Multiscale Simulation Of Platelet Aggregation And Adhesion Under Flow In 3D

Abstract

Hemostasis is a self-defensive mechanism that prevents injured blood vessels from excessive bleeding. Its initiation is mediated by physical contact between flowing platelets, which are ellipsoid-shaped cell fragmentations from megakaryocytes, and the injured vessel surface, where the extracellular matrix is exposed to the blood flow. Such physical contacts-either short-term tethering, intermediate translocation (rolling) or permanent attachment, are primarily mediated by the interaction between GPIb[alpha] receptor presented on the platelet surface and immobilized von Willibrand Factor (vWF) recruited to the injured vessel surface. GPIb[alpha]-vWF bond was known to exhibit kinetics that follows the classical Bell Model, where the slip bond behavior (bond lifetime reduces with increasing bond force) was well studied. Recently, a catch bond (bond lifetime increases with increasing bond force) regime was discovered and scientists believed that the combination of slip-catch behaviors is a better way to characterize the bond kinetics. Other blood components, including red blood cells (RBCs) and vessel geometry also play important roles in the initiation of hemostasis. RBCs are known to be enriched at the center region of the vessel lumen due to their rheological properties. This results in a margination effect where smaller platelets are pushed towards the vessel wall. Such margination effect combines with the geometrical aspect of the thrombotic / stenotic region to enhance potential platelet-wall interaction once vessel injury occurs. Platelet interaction with an injured vessel is a complicated physiological process and is challenging to study thoroughly in experiments, either in vitro or in vivo. Simulation studies overcome many experimental restrictions, such as environmental condition control, physiological prediction and multiscale observation. It has been more than a decade since computational methods were first applied to study hemostasis and the field is developing rapidly. In this thesis, two computational models are built, modified and applied. One focuses on the close interaction between platelets and a plane vessel wall mediated by GPIb[alpha]-vWF bond. The other model emphasizes hydrodynamic interactions between deformable RBCs, platelets, a developing thrombus and cylindrical vessel geometry. These models are validated by experimental results, either published in vitro results or new in vivo data. Author expects that by establishing these models to simulate the initiation of hemostasis, more quantitative insight of this delicate process can be revealed.