Abstract
ObjectivesPlatelet activation underpins thrombus formation in ischemic stroke. The active, dimeric form of platelet receptor glycoprotein (GP) VI plays key roles by binding platelet ligands collagen and fibrin, leading to platelet activation. We investigated whether patients presenting with stroke expressed more GPVI on their platelet surface and had more active circulating platelets as measured by platelet P-selectin exposure.Methods129 ischemic or hemorrhagic stroke patients were recruited within 8h of symptom onset. Whole blood was analyzed for platelet-surface expression of total GPVI, GPVI-dimer, and P-selectin by flow cytometry at admission and day-90 post-stroke. Results were compared against a healthy control population (n = 301).ResultsThe platelets of stroke patients expressed significantly higher total GPVI and GPVI-dimer (P<0.0001) as well as demonstrating higher resting P-selectin exposure (P<0.0001), a measure of platelet activity, compared to the control group, suggesting increased circulating platelet activation. GPVI-dimer expression was strongly correlated circulating platelet activation [r2 = 0.88, P<0.0001] in stroke patients. Furthermore, higher platelet surface GPVI expression was associated with increased stroke severity at admission. At day-90 post-stroke, GPVI-dimer expression and was further raised compared to the level at admission (P<0.0001) despite anti-thrombotic therapy. All ischemic stroke subtypes and hemorrhagic strokes expressed significantly higher GPVI-dimer compared to controls (P<0.0001).ConclusionsStroke patients express more GPVI-dimer on their platelet surface at presentation, lasting at least until day-90 post-stroke. Small molecule GPVI-dimer inhibitors are currently in development and the results of this study validate that GPVI-dimer as an anti-thrombotic target in ischemic stroke.
Highlights
Platelet activation and subsequent thromboembolism underpins the pathophysiology of ischemic stroke
Higher platelet surface GPVI expression was associated with increased stroke severity at admission
Glycoprotein VI-dimer is overexpressed in stroke regression revealed that age and mean platelet volume (MPV) were significantly associated with GPVI expression in the stroke patients
Summary
Platelet activation and subsequent thromboembolism underpins the pathophysiology of ischemic stroke. Current antithrombotic agents used in stroke are effective at reducing ischemic events [1], but have serious systemic side effects such as bleeding [2]. Platelet activation increases surface GPVI-dimer expression and binding to collagen induces GPVI-dimer clustering, which increases GPVI avidity, causing further platelet activation [6, 7]. GPVI has been shown to bind to fibrin and cause platelet activation [8, 9]. Our work has shown that GPVI-dimer recognizes and binds to the D-domain of fibrin(ogen) [10] and that GPVI-dimer binds with classical receptor kinetics to fibrin clots formed in vitro [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
