Study on the mechanism of the combined effects of high shear stress and antiplatelet drug on platelet haemostatic function

Background and Purpose Blood pumps generate non‐physiological shear stress (NPSS) that activates platelets and disrupts haemostasis. Ticagrelor is used in antiplatelet therapy for mechanical circulatory support, yet its effects under NPSS remain unclear. This study investigated how ticagrelor and NPSS interact to modulate platelet haemostatic function. Experimental Approach Citrated bovine blood was circulated in a Rotaflow loop (500 ml, 5.0 l·min −1 , Δ P of 0, 100 and 350 mmHg) for up to 3 h. Ticagrelor (20 μM) was administered either before circulation or after shear stress exposure. Flow cytometry and aggregometry quantified platelet activation, P2Y 12 receptor surface expression, adhesion and aggregation. Proteomics compared signalling across treatment sequences, and thromboelastography (TEG) assessed clot kinetics. Results NPSS increased P‐selectin, GPIIb/IIIa expression and fibrinogen adhesion and reduced P2Y₁ 2 receptor surface expression. Ticagrelor suppressed adenosine diphosphate (ADP)‐induced aggregation and attenuated shear‐driven platelet activation and also mitigates shear‐induced loss of platelet P2Y₁ 2 surface expression. Proteomics showed lower Gi‐coupled signalling and relative preservation of cAMP‐PKA‐related proteins, with the post‐ticagrelor group showing the strongest suppression of activation signalling. As the ΔP of loop increases, the drug's ability to inhibit activation decreases. TEG showed faster clot initiation and growth after shear exposure, and these changes were most effectively moderated when ticagrelor was administered after shear exposure. Conclusion and Implications NPSS activates platelets through pathways linked to Gi signalling. Ticagrelor reduced shear‐induced activation, with the greatest reduction when used after shear. These findings support timing as a controllable variable during blood pump support.