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

高剪切应力和抗血小板药物联合作用对血小板止血功能的影响机制研究

Hongyu Wang, Yuan Li, Jinze Jia, Yifeng Xi, Xianghao Zhang, Wenbo Zhang, Zengsheng Chen (2026) Study on the mechanism of the combined effects of high shear stress and antiplatelet drug on platelet haemostatic function. Br J Pharmacol (IF: 7.7) 2 区

Abstract

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.Citrated bovine blood was circulated in a Rotaflow loop (500 ml, 5.0 l·min-1, ΔP 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, P2Y12 receptor surface expression, adhesion and aggregation. Proteomics compared signalling across treatment sequences, and thromboelastography (TEG) assessed clot kinetics.NPSS increased P-selectin, GPIIb/IIIa expression and fibrinogen adhesion and reduced P2Y₁2 receptor surface expression. Ticagrelor suppressed adenosine diphosphate (ADP)-induced aggregation and attenuated shear-driven platelet activation and also mitigates shear-induced loss of platelet P2Y₁2 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.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.© 2026 British Pharmacological Society.

血液泵产生的非生理性剪切应力（NPSS）会激活血小板并破坏止血功能。替格瑞洛用于机械循环支持的抗血小板治疗，但其在NPSS下的作用尚不明确。本研究旨在探讨替格瑞洛与NPSS如何相互作用以调节血小板止血功能。将枸橼酸抗凝牛血置于Rotaflow循环回路中（500 ml，5.0 l·min⁻¹，ΔP分别为0、100和350 mmHg），循环时间长达3小时。分别在循环前或剪切应力暴露后给予替格瑞洛（20 μM）。采用流式细胞术和血小板聚集试验定量分析血小板活化、P2Y12受体表面表达、黏附和聚集情况。蛋白质组学比较了不同治疗顺序下的信号通路，血栓弹力图（TEG）评估了血栓动力学。NPSS 增加了 P-选择素、GPIIb/IIIa 的表达和纤维蛋白原的黏附，并降低了 P2Y₁2 受体的表面表达。替格瑞洛抑制了二磷酸腺苷（ADP）诱导的血小板聚集，减弱了剪切力驱动的血小板活化，并减轻了剪切力诱导的血小板 P2Y₁2 表面表达的丢失。蛋白质组学显示 Gi 偶联信号通路活性降低，cAMP-PKA 相关蛋白相对保留，其中替格瑞洛治疗后组的活化信号抑制作用最强。随着环路 ΔP 的增加，药物抑制活化的能力下降。TEG 显示剪切力暴露后血栓形成和生长速度加快，而当在剪切力暴露后给予替格瑞洛时，这些变化得到最有效的缓解。NPSS 通过与 Gi 信号通路相关的途径激活血小板。替格瑞洛可降低剪切力诱导的活化，在剪切力作用后使用时降低效果最为显著。这些发现支持将给药时机作为血液泵支持期间的一个可控变量。© 2026 英国药理学会。

Links

http://www.ncbi.nlm.nih.gov/pubmed/41980755
http://dx.doi.org/10.1111/bph.70433

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