Von Willebrand factor (VWF) is a multimeric glycoprotein essential for primary hemostasis, where it mediates platelet adhesion under elevated shear stress [1]. Its activity is regulated by hydrodynamic forces. At low to moderate shear rates, VWF remains in a compact, coiled conformation [1]. At high shear rates, such as those found at sites of vascular injury or in stenosed arteries, the multimer elongates, enabling platelet binding and shear-induced platelet aggregation [1,2]. During elongation, tensile forces develop along the VWF backbone, and self-association occurs once a tensile force threshold is exceeded [2]. Self-association is essential for stable clot formation [3], but the mechanism behind this process remains unknown. VWF activation under high-shear flow, such as in stenosed arteries, carries significant thrombotic risk. This motivates the development of shear-sensitive antithrombotic therapies for patients with stenotic vascular disease [4]. For this a detailed understanding of the mechanical behavior of VWF is required, however, current experimental techniques cannot provide sufficient detail. We developed and validated a mechanistic coarse-grained model for single VWF multimers. Self-association dynamics under shear flow were studied using coupled mesoscopic simulations, a lattice Boltzmann method for the fluid with a bead–spring model for linear VWF polymers, a representation previously used to reproduce the force-dependent elongation and mechanosensitive response of VWF [3,5]. Self-association was modeled as a tensile force-activated bonding between particles, based on a force threshold from Fu et al. [2]. The model was applied to three geometries, including a straight channel, a medical-device-like channel, and a stenosed channel. By comparing simulations with and without self-association, we identified conditions where VWF–VWF interactions become mechanically significant. Results show that self-association reduces the average tensile load along VWF multimers. The resulting mechanistic insight can guide future in vitro studies and support the development of shear-dependent antithrombotic medication [4]. REFERENCES [1] Springer, T. A., 2014. [2] Fu, H., et al., 2017. [3] Topuz, A., et al., 2025. [4] Ku, D. N., et al., 2025. [5] Belyaev, A. V., et al., 2023.