Key result
Inhibition or deficiency of platelet P2Y12 receptors significantly reduced thrombus size and increased embolization events on ruptured atherosclerotic plaques under high shear flow conditions.
Why the study?
Does P2Y12 inhibition with ticagrelor or cangrelor reduce thrombus size and improve stability on ruptured atherosclerotic plaques under high shear flow?
Does P2Y12 inhibition with ticagrelor or cangrelor reduce thrombus size and improve stability on ruptured atherosclerotic plaques under high shear flow?
P2Y12 receptors play a crucial role in stabilizing thrombi on ruptured atherosclerotic plaques specifically under high shear flow conditions, providing mechanistic insight into the efficacy of P2Y12 inhibitors like ticagrelor.
Answers are grounded in this paper and cite their sources.
P2Y12 inhibition may alter thrombus dynamics on ruptured plaques; hypothesis-generating and should not change practice pending human data.
BACKGROUND: In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y(12) receptors. However, such models do not predict involvement of P2Y(12) in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques. We investigated the role of P2Y(12) in thrombus formation on (collagen-containing) atherosclerotic plaques in vitro and in vivo, by using a novel mouse model of atherothrombosis. METHODOLOGY: Plaques in the carotid arteries from Apoe(-/-) mice were acutely ruptured by ultrasound treatment, and the thrombotic process was monitored via intravital fluorescence microscopy. Thrombus formation in vitro was assessed in mouse and human blood perfused over collagen or plaque material under variable conditions of shear rate and coagulation. Effects of two reversible P2Y(12) blockers, ticagrelor (AZD6140) and cangrelor (AR-C69931MX), were investigated. PRINCIPAL FINDINGS: Acute plaque rupture by ultrasound treatment provoked rapid formation of non-occlusive thrombi, which were smaller in size and unstable in the presence of P2Y(12) blockers. In vitro, when mouse or human blood was perfused over collagen or atherosclerotic plaque material, blockage or deficiency of P2Y(12) reduced the thrombi and increased embolization events. These P2Y(12) effects were present at shear rates >500 s(-1), and they persisted in the presence of coagulation. P2Y(12)-dependent thrombus stabilization was accompanied by increased fibrin(ogen) binding. CONCLUSIONS/SIGNIFICANCE: Platelet P2Y(12) receptors play a crucial role in the stabilization of thrombi formed on atherosclerotic plaques. This P2Y(12) function is restricted to high shear flow conditions, and is preserved in the presence of coagulation.
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Nergiz‐Unal et al. (2010) studied Atherothrombosis. P2Y12 inhibitors (ticagrelor and cangrelor) vs. Vehicle was evaluated on Thrombus size and stability (embolization events) (p=<0.05). Inhibition or deficiency of platelet P2Y12 receptors significantly reduced thrombus size and increased embolization events on ruptured atherosclerotic plaques under high shear flow conditions.
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