Presence of red blood cells promotes tension-dependent cleavage of von Willebrand factor under high shear*

Von Willebrand factor (VWF) is a mechanosensitive plasma glycoprotein that controls thrombosis and hemostasis. Once secreted from endothelial cells, VWV remains ultra-large in size and must be cleaved by ADAMTS13 in circulation to maintain healthy hemostasis. A recent study suggests that laminar high shear in a single-phase flow can only lead to moderate cleavage of high molecular weight VWF, suggesting additional mechanisms in circulation that regulate VWF cleavage. In this study, we investigate the effect of red blood cells (RBCs) on VWF cleavage under simple shear flows using computational and experimental rheometer techniques. Our experiments demonstrate that the presence of RBCs at physiological hematocrit (40%) can significantly enhance VWF cleavage under shear while elevating plasma viscosity to the whole blood level (4 cP) without adding RBCs does not enhance cleavage as much. Through the computational study of the VWF conformation in a sheared RBC suspension, we observe instantaneously elevated VWF tensile forces beyond ~10 pN required for VWF cleavage. The elevated tension levels are strongly correlated with the percentage of VWF cleavage. This study suggests a new RBC-enhanced tension-dependent VWF cleavage mechanism, highlighting the intricate interplay between hemorheology and human pathophysiology.