Computational Modeling of the Effects of Shear Stress on von Willebrand Factor Proteolysis

Open Access
Author:
Tramontozzi, Michael William
Area of Honors:
Bioengineering
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Keefe B Manning, Thesis Supervisor
  • Keefe B Manning, Honors Advisor
  • Peter J Butler, Faculty Reader
  • Margaret June Slattery, Faculty Reader
Keywords:
  • Biomedical
  • Engineering
  • COMSOL
  • von Willebrand Factor
  • Ventricular Assist Device
  • Computational
  • Optical Trap
  • Shear
Abstract:
Heart failure continues to be a worldwide epidemic, affecting millions of people each year. Physicians are more frequently treating patients who experience heart failure with ventricular assist devices (VADs) as opposed to heart transplantation, due to the lack of viable donors and the complications that arise from the procedure. Most patients who receive VADs develop some degree of Acquired von Willebrand Disease (AvWD), a bleeding disorder found in patients who have a defective form of the von Willebrand Factor (vWF) protein. The high levels of nonphysiological shear stress imparted on blood components from VADs are believed to cause the proteolysis of vWF and result in AvWD. This investigation seeks to characterize the effects of shear stress on vWF proteolysis using a computational modeling platform. A model was built using COMSOL Multiphysics Software to simulate the stresses experienced by vWF molecules attached to a bead in an optical trap. vWF is modeled as a porous media, and the Brinkman and Navier-Stokes equations are used to analyze the hydrodynamic drag force experienced by the bead. The simulations provide insight into how vWF is sheared by comparing the effective radius of the bead in the optical trap to the height of the porous layer on the bead in the model at a given hydrodynamic force. A correction factor for the actual unfurling of the vWF protein was obtained, suggesting that the experimental optical trap is underestimating the unfurling of vWF molecules. This correction factor can be used to determine the actual extent of vWF unfurling given a set of experimental data, and that information can offer insight into how vWF is unfurled and sheared clinically in patients with medical devices.