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Characterization of large in-frame von Willebrand factor deletions highlights differing pathogenic mechanisms

Cartwright, Ashley; Webster, Simon J.; de Jong, Annika; Dirven, Richard J.; Bloomer, Lisa D. S.; Al-Buhairan, Ahlam M.; Budde, Ulrich; Halldén, Christer; Habart, David; Goudemand, Jenny; Peake, Ian R.; Eikenboom, Jeroen C. J.; Goodeve, Anne C.; Hampshire, Daniel J.


Ashley Cartwright

Simon J. Webster

Annika de Jong

Richard J. Dirven

Lisa D. S. Bloomer

Ahlam M. Al-Buhairan

Ulrich Budde

Christer Halldén

David Habart

Jenny Goudemand

Ian R. Peake

Jeroen C. J. Eikenboom

Anne C. Goodeve


Copy number variation (CNV) is known to cause all von Willebrand disease (VWD) types, although the associated pathogenic mechanisms involved have not been extensively studied. Notably, in-frame CNV provides a unique opportunity to investigate how specific von Willebrand factor (VWF) domains influence the processing and packaging of the protein. Using multiplex ligation-dependent probe amplification, this study determined the extent to which CNV contributed to VWD in the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease cohort, highlighting in-frame deletions of exons 3, 4-5, 32-34, and 33-34. Heterozygous in vitro recombinant VWF expression demonstrated that, although deletion of exons 3, 32-34, and 33-34 all resulted in significant reductions in total VWF (P < .0001, P < .001, and P < .01, respectively), only deletion of exons 3 and 32-34 had a significant impact on VWF secretion (P < .0001). High-resolution microscopy of heterozygous and homozygous deletions confirmed these observations, indicating that deletion of exons 3 and 32-34 severely impaired pseudo-Weibel-Palade body (WPB) formation, whereas deletion of exons 33-34 did not, with this variant still exhibiting pseudo-WPB formation similar to wild-type VWF. In-frame deletions in VWD, therefore, contribute to pathogenesis via moderate or severe defects in VWF biosynthesis and secretion.


Cartwright, A., Webster, S. J., de Jong, A., Dirven, R. J., Bloomer, L. D. S., Al-Buhairan, A. M., …Hampshire, D. J. (2020). Characterization of large in-frame von Willebrand factor deletions highlights differing pathogenic mechanisms. Blood Advances, 4(13), 2979-2990.

Journal Article Type Article
Acceptance Date May 2, 2020
Online Publication Date Jul 1, 2020
Publication Date Jul 14, 2020
Deposit Date Jul 22, 2020
Publicly Available Date Jul 22, 2020
Journal Blood Advances
Print ISSN 2473-9529
Electronic ISSN 2473-9537
Publisher American Society of Hematology
Peer Reviewed Peer Reviewed
Volume 4
Issue 13
Pages 2979-2990
Keywords Thrombosis and Hemostasis; bodily secretions; copy number polymorphism; heterozygote; homozygote; von willebrand disease; von willebrand factor; biosynthesis; ligation; exons; von willebrand disease; type 1
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