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Journal article
VWF-ADAMTS13 axis dysfunction in children with sickle cell disease treated with hydroxycarbamide versus blood transfusion
Blood advances, Vol.7(22), pp.6974-6989
2023
Abstract
Previous studies have reported elevated von Willebrand factor (VWF) levels in patients with sickle cell disease (SCD) and demonstrated a key role for the VWF-ADAMTS13 axis in the pathobiology of SCD vaso-occlusion. Although blood transfusion is the gold standard for stroke prevention in SCD, the biological mechanisms underpinning its improved efficacy compared to hydroxycarbamide are not fully understood. We hypothesized that the improved clinical efficacy of blood transfusion might relate to differences in endothelial cell activation and VWF-ADAMTS13 axis dysfunction. One-hundred-eighty children with a confirmed diagnosis of SCD (HbSS) on hydroxycarbamide (n=96) or blood transfusion (n=84) were included. Despite disease-modifying treatment, plasma VWF and VWF propeptide were elevated in a significant proportion of SCD children (33% and 47% respectively). Crucially, all VWF parameters were significantly higher in the hydroxycarbamide compared to the blood transfusion cohort (p<0.05). Additionally, increased levels of other Weibel-Palade-body-stored proteins, including factor VIII (FVIII), angiopoietin-2, and osteoprotegerin were observed, indicated ongoing endothelial cell activation. Children treated with hydroxycarbamide also had higher FVIII activity and enhanced thrombin generation compared to the blood transfusion cohort (p<0.001), contributing to their thrombotic risk. Finally, hemolysis markers strongly correlated with VWF levels (p<0.001) and significantly reduced in the blood transfusion cohort (p<0.001). Cumulatively, our findings demonstrate for the first time that despite treatment, ongoing dysfunction of the VWF-ADAMTS13 axis is present in a significant sub-group of pediatric SCD patients, especially those treated with hydroxycarbamide. Since VWF plays an important role in vaso-occlusion pathogenesis, these data are of direct translational relevance.
Details
- Title
- VWF-ADAMTS13 axis dysfunction in children with sickle cell disease treated with hydroxycarbamide versus blood transfusion
- Authors/Creators
- Helen Fogarty - Royal College of Surgeons in IrelandAzaz Ahmad - Royal College of Surgeons in IrelandFerdows Atiq - Royal College of Surgeons in IrelandDearbhla Doherty - Royal College of Surgeons in IrelandSoracha Ward - Royal College of Surgeons in IrelandEllie Karampini - Royal College of Surgeons in IrelandAisling Rehill - Royal College of Surgeons in IrelandGemma Leon - Royal College of Surgeons in IrelandCiara Byrne - Royal College of Surgeons in IrelandRosena Geoghegan - Children's Health Ireland at CrumlinHelena Conroy - Children's Health Ireland at CrumlinMary Byrne - St. James's HospitalUlrich Budde - Medizinisches Versorgungszentrum Prof. Mathey, Prof. SchoferSonja Schneppenheim - Medizinisches Versorgungszentrum Prof. Mathey, Prof. SchoferCiara Sheehan - St. James's HospitalNoel Ngwenya - St. James's HospitalRoss I. Baker - Murdoch University, Centre for Molecular Medicine and Innovative TherapeuticsRoger J.S. Preston - Royal College of Surgeons in IrelandEmma Tuohy - St. James's HospitalCorrina McMahon - Children's Health Ireland at CrumlinJames S. O’Donnell - Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland
- Publication Details
- Blood advances, Vol.7(22), pp.6974-6989
- Publisher
- Ash Publications
- Identifiers
- 991005619763207891
- Copyright
- © 2023 by The American Society of Hematology.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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