Fig 1.
Multiscale model for thrombus growth under flow.
The multiscale simulation of thrombus growth under flow required simultaneous solutions of the instantaneous velocity field over a complex and evolving platelet boundary by LB, concentration fields of ADP and TXA2 by FVM, individual intracellular platelet state ([Ca]i) and release reactions (R) for ADP and TXA2 by NN, and all platelet positions and adhesion/detachment by LKMC.
Fig 2.
Simulation results of platelet aggregation under flow in the microfluidic device.
Schematic of the microfluidic device geometry: (A) oblique view and (D) side view. Inlet flow: 200s-1; reactive surface containing collagen and TF: red bar. (B,E) Platelet activation (blue indicates inactivated and red, fully activated) and deposition after 400 seconds. (C) Dynamics of platelet aggregate count observed over time. Released (F) ADP and (G) TXA2, and (H) the local shear rate contours plotted along the center of the channel after 400 seconds.
Fig 3.
Comparison between prior 2D simulations and present 3D simulations.
(A) Thrombus morphology observed in 2D simulations (top) showing highly dendritic aggregate growth. A clot remodeling scheme was required in 2D to obtain a realistic morphology (middle). Thrombus morphology observed in 3D without employing a remodeling scheme (bottom). (B) Thrombus morphology observed in present work in 3D. Dendritic aggregate formation is drastically reduced due to realistic platelet trajectories in 3D, as evidenced by flow streamlines (black lines) that show flow around aggregates.
Fig 4.
Comparison between model predictions and typical clot morphologies observed in microfluidic perfusion experiments.
(A) Model predictions of deposited platelets (gray) agree well with fluorescent micrographs of thrombi observed over time in experiments (red). (B) Comparison between model predictions and clot heights observed in microfluidic perfusion experiments. Profiles represent average aggregate height determined using vertical line scans in the direction of flow over collagen or collagen with TF.
Fig 5.
Comparison between thrombus growth dynamics observed in experiments and multiscale simulations under different agonist conditions.
(A) Measured platelet deposition in the presence of aspirin, indomethacin, MRS 2179 and iloprost treatment by Flamm et al. and (B) corresponding multiscale simulations with no TXA2, no ADP and iloprost stimulation.
Fig 6.
Simulation results of platelet aggregation under flow in a cylindrical tube.
Schematic of the cylindrical tube geometry: (A) oblique view and (D) side view. Inlet flow: 100s-1; reactive surface containing collagen and TF: red bar. (B,E) Platelet activation (blue indicates inactivated and red, fully activated) and deposition after 400 seconds. (C) Dynamics of platelet aggregate count observed over time. Released (F) ADP and (G) TXA2, and (H) the local shear rate contours plotted along the center of the tube after 400 seconds.
Fig 7.
Simulation results of platelet aggregation under pathological shear rates in a stenosis at the time of vessel occlusion.
Schematic of the stenotic geometry: (A) oblique view and (D) side view. Inlet and outlet of the stenosis maintained at a constant pressure drop across the length of the geometry that corresponded to an initial inlet wall shear rate of 1000s-1. Surface collagen: red bar. (B,E) Platelet activation (blue indicates inactivated and red, highly activated) and deposition at occlusion time. (C) Dynamics of platelet aggregate density observed over time. Released (F) ADP and (G) TXA2 contours plotted along the along the center of the tube at the time of occlusion.
Fig 8.
Effect of VWF mediated platelet capture at pathological shear rates.
Simulation results of platelet activation (blue indicates inactivated and red, highly activated) in the (A) presence and (B) absence of enhanced clotting function due to VWF stretching at pathological shear rates > 3000s-1.
Fig 9.
Platelet aggregation in a stenosis under agonist inhibition.
(A) Observed occlusion times and (B) inlet volumetric flow rates (Q) versus time for different agonist conditions. The initial inlet flow rate (Q0) was set to 1.3μL/min, giving an initial inlet wall shear rate of 1000s-1.
Fig 10.
Effect of stenosis severity on platelet aggregation.
Snapshots of platelets (blue indicates inactivated and red, highly activated) observed after 500 seconds are shown for stenoses with reductions in flow area of (A) 37%, (B) 50%, (C) 63%, and (D) 75%. Simulations were carried out under constant pressure drop that corresponded to an initial inlet wall shear rate of 1000s-1.