Abstract

Acquired von Willebrand syndrome (AVWS) is a bleeding disorder characterized by the loss of high molecular weight von Willebrand factor (VWF) multimers. It is often associated with a wide range of underlying diseases, including individuals who receive mechanical circulatory support (MCS) and myeloproliferative neoplasm (MPN) patients, yet the mechanical mechanisms remain incompletely understood. In circulation, VWF undergoes force-dependent conformational changes that regulate its susceptibility to cleavage by the metalloprotease ADAMTS13. While elevated shear has long been believed to the main cause, pathological VWF cleavage cannot always be explained by shear alone, suggesting more factors are at play. The goal of this dissertation was to investigate how complex flow environments and blood cellular components influence VWF proteolysis and platelet activation. First, we examined the role of turbulent flow in mediating VWF proteolysis and shear-induced platelet activation. Using a combination of in-vivo models and benchtop systems, we demonstrate that turbulent flow conditions promote the loss of high molecular weight VWF multimers and enhance platelet activation, indicating that flow instability is a critical contributor to VWF dysfunction in pathological cardiovascular environments. Next, we investigated the role of red blood cells (RBCs) in regulating VWF cleavage under shear flow. Through ex-vivo experiments and computational modeling, we show that increasing hematocrit significantly increases VWF proteolysis. These findings demonstrate that RBCs act as a cofactor in VWF proteolysis, with an effect much larger than previously believed. The results gathered in this dissertation provide a mechanistic link between unstable flow environments and the development of AVWS across multiple disease contexts. Turbulence promotes VWF tension in MPNs. By integrating experimental and computational approaches, we advance the understanding of how hemodynamic forces and cellular interactions regulate VWF proteolysis and platelet function. These insights may improve clinical management of bleeding and clotting complications in disease characterized by abnormal blood flow and altered hemostasis.

Committee Chair

Nathaniel Huebsch

Committee Members

David Bark; Guy Genin; Jessica Wagenseil; Jorge Di Paola

Degree

Doctor of Philosophy (PhD)

Author's Department

Biomedical Engineering

Author's School

McKelvey School of Engineering

Document Type

Dissertation

Date of Award

4-29-2026

Language

English (en)

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