CO108 | MECHANOCHEMICAL REPROGRAMMING OF VWF–GPIB INTERACTIONS UNCOUPLES AFFINITY FROM AVIDITY AND LINKS THROMBOCYTOPENIA TO ANGIODYSPLASIA IN TYPE 2B VON WILLEBRAND DISEASE
A. Ferretti1, M. Sacco1, S. Lancellotti1, P. Concolino2, A. Minucci2, R. De Cristofaro1|3 | 1Center for Hemorrhagic and Thrombotic Diseases; 2Molecular and Genomic Diagnostics Unit, Fondazione Policl.nico Univ. Gemelli IRCCS, Roma, Italy; 3Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, Roma, Italy
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Background and Aims. Gain-of-function variants of the von Willebrand factor (VWF) A1 domain, including p.R1308L and p.V1316M, are associated with enhanced platelet binding via glycoprotein Ib (GpIb) and a high incidence of angiodysplasia lesions, as shown by two clinical cases herein described. Here, we combine structural interface analysis with thermodynamic and kinetic considerations to investigate the possible mechanisms responsible for these phenomena.
Methods. The combined use of I-TASSER, HADDOCK v2.4, and Prodigy programs allowed getting structural and energetic details of the complexes between WT, p.R1308L, and p.V1316M VWF variants and the GpIb-A1 domain.
Results. The results showed comparable binding free energies between these VWF species and even slightly reduced equilibrium affinity for p.V1316M relative to wild type (WT). Structural metrics reveal a redistribution of interfacial contacts toward a compact, high-density interaction core for the p.V1316M and p.R1308L variants. This configuration for the p.V1316M variant reduces geometric constraints for binding, enhancing association rates (kon), while promoting force-dependent stabilization through catch-bond behavior. We propose that the two variants shift the interaction from thermodynamic to kinetic and mechanical control, thereby increasing effective avidity under physiological shear (Fig. 1). Molecular modeling of WT-, p.R1308L-, and p.V1316M-VWF variants with angiopoietin-2 showed that the latter are characterized by significantly lower affinity for angiopoietin-2, which, being less buffered by VWF2B, contributes to the formation of angiodyplasia lesions.
Conclusions. These findings highlight the limitations of static ΔG predictions in mechanosensitive systems and provide a unified framework for understanding gain-of-function VWF variants and their angiodysplastic potential.
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