Platelet adhesive dynamics: A multiscale model of receptor-mediated platelet adhesion under flow

Initial recruitment of platelets to the injured subendothelial surface involves transient binding between platelet surface receptor GPIb(alpha) and von Willebrand factor (vWF), a polydisperse multimeric glycoprotein. Abnormalities in vWF size, irregular plasma vWF concentrations, or mutations in its A1 domain can cause a wide range of pathological conditions ranging from thrombotic occlusion of narrow vessels (thrombotic thrombocytopenic purpura or TTP) to hemorrhagic disorders (type 2B Von Willebrand Disease). Computational models of the adhesive behavior of platelets near a surface are lacking due the limited availability of theoretical studies on hydrodynamic interactions of non-spherical particles under flow, and the complexity of existing solutions for 3-D ellipsoid motion near a wall. The Platelet Adhesive Dynamics (PAD) computational algorithm is developed in this dissertation to study platelet motion and adhesive phenomena near the vessel wall at an unprecedented level of spatial and temporal resolution. The PAD model integrates the 3-D hydrodynamic motion of multiple non-spherical cells near a wall with the dynamics of receptor-ligand binding. Application of PAD revealed that a platelet-shaped cell exhibits 3 distinct regimes of flow near a wall. A 2-D analytical model was developed to calculate the motion of a tethered platelet on surface-immobilized vWF-A1. Both the 2-D analytical model and the 3-D PAD model demonstrated that a flowing platelet undergoes surface contact only in certain favorable orientations that are predicted to result in compression along the platelet length. The chaotic Brownian motion of platelets was demonstrated to play a negligible role in influencing flow characteristics, platelet-surface contact frequency and dissociative binding phenomena at physiological shear rates. Particle size and proximity of a planar boundary were found to strongly influence particle collision trajectories, collision time, surface contact areas, and collision frequency. Computational modeling of platelet aggregation via formation of GPIb(alpha)-vWF-GPIb(alpha) bond bridges demonstrated the significant effects of vWF multimer size, governing receptor-ligand binding kinetics, and nature of cell-cell collisions on the extent of initial shear-induced thrombus formation. Inter-platelet bond force-loading is predicted to be complex and highly non-linear. The multiscale PAD model is, to date, the most advanced and powerful predictive tool developed for elucidating platelet flow and adhesive phenomena near the vascular wall.