Alenazy Fawaz O, Harbi Maan H, Kavanagh Dean P, Price Joshua, Brady Paul, Hargreaves Oscar, Harrison Paul, Slater Alexandre, Tiwari Alok, Nicolson Phillip L R, Connolly Derek L, Kirchhof Paulus, Kalia Neena, Jandrot-Perrus Martine, Mangin Pierre H, Watson Steve P, Thomas Mark R
Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia.
Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom; Pharmacology and Toxicology Department, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
J Thromb Haemost. 2023 Nov;21(11):3236-3251. doi: 10.1016/j.jtha.2023.07.018. Epub 2023 Aug 3.
Aspirin and platelet P2Y inhibitors, such as ticagrelor, suboptimally inhibit microvascular thrombosis during ST-elevation myocardial infarction. Glycoprotein (GP) IIb/IIIa inhibitors may further inhibit this but cause excessive bleeding.
We investigated whether combination of glenzocimab, a GPVI inhibitor, with aspirin and ticagrelor provides additional antithrombotic effects, as GPVI has a critical role in atherothrombosis but minimal involvement in hemostasis.
We investigated the effects of glenzocimab (monoclonal antibody Fab fragment) using blood from healthy donors and patients with acute coronary syndrome treated with aspirin and ticagrelor. Platelets were stimulated with multiple agonists, including atherosclerotic plaque, from patients undergoing carotid endarterectomy.
Aspirin and ticagrelor partially inhibited atherosclerotic plaque-induced platelet aggregation by 48% compared with control (34 ± 3 vs 65 ± 4 U; P < .001). Plaque-induced platelet aggregation, adhesion, secretion, and activation were critically dependent on GPVI activation. Glenzocimab alone reduced plaque-induced aggregation by 75% compared with control (16 ± 4 vs 65 ± 4 U; P < .001) and by >95% when combined with aspirin and ticagrelor (3 ± 1 vs 65 ± 4 U; P < .001). Glenzocimab reduced platelet aggregation, adhesion, and thrombin generation when added to blood of aspirin- and ticagrelor-treated patients with acute coronary syndrome. Glenzocimab shared several antithrombotic effects with the GPIIb/IIIa inhibitor eptifibatide with less effect on general hemostasis assessed by rotational thromboelastometry. In a murine intravital model of ST-elevation myocardial infarction, genetic depletion of GPVI reduced microvascular thrombosis.
Addition of glenzocimab to aspirin and ticagrelor enhances platelet inhibition via multiple mechanisms of atherothrombosis. Compared with a GPIIb/IIIa inhibitor, glenzocimab shares multiple antithrombotic effects, with less inhibition of mechanisms involved in general hemostasis.
阿司匹林和血小板P2Y抑制剂，如替格瑞洛，在ST段抬高型心肌梗死期间对微血管血栓形成的抑制作用欠佳。糖蛋白（GP）IIb/IIIa抑制剂可能会进一步抑制这种情况，但会导致出血过多。
我们研究了糖蛋白VI（GPVI）抑制剂格伦佐单抗与阿司匹林和替格瑞洛联合使用是否能提供额外的抗血栓作用，因为GPVI在动脉粥样硬化血栓形成中起关键作用，但对止血的影响极小。
我们使用健康供者以及接受阿司匹林和替格瑞洛治疗的急性冠状动脉综合征患者的血液，研究了格伦佐单抗（单克隆抗体Fab片段）的作用。用多种激动剂刺激血小板，包括来自接受颈动脉内膜切除术患者的动脉粥样硬化斑块。
与对照组相比，阿司匹林和替格瑞洛使动脉粥样硬化斑块诱导的血小板聚集部分抑制了48%（34±3对65±4 U；P<.001）。斑块诱导的血小板聚集、黏附、分泌和活化严重依赖于GPVI的激活。单独使用格伦佐单抗时，与对照组相比，斑块诱导的聚集减少了75%（16±4对65±4 U；P<.001），与阿司匹林和替格瑞洛联合使用时减少了>95%（3±1对65±4 U；P<.001）。将格伦佐单抗添加到接受阿司匹林和替格瑞洛治疗的急性冠状动脉综合征患者的血液中时，可减少血小板聚集、黏附和凝血酶生成。格伦佐单抗与GPIIb/IIIa抑制剂依替巴肽具有多种共同的抗血栓作用，对通过旋转血栓弹力图评估的一般止血作用较小。在ST段抬高型心肌梗死的小鼠活体模型中，GPVI的基因缺失减少了微血管血栓形成。
在阿司匹林和替格瑞洛中添加格伦佐单抗可通过多种动脉粥样硬化血栓形成机制增强血小板抑制作用。与GPIIb/IIIa抑制剂相比，格伦佐单抗具有多种共同的抗血栓作用，对一般止血相关机制的抑制作用较小。
