Research advances on platelet glycoprotein VI in ischemic stroke

Atherosclerosis is one cause of ischemic stroke. Subcutaneous collagen is exposed when the fibrous cap of an atherosclerotic plaque ruptures. Platelets bind to collagen, leading to platelet activation, aggregation, and thrombus formation. So, antiplatelet agents play a crucial role in the prevention and treatment of ischemic stroke. Nowadays, widely used antiplatelet agents, like aspirin, clopidogrel, and ticagrelor, inhibit thrombus formation while interfering with normal hemostasis, thereby increasing the risk of bleeding. Therefore, there is an urgent need for an antiplatelet agent that can prevent pathological thrombus formation without increasing the risk of bleeding. Glycoprotein Ⅵ (GPⅥ) is a glycoprotein specifically expressed on megakaryocytes and platelets. In patients and mouse models with GPⅥ deficiency, collagen-induced platelet adhesion and aggregation were reduced, resulting in only a mild bleeding tendency. Further research has revealed that targeting GPⅥ can inhibit thrombus formation, reduce thromboinflammation, decrease ischemia-reperfusion injury, and improve neurological deficits. Importantly, targeting GPVI didn’t increase the risk of bleeding or resulted in only minor bleeding. Additionally, its combination with thrombolytic agents, endovascular treatment, or other antiplatelet agents has been proven to be safe and effective. However, Phase II/III trials of agents targeting platelet GPVI failed to demonstrate positive efficacy outcomes in the treatment of ischemic stroke. While GPVI remains a promising antiplatelet target with favorable preclinical and early-phase safety data, clinical efficacy has not yet been demonstrated. Therefore, this review summarizes the potential mechanisms of targeting GPⅥ for antiplatelet therapy and reviews the evidence supporting the benefits of targeting GPⅥ for the prevention, treatment, and prognosis of ischemic stroke. It also summarizes the latest research progress on anti-GPⅥ agents, aiming to bring greater therapeutic benefits to patients with ischemic stroke.