shiu-Ki Rocky Hui.

   BACKGROUND: Hyperhemolysis syndrome (HS) is a rare but severe transfusion-associated complication seen in patients with sickle cell disease (SCD). The management of HS includes avoidance of post-hyperhemolysis red blood cell (RBC) transfusion to avoid reoccurrence of HS (recurrent HS). However, complete avoidance of post-hyperhemolysis RBC transfusion (PHRT) is sometimes not clinically possible, and the standard of care for recurrent HS prophylaxis for patients requiring PHRT has not been established.
CASE REPORT: We present a retrospective case series of four pediatric patients with SCD and a history of HS requiring PHRT, and describe their HS prophylaxis and outcomes. All patients received HS prophylaxis before transfusion, and three patients received an additional prophylactic regimen post-transfusion. Three patients were transfused with extended phenotype-matched RBCs, while one patient received only Rh (D, C/c, E/e) and K antigens matched RBCs. Only one patient did not develop recurrent HS after PHRT. Three patients had documented hemolysis, and two patients met our criteria for recurrent HS, all requiring escalation of care.
DISCUSSION: Even though the patients were treated in the same institution, there was variability in the choice of HS prophylaxis therapy and selection of RBCs, which can be attributed to the lack of guidance on PHRT management. We observed a lack of conclusive evidence in the effectiveness of prophylactic combination immunosuppressive therapy. Our observations suggest caution must be taken when transfusing patients with SCD and a history of HS, as there are no definitive therapies to effectively mitigate the risk of recurrent HS.

Keywords:  Hyperhemolysis syndrome; hyperhemolysis prophylaxis; pediatrics; sickle cell disease

DOI:  https://doi.org/10.1111/trf.18227
Blood Cells Mol Dis. 2025 Mar 22. pii: S1079-9796(25)00014-2. [Epub ahead of print]112 102922

Factors associated with the occurrence of leg ulcers in people with sickle cell disease: A case-control study.

Josimare Aparecida Otoni Spira, Mery Natali Silva Abreu, Antônio Carlos Martins Guedes, Eline Lima Borges.

   AIM: To identify factors associated with the occurrence of leg ulcers in people with sickle cell disease.
METHODS: Unpaired case-control study, conducted in 11 specialized services, between August 2019 and April 2020. The convenience sample consisted of 262 people over 18 years of age, diagnosed with sickle cell disease, with 190 controls and 72 cases. To evaluate the possible factors associated with the occurrence of ulcers, both univariate and multivariate binary logistic regression models were used.
FINDINGS: The factors associated with the occurrence of leg ulcers were previously healed ulcers (odds ratio 48.48), presence of edema in the lower limbs (5.75), use of antibiotics in the last six months (3.08), daily rest (4.59), and use of compression stockings (6.24). Overweight (0.16), physical leisure (0.33), and domestic (0.37) activities were associated with a lower chance of occurrence of ulcers.
CONCLUSION: Identifying the factors that increase the likelihood of leg ulcers occurring in people with sickle cell disease adds to our knowledge of the subject, especially by determining factors that mitigate the occurrence of ulcers and that go beyond clinical variables.

Keywords:  Anemia, sickle cell; Chronic disease; Leg ulcer; Wounds and injuries

DOI:  https://doi.org/10.1016/j.bcmd.2025.102922
Front Biosci (Landmark Ed). 2025 Mar 06. 30(3): 25331

Historical View and Some Unsolved Problems in Red Blood Cell Membrane Research.

Ingolf Bernhardt, Lars Kaestner.

  The article provides a comprehensive overview of biological membrane lipid composition and distribution and ion transport processes, focusing particularly on red blood cells (RBCs). It begins with a historical perspective, detailing the introduction of the terms 'cell' and 'membrane' in biological sciences, and the development of the fluid-mosaic model of membrane structure. Early findings on ion transport highlighted the non-equilibrium distribution of Na+ and K+ across cell membranes, leading to the discovery of the Na+/K+ pump. The article delves into the lipid composition of RBC membranes, emphasising the roles of various lipids, including cardiolipin, and the concept of lipid rafts. These rafts, enriched with sphingolipids and cholesterol, play crucial roles in cellular processes. Variations in RBC shapes are discussed, with biophysical theories explaining transformations and pathological conditions affecting RBC morphology, such as sickle cell anaemia. Na+ and K+ transporters in RBC membranes are explored, highlighting the almost ubiquitous presence of the Na+/K+ pump (absent in Carnivora RBCs) and various ion channels, including the Gárdos and Piezo1 channels. The article notes species-specific differences in ion transport mechanisms and the activation or suppression of transporters during RBC maturation. The mechanism of residual ion transport is examined, questioning whether a Na+(K+)/H+ antiporter exists in the human RBC membrane. Residual ion fluxes are mediated by this antiporter, influenced by the fatty acid composition of the RBC membrane. The outlook section underscores the need for further research to fully understand the complexities of RBC membrane structure and function, suggesting that many questions remain unanswered despite significant advances.

Keywords:  lipid rafts; membrane lipid composition; red blood cell; red blood cell deformability; red blood cell shapes; residual (leak) ion transport

DOI:  https://doi.org/10.31083/FBL25331