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Increased galactose expression and enhanced clearance in patients with Low von Willebrand factor

Sonia Aguila, Michelle Lavin, Niall Dalton, Sean Patmore, Alain Chion, George D. Trahan, Kenneth L. Jones, Catriona Keenan, Teresa M. Brophy, Niamh M. O'Connell, Kevin Ryan, Mary Byrne, Margaret Nolan, Anjali Patel, Roger J.S. Preston, Paula James, Jorge Di Paola, Jamie M. O'Sullivan and James S. O'Donnell

Key points

  • Terminal galactose exposure on VWF is significantly increased in a subgroup of patients with Low VWF compared to controls.

  • Enhanced clearance of aberrantly glycosylated VWF contributes to the etiology underlying Low VWF.

Abstract

Glycan determinants on von Willebrand factor (VWF) play critical roles in regulating its susceptibility to proteolysis and clearance. Abnormal glycosylation has been shown to cause VWD in a number of different mouse models. However, due to the significant technical challenges associated with accurate assessment of VWF glycan composition, the importance of carbohydrates in human VWD pathogenesis remains largely unexplored. To address this, we developed a novel lectin-binding panel to enable human VWF glycan characterization. This methodology was then utilized to study glycan expression in a cohort of 110 patients with Low VWF compared to O blood group-matched healthy controls. Interestingly, significant inter-individual heterogeneity in VWF glycan expression was seen in the healthy control population. This variation included terminal sialylation and ABO(H) blood group expression on VWF. Importantly, we also observed evidence of aberrant glycosylation in a subgroup of patients with Low VWF. In particular, terminal α2-6 linked sialylation was reduced in patients with Low VWF, with a secondary increase in galactose (Gal) exposure. Furthermore, an inverse correlation between Gal exposure and estimated VWF half-life was observed in those patients with enhanced VWF clearance. Together, these findings support the hypothesis that loss of terminal sialylation contributes to the pathophysiology underpinning Low VWF in at least a sub-group of patients by promoting enhanced clearance. In addition, alterations in VWF carbohydrate expression are likely to contribute to quantitative and qualitative variations in VWF levels in the normal population. This trial was registered at www.clinicaltrials.gov as #NCT03167320.

  • Submitted September 12, 2018.
  • Accepted February 6, 2019.