VWF-ADAMTS13 axis dysfunction in children with sickle cell disease treated with hydroxyurea versus blood transfusion.

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.