Multiscale simulation of thrombus growth and vessel occlusion triggered by collagen/tissue factor using a data-driven model of combinatorial platelet signalling

Abstract

During clotting under flow, platelets bind and activate on collagen and release autocrinic factors such as ADP and thromboxane, while tissue factor (TF) on the damaged wall leads to localized thrombin generation. Towards patient-specific simulation of thrombosis, a multiscale approach was developed to account for: platelet signalling [neural network (NN) trained by pairwise agonist scanning (PAS), PAS-NN], platelet positions (lattice kinetic Monte Carlo, LKMC), wall-generated thrombin and platelet-released ADP/thromboxane convection-diffusion (partial differential equation, PDE) and flow over a growing clot (lattice Boltzmann). LKMC included shear-driven platelet aggregate restructuring. The PDEs for thrombin, ADP and thromboxane were solved by finite element method using cell activation-driven adaptive triangular meshing. At all times, intracellular calcium was known for each platelet by PAS-NN in response to its unique exposure to local collagen, ADP, thromboxane and thrombin. When compared with microfluidic experiments of human blood clotting on collagen/TF driven by constant pressure drop, the model accurately predicted clot morphology and growth with time. In experiments and simulations at TF at 0.1 and 10 molecule-TF/$\mu$m$^{2}$ and initial wall shear rate of 200 s$^{-1}$, the occlusive blockade of flow for a 60-$\mu$m channel occurred relatively abruptly at 600 and 400 s, respectively (with no occlusion at zero TF). Prior to occlusion, intrathrombus concentrations reached 50 nM thrombin, ~ 1 $\mu$M thromboxane and ~ 10 $\mu$M ADP, while the wall shear rate on the rough clot peaked at ~ 1000-2000 s$^{-1}$. Additionally, clotting on TF/collagen was accurately simulated for modulators of platelet cyclooxygenase-1, P2Y$_{1}$ and IP-receptor. This multiscale approach facilitates patient-specific simulation of thrombosis under hemodynamic and pharmacological conditions.

Keywords: multiscale modelling; platelet aggregation; stenosis; thrombin; thrombosis.