Multiscale Modeling of Blood Flow-Mediated Platelet Thrombosis

Abstract

The blood coagulation cascade that leads to thrombus formation may be initiated by flow-induced platelet activation, which prompts clot formation in prosthetic cardiovascular devices and in arterial disease processes. Upon activation, platelets undergo complex morphological changes of filopodia formation that play a major role in aggregation and attachment to surfaces. Numerical simulations based on continuum approaches fail to capture such molecular-scale mechano-transduction processes. Utilizing molecular dynamics (MD) to model these complex processes across the scales is computationally prohibitive. We describe multiscale numerical methodologies that integrate four key components of blood clotting, namely, blood rheology, cell mechanics, coagulation kinetics and transport of species, and platelet adhesive dynamics across a wide range of spatiotemporal scales. Whereas mechanics of binding/unbinding for singlemolecule receptor-ligand complexes can be simulated by molecular dynamics (MD), the mechanical structure of platelets in blood flow and their interaction with flow-induced stresses that may lead to their activation can be efficiently described by a model at coarser scales, using numerical approaches such as coarse-grained molecular dynamics (CGMD). Additionally, CGMD provides an excellent platform to inform other coarser-scale models in a bottom-up approach in the multiscale hierarchy. The microenvironment of most biological systems such as coagulation normally involves a large number of cells, e.g., blood cells suspended in plasma, limiting the utility of CGMD at the larger transport scales of blood flow. However, dissipative particle dynamics (DPD), along with its sub-models such as energy conserving and transport DPD, provides a very flexible platform for scaling up these mesoscopic systems. At the macroscopic top scales of the vasculature and cardiovascular devices, simulating blood and tissues using continuum-based methods becomes viable and efficient. However, the challenge of interfacing these larger transport scales with the orders of magnitude smaller spatiotemporal scales that characterize blood coagulation, and given the issue of the slow-dynamic timescales of biological processes, makes long-term simulations of such systems computationally prohibitive. In this chapter, we describe various numerical remedies based on these methodologies that facilitate overcoming this multiscale simulation challenge.