Tortuosity triggers platelet activation and thrombus formation in microvessels

Abstract

Tortuous blood vessels are often seen in humans in association with thrombosis, atherosclerosis, hypertension, and aging. Vessel tortuosity can cause high fluid shear stress, likely promoting thrombosis. However, the underlying physical mechanisms and microscale processes are poorly understood. Accordingly, the objectives of this study were to develop and use a new computational approach to determine the effects of venule tortuosity and fluid velocity on thrombus initiation. The transport, collision, shear-induced activation, and receptor-ligand adhesion of individual platelets in thrombus formation were simulated using discrete element method. The shear-induced activation model assumed that a platelet became activated if it experienced a shear stress above a relative critical shear stress or if it contacted an activated platelet. Venules of various levels of tortuosity were simulated for a mean flow velocity of 0.10 cm s(-1), and a tortuous arteriole was simulated for a mean velocity of 0.47 cm s(-1). Our results showed that thrombus was initiated at inner walls in curved regions due to platelet activation in agreement with experimental studies. Increased venule tortuosity modified fluid flow to hasten thrombus initiation. Compared to the same sized venule, flow in the arteriole generated a higher amount of mural thrombi and platelet activation rate. The results suggest that the extent of tortuosity is an important factor in thrombus initiation in microvessels.

Fig. 1

Schematic of a tortuous vessel model showing the inner and outer walls of each bend. Each bend is labeled by a circled number.

Fig. 2

Thrombus initiation in venules including: (a) a drawing of an experimental image [14] and (b) to (h) simulations of validation cases at the same time t with activated platelets (filled circles) and unactivated platelets (open circles)

Fig. 3

Flow field showing: (a) contours of velocity magnitude normalized by mean velocity magnitude and (b) locations of critical shear regions (filled in black)

Fig. 4

Thrombus formation in venules with activated platelets (filled circles) and unactivated platelets (open circles), including: (a) TI = 0.09 (Case LT) for t = 4.6, 10.0, and 25.0 s, (b) TI = 0.12 (Case MT) for t = 3.1, 10.0, and 25.0 s, and (c) TI = 0.16 (Case HT) for t = 2.2, 10.0, and 25.0 s. Time t increases from top panel to bottom panel for each tortuosity case.

Fig. 5

Time variations of measures of thrombus formation in venules for different tortuosity values (Cases LT, MT, HT), including: (a) number of platelets in mural thrombi, (b) number of platelets in contact with the wall, (c) cumulative number of activation events near the time of thrombus initiation, and (d) cumulative number of activation events during the entire simulation

Fig. 6

Thrombus formation with activated platelets (filled circles) and unactivated platelets (open circles) for a venule (a) with Re = 0.02 (Case HT) and an arteriole (b) with Re = 0.1 (Case HTHV) at the following normalized times from top panel to bottom panel: 86, 400, and 900

Fig. 7

Time variations of measures of thrombus formation in a vessel with high tortuosity TI = 0.16 for two fluid velocities corresponding to a venule (Case HT) and an arteriole (Case HTHV). Thrombus formation measures include the following: (a) and (b) number of platelets in mural thrombi, (c) and (d) number of platelets in contact with the wall, and (e) and (f) cumulative number of activation events.