Shear‐Activated von Willebrand Factor Captures Extracellular Vesicles to Promote Platelet Activation and Metastasis

Plasma proteins are increasingly recognized as key regulators of extracellular vesicle (EV) behaviour in circulation. However, von Willebrand factor (vWF)-the largest multimeric glycoprotein in blood and the only blood protein activated by shear-has received little attention in this context. Under elevated shear stress, vWF transitions from a compact globular form to an extended adhesive conformation. Although elevated plasma vWF levels are associated with hypercoagulation in conditions such as malaria, COVID-19, and cancer, its interactions with EVs or cells under physiological flow have not been systematically investigated. Here, we show that shear-activated vWF functions as a size-selective molecular filter that preferentially captures objects smaller than ∼4 µm, including platelets and tumour-derived EVs, while excluding larger cells. Although intact tumour cells do not directly bind vWF under physiological flow, the coordinated binding of EVs and platelets to extended vWF promotes platelet aggregation, which subsequently traps circulating tumour cells and fosters metastatic dissemination. Our findings reveal a previously unrecognized role of vWF as a shear-dependent EV-binding protein that brings EVs and platelets together to enhance coagulation and metastasis. These EV-vWF-platelet aggregates may represent promising biomarkers or therapeutic targets for the prevention of hypercoagulation in cancer and other thrombo-inflammatory diseases.