The pivotal role of von Willebrand factor binding to platelet αIIbβ3 in stabilizing the formation of a platelet plug at sites of injury. Haematologica 2025 Oct 01;110(10):2343-2355
Date
05/22/2025Pubmed ID
40400463Pubmed Central ID
PMC12485351DOI
10.3324/haematol.2025.287685Scopus ID
2-s2.0-105017783600 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
The interaction between von Willebrand factor (VWF) and platelet αIIbβ3 is thought to be essential for clot formation at injury sites, but its biological properties remain poorly understood due to the complexity and overlap with other αIIbβ3 ligands. Here, we developed a novel binding assay using a recombinant αIIbβ3 headpiece to evaluate VWF-αIIbβ3 binding in plasma from 441 Zimmerman Program participants. The VWF:αIIbβ3 to VWF:Ag ratio was significantly lower in patients with type-1, 2A, and 2B VWD than healthy controls. We identified five index cases with the p.R2464C variant in the VWF-C-domain, where affected family members displayed significantly reduced VWF:αIIbβ3/VWF:Ag ratios. To investigate the function of the VWF-αIIbβ3 interaction, we created a mouse model (VWFRGES/RGES) by altering the VWF-RGDS motif to RGES, which abolished VWF-αIIbβ3 binding. VWFRGES/RGES mice exhibited increased blood loss following lateral tail vein transection and reduced thrombus stability in a laser injury model, showing a 59-fold larger AUC for emboli compared to wild-type. However, initial bleeding times and outcomes of carotid artery injury were comparable. Overall, our VWF:αIIbβ3 binding assay is valuable for characterizing VWD, and the VWFRGES mouse model underscores the physiological significance of the VWF-αIIbβ3 interaction, highlighting that VWF-αIIbβ3 interaction is crucial for stabilizing platelet plug formation at injury sites.
Author List
Shi Q, Mattson JG, Morateck PA, Christopherson PA, Schroeder JA, Fahs SA, Rapten J, Schulte ML, Weiler H, Zhu J, Haberichter SL, Flood VH, Montgomery RRAuthors
Veronica H. Flood MD Chief, Professor in the Pediatrics department at Medical College of WisconsinQizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
Jieqing Zhu PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBlood Platelets
Disease Models, Animal
Female
Humans
Male
Mice
Platelet Glycoprotein GPIIb-IIIa Complex
Protein Binding
Thrombosis
von Willebrand Diseases
von Willebrand Factor
