Type 2B VWD substitutions trigger enhanced macrophage-mediated clearance that is attenuated by the BT200 aptamer
- 1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
Abstract
Type 2B von Willebrand disease (VWD) is characterized by missense variants in exon 28 of the von Willebrand factor (VWF) gene that encodes the VWF-A1 domain. These missense mutations result in single amino acid residue substitutions that cause activation of VWF-A1 and promote spontaneous interaction with platelet GPIba;. Importantly, enhanced VWF clearance has been shown to play a key pathogenic role in >90% patients with Type 2B VWD. Although this VWF clearance occurs via mechanisms that are independent of VWF-platelet complex formation, the biological mechanisms responsible for the increased clearance of type 2B VWD variants remain poorly understood. In this study, we investigated a series of different type 2B amino acid substitutions within the VWF-A1 domain (R1306W, R1308C, W1313C and R1379L). We demonstrate that these variants all exhibit significantly increased macrophage binding. In part, the enhanced macrophage interactions are mediated via increased binding of type 2B VWD variants to LRP1 extracellular cluster II and IV. Our findings further demonstrate that the K1405-K1408 lysine cluster in the VWF-A1 domain plays a key role in enabling enhanced LRP1 interactions for type 2B VWD variants. In addition, we show that type 2B VWF variants demonstrate significantly enhanced interaction with the macrophage MGL receptor. Finally, and importantly from a clinical perspective, we demonstrate that the increase in macrophage binding for type 2B variants is significantly attenuated in the presence of BT200. Collectively, our findings have direct translational relevance with respect to the clinical heterogeneity and treatment of type 2B VWD.
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BibTeX
@misc{chion2026type,
title = {{Type 2B VWD substitutions trigger enhanced macrophage-mediated clearance that is attenuated by the BT200 aptamer}},
author = {A. Chion and C. Byrne and A.-M. Hulshof and T. Albrecht and B. Baci and P. Lopes and E. Karampini and L. Puertas-Umbert and T. A. McKinnon and J. M. O'Sullivan and R. J. Preston and S. Zhu and J. Gilbert and B. Jilma and R. Baker and F. Atiq and J. S. O'Donnell},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.07.749810},
url = {https://www.biorxiv.org/content/10.64898/2026.09.07.749810v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Type 2B VWD substitutions trigger enhanced macrophage-mediated clearance that is attenuated by the BT200 aptamer
AU - A. Chion
AU - C. Byrne
AU - A.-M. Hulshof
AU - T. Albrecht
AU - B. Baci
AU - P. Lopes
AU - E. Karampini
AU - L. Puertas-Umbert
AU - T. A. McKinnon
AU - J. M. O'Sullivan
AU - R. J. Preston
AU - S. Zhu
AU - J. Gilbert
AU - B. Jilma
AU - R. Baker
AU - F. Atiq
AU - J. S. O'Donnell
PY - 2026
DA - 2026/09/07
PB - bioRxiv
DO - 10.64898/2026.09.07.749810
UR - https://www.biorxiv.org/content/10.64898/2026.09.07.749810v1
AB - Type 2B von Willebrand disease (VWD) is characterized by missense variants in exon 28 of the von Willebrand factor (VWF) gene that encodes the VWF-A1 domain. These missense mutations result in single amino acid residue substitutions that cause activation of VWF-A1 and promote spontaneous interaction with platelet GPIba;. Importantly, enhanced VWF clearance has been shown to play a key pathogenic role in >90% patients with Type 2B VWD. Although this VWF clearance occurs via mechanisms that are independent of VWF-platelet complex formation, the biological mechanisms responsible for the increased clearance of type 2B VWD variants remain poorly understood. In this study, we investigated a series of different type 2B amino acid substitutions within the VWF-A1 domain (R1306W, R1308C, W1313C and R1379L). We demonstrate that these variants all exhibit significantly increased macrophage binding. In part, the enhanced macrophage interactions are mediated via increased binding of type 2B VWD variants to LRP1 extracellular cluster II and IV. Our findings further demonstrate that the K1405-K1408 lysine cluster in the VWF-A1 domain plays a key role in enabling enhanced LRP1 interactions for type 2B VWD variants. In addition, we show that type 2B VWF variants demonstrate significantly enhanced interaction with the macrophage MGL receptor. Finally, and importantly from a clinical perspective, we demonstrate that the increase in macrophage binding for type 2B variants is significantly attenuated in the presence of BT200. Collectively, our findings have direct translational relevance with respect to the clinical heterogeneity and treatment of type 2B VWD.
ER -