Platelet Biorheology and Mechanobiology in Thrombosis and Hemostasis: Perspectives from Multiscale Computation

Abstract

Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s^-1) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s^-1) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.

Keywords: biorheology; platelet activation; platelet adhesion; platelet margination; platelet mechanobiology; shear-induced platelet aggregation; thrombosis; von Willebrand factor.

Figure 2

(a) Cellular and molecular components related to platelet adhesion ranging from nano (nm) to micron (μm) scales (created with BioRender.com). (b) Binding kinetics of GPIb-VWF A1 in flow can be decoupled into transport and reaction components (adapted with permission from Liu et al., 2021 [7]). (c) Snapshots of single platelet flipping motion correlating with in vitro observations (adapted with permission from Wang et al., 2023 [47]). (d) Platelet rolling velocity measured based on a multiscale computational model built incorporating molecular and cellular components and their binding kinetics [41] (adapted with permission from Liu et al., 2022 [3]).

Figure 3

(a) Platelets experience wall shear stress as they move through layers of flowing blood and roll along the blood vessel wall (adapted with permission from Zainal Abidin et al., 2023 [107]). (b) Platelets elongate as they experience extensional stresses due to fluid acceleration parallel to the wall, particularly in areas of stenoses (adapted with permission from Zainal Abidin et al., 2023 [107]). (c) Upstream and downstream participants are involved in shear-mediated platelet mechanotransduction, with PI3K as the primary driver. (d) Stress distribution on the platelet membrane and the actin filaments modeled using the hybrid coarse-grained molecular dynamics (CGMD) method. (e) The simulation directly captures microtubule reorganization that supports filopodia growth, all occurring during the mechanotransduction-induced platelet activation process. (f) CGMD model of platelet activation-induced filopodia formation in comparison with experimental observations: (i) scanning electron microscopy image after exposure to 1 dyne/cm² for 4 min, (ii) 70 dyne/cm² for 4 min, and (iii) 70 dyne/cm² for 1 min (adapted with permission from Pothapragada et al., 2015 [105]).

Figure 4

(a) Different pathways of platelet aggregation under various levels of shear rates (adapted with permission from Maxwell et al. [108]). (b) Simulated aggregation of three adjacent platelets through a DPD-CGMD coupled multiscale method. (adapted with permission from Gupta et al. [112]). (c) Snapshots of platelet aggregate formation at the wall due to agonist-induced platelet activation (adapted with permission from Shankar et al. [115]). (d) Activation-independent platelet aggregation occurs in less than 10 ms (adapted with permission from Liu et al. [3]).

Figure 1

(a) Platelet imagination in a 3-D microvessel (adapted with permission from Reasor et al. [26]). (b) Snapshots of platelet imagination and flipping near the wall in a 2-D channel flow (adapted with permission from Zhao and Shaqfeh [27]). (c) Margination occurs only for microscale particles, not for nanoscale particles. (adapted with permission from Liu et al. [28]).

Figure 5

(a) Successful computational multiscale models are increasingly integrated with both experimental validation and AI/ML tools. (b) Emerging applications of platelet-based multiscale models of thrombosis include intraplatelet structure-function interdependence, interaction with other cell types, effects of aging on platelet properties and function, and antiplatelet drug development).