Topuz, A. | Search bioRxiv

bioRxiv2025

Binding of extracellular vesicles to stretched von Willebrand factor promotes platelet activation

Von Willebrand factor (vWF), promoting platelet aggregation in various diseases such as COVID-19, malaria and cancer, is a huge multimeric glycoprotein. This extraordinary size makes vWF a unique shear stress sensing molecule. Below a critical shear stress, vWF is in a globular conformation that prevents platelet binding. Above the critical shear stress, vWF is stretched into platelet accessible fibers. Although previous studies have suggested that leukocytes or cancer cells can bind to vWF fibers, acting forces and the likelihood of cell adhesion has remained largely unexplored. Here, we report that vWF is a size-selective protein that prefers to interact with objects smaller than 4 m in diameter. Consistently, tumor cell-derived extracellular vesicles (EVs) were able to interact with vWF in parallel to platelets. Although whole tumor cells under flow were unable to bind to vWF per se, binding of EVs and platelets along the vWF fiber promoted platelet aggregation, which in turn entrapped circulating tumor cells. In conclusion, our study highlights the shear-sensitive nature of vWF and its ability to bring EVs and platelets together to enhance coagulation. While EVs-vWF-platelet aggregates may serve as novel biomarkers, their therapeutic disruption may prevent hypercoagulation in disease.

cancer biology↗

bioRxiv2024

Aggregation and disaggregation of red blood cells: depletion versus bridging

The aggregation of red blood cells (RBCs) is a complex phenomenon that strongly impacts blood flow and tissue perfusion. Despite extensive research for more than 50 years, physical mechanisms that govern RBC aggregation are still under debate. Two proposed mechanisms are based on bridging and depletion interactions between RBCs due to the presence of macromolecules in blood plasma. The bridging hypothesis assumes the formation of bonds between RBCs through adsorbing macromolecules, while the depletion mechanism results from the exclusion of macromolecules from the inter-cellular space, leading to effective attraction. Existing experimental studies generally cannot differentiate between these two aggregation mechanisms, though several recent investigations suggest concurrent involvement of the both mechanisms. We explore dynamic aggregation and disaggregation of two RBCs using three simulation models: a potential-based model mimicking depletion interactions, a bridging model with immobile bonds, and a new bridging model with mobile bonds which can slide along RBC membranes. Simulation results indicate that dynamic aggregation of RBCs primarily arises from depletion interactions, while disaggregation of RBCs involves both mechanisms. The bridging model with mobile bonds reproduces well the corresponding experimental data, offering insights into the interplay between bridging and depletion interactions and providing a framework for studying similar interactions between other biological cells.

biophysics↗