Modeling the cleavage of von Willebrand factor by ADAMTS13 protease in shear flow.

Von Willebrand factor (VWF) is a key protein in hemostasis as it mediates adhesion of blood platelets to a site of vascular injury. A proper distribution of VWF lengths is important for normal functioning of hemostatic processes, because a diminished number of long VWF chains may significantly limit blood clotting and lead to bleeding, while an abundant number of long VWFs may result in undesired thrombotic events. VWF size distribution is controlled by ADAMTS13 protease, which can cleave VWF chains beyond a critical shear rate when the chains are stretched enough such that cleavage sites become accessible. To better understand the cleavage process, we model VWF cleavage in shear flow using mesoscopic hydrodynamic simulations. Two cleavage models are proposed, a geometrical model based on the degree of local stretching of VWF, and a tension-force model based on instantaneous tension force within VWF bonds. Both models capture the susceptibility of VWF to cleavage at high shear rates; however, the geometrical model appears to be much more robust than the force model. Our simulations show that VWF susceptibility to cleavage in shear flow becomes a universal function of shear rate, independent of VWF length for long enough chains. Furthermore, VWF is cleaved with a higher probability close to its ends in comparison to cleaving in the middle, which results into longer circulation lifetimes of VWF multimers. Simulations of dynamic cleavage of VWF show an exponential distribution of chain lengths, consistently with available in vitro experiments. The proposed cleavage models can be used in realistic simulations of hemostatic processes in blood flow.