Platelet size and density affect shear-induced thrombus formation in tortuous arterioles

Abstract

Thrombosis accounts for 80% of deaths in patients with diabetes mellitus. Diabetic patients demonstrate tortuous microvessels and larger than normal platelets. Large platelets are associated with increased platelet activation and thrombosis, but the physical effects of large platelets in the microscale processes of thrombus formation are not clear. Therefore, the objective of this study was to determine the physical effects of mean platelet volume (MPV), mean platelet density (MPD) and vessel tortuosity on platelet activation and thrombus formation in tortuous arterioles. A computational model of the transport, shear-induced activation, collision, adhesion and aggregation of individual platelets was used to simulate platelet interactions and thrombus formation in tortuous arterioles. Our results showed that an increase in MPV resulted in a larger number of activated platelets, though MPD and level of tortuosity made little difference on platelet activation. Platelets with normal MPD yielded the lowest amount of mural thrombus. With platelets of normal MPD, the amount of mural thrombus decreased with increasing level of tortuosity but did not have a simple monotonic relationship with MPV. The physical mechanisms associated with MPV, MPD and arteriole tortuosity play important roles in platelet activation and thrombus formation.

Figure 1

Schematic of a representative arteriole with tortuosity index T = 0.16, showing the locations of inner walls, outer walls, and bends, which are labeled numerically.

Figure 2

Schematic showing the flattened circular region of contact of radius a(t) between two colliding spherical platelets. The gap distance (x_b − x_e) between platelet surfaces is larger than normal to show detail (left). Schematic of adhesive interactions of vWF, GPIb, and GPIIb-IIIa in the region of contact (right).

Figure 3

Shear rate contours of a representative arteriole with tortuosity index T = 0.16 (a). Maximum shear rate versus tortuosity index (b).

Figure 4

Thrombus formation showing activated platelets (solid circles) and unactivated platelets (open circles) at (a) t_i = 0.4 s and (b) t_f = 1.7 s. Tortuosity index increases from the top vessel to the bottom vessel as follows: T = 0.09, 0.12, 0.16, 0.21. Platelets had normal MPV and MPD, and were subjected to collision, aggregation, and adhesion.

Figure 5

Measures of thrombosis versus tortuosity index at t_i = 0.4 s (circles) and t_f = 1.7 s (squares), including (a) activation count, (b) mural thrombus size, and (c) wall contact. Platelets had normal MPV and MPD, and were subjected to collision, aggregation, and adhesion.

Figure 6

Measures of thrombosis versus tortuosity index, including (a) activation count, and (b-c) wall contact, in two hypothetical cases at t_f = 1.7 s. Platelets were subjected to either “no interactions” (circles) or “collisions only” (squares). In both cases, platelets had normal MPV and MPD.

Figure 7

Measures of thrombosis for different models of shear-induced platelet activation including critical-shear model (top vessel, white bars), shear-history model with β = 40 (middle vessel, gray bars), and shear-history model with β = 60 (bottom vessel, black bars). (a) Thrombus formation showing activated platelets (solid circles), unactivated platelets (open circles), and boundaries that separate convex and concave walls (dashed lines). (b) Measures of thrombosis, including activation count, mural thrombus size, and wall contact. (c) Mural thrombus density on specified walls, for which wall boundaries are marked in (a). Platelets had normal MPV and MPD, and were subjected to collision, aggregation, and adhesion. Tortuosity index is T = 0.21, and time is t_f = 1.7 s.

Figure 8

Measures of thrombosis versus MPV at t_i = 0.4 s (circles) and t_f = 1.7 s (squares), including (a) activation count, (b) mural thrombus size, and (c) wall contact. Tortuosity index is T = 0.21. Platelets had normal MPD and were subjected to collision, aggregation, and adhesion.

Figure 9

Measures of thrombosis versus MPV for the straight arteriole (T = 0, solid squares) and a tortuous arteriole (T = 0.21, open squares) at t_f = 1.7 s, including (a) activation count and (b) wall contact. Platelets had normal MPD and were subjected to “collisions only”.

Figure 10

Measures of thrombosis versus MPD at t_i = 0.4 s (circles) and t_f = 1.7 s (squares), including (a) activation count, (b) mural thrombus size, and (c) wall contact. Tortuosity index is T = 0.21. Platelets had normal MPV and were subjected to collision, aggregation, and adhesion.

Figure 11

Measures of thrombosis versus MPD for the straight arteriole (T = 0, solid squares) and a tortuous arteriole (T = 0.21, open squares) at t_f = 1.7 s, including (a) activation count and (b) wall contact. Platelets had normal MPV and were subjected to “collisions only.”