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VWF–ADAMTS13 axis dysfunction in children with sickle cell disease treated with hydroxycarbamide vs blood transfusion

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posted on 2024-01-05, 16:27 authored by Helen Fogarty, Azaz Ahmad, Ferdows AtiqFerdows Atiq, Dearbhla Doherty, Soracha Enright Ward, Ellie KarampiniEllie Karampini, Aisling Rehill, Gemma LeonGemma Leon, Ciara ByrneCiara Byrne, Rosena Geoghegan, Helena Conroy, Mary Byrne, Ulrich Budde, Sonja Schneppenheim, Ciara Sheehan, Noel Ngwenya, Ross Baker, Roger PrestonRoger Preston, Emma Tuohy, Corinna McMahon, James O'DonnellJames O'Donnell
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 with hydroxycarbamide are not fully understood. We hypothesized that the improved efficacy of blood transfusion might relate to differences in VWF–ADAMTS13 axis dysfunction. In total, 180 children with a confirmed diagnosis of SCD (hemoglobin SS) 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 children with SCD (33% and 47%, respectively). Crucially, all VWF parameters were significantly higher in the hydroxycarbamide compared with the blood transfusion cohort (P < .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 with those in the blood transfusion cohort (P < .001). Finally, hemolysis markers strongly correlated with VWF levels (P < .001) and were significantly reduced in the blood transfusion cohort (P < .001). Cumulatively, to our knowledge, our findings demonstrate for the first time that despite treatment, ongoing dysfunction of the VWF–ADAMTS13 axis is present in a significant subgroup of pediatric patients with SCD, especially those treated with hydroxycarbamide.

Funding

Wellcome Trust and the Health Research Board (grant number 203930/B/16/Z)

Health Service Executive, National Doctors Training and Planning

Health and Social Care, Research and Development Division, Northern Ireland

National Children’s Research Centre Project award H/19/1

Science Foundation Ireland Frontiers for the Future award 20/FFP-A/8952

History

Comments

The original article is available at https://ashpublications.org/

Published Citation

Fogarty H. et al. VWF-ADAMTS13 axis dysfunction in children with sickle cell disease treated with hydroxycarbamide vs blood transfusion. Blood Adv. 2023;7(22):6974-6989

Publication Date

17 November 2023

PubMed ID

37773926

Department/Unit

  • Irish Centre for Vascular Biology
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Health Professions Education
  • Immunity, Infection and Inflammation
  • Vascular Biology

Publisher

American Society of Hematology

Version

  • Published Version (Version of Record)