Inhibition of the platelet glycoprotein VI receptor as a potential treatment for acute coronary syndromes

Alenazy, Fawaz Obaidullah M. (2021). Inhibition of the platelet glycoprotein VI receptor as a potential treatment for acute coronary syndromes. University of Birmingham. Ph.D.

Preview

Alenazy2021PhD.pdf
Text - Accepted Version
Available under License All rights reserved.
Download (9MB) | Preview

Abstract

Aspirin and a P2Y\(_{12}\) inhibitor, such as ticagrelor, are routine treatments for myocardial infarction. However, these drugs are not always sufficient for heavy coronary thrombus burden during ST-elevation myocardial infarction (STEMI). More potent antiplatelet drugs (glycoprotein IIb/IIIa inhibitors) may help in this setting but are limited by excessive bleeding. As glycoprotein VI (GPVI) plays major roles in thrombosis, this thesis aimed to investigate whether a novel platelet GPVI inhibitor, glenzocimab (Acticor Biotech), provides additional antithrombotic effects when combined with aspirin and ticagrelor. Glenzocimab showed an amplified antiplatelet effect on collagen and atherosclerotic plaque-induced platelet aggregation without showing off-target effects on platelet activation mediated by non-GPVI agonists. Glenzocimab and eptifibatide (a glycoprotein IIb/IIIa antagonist) both exhibited similar inhibitory effects on collagen- and atherosclerotic plaque-induced platelet aggregation when used in combination with aspirin and ticagrelor. Glenzocimab also reduced fibrin-stimulated platelet aggregation more than aspirin and ticagrelor. Glenzocimab provided additional antiplatelet effects on platelet aggregation and adhesion and thrombus formation in blood sampled from patients with acute coronary syndromes treated with aspirin and ticagrelor. Glenzocimab blocked platelet procoagulant activity and reduced tissue factor-mediated peak thrombin generation. Glenzocimab did not affect early phases of coagulation (initiation, formation, and strength), which were greatly affected by eptifibatide, but it exerted some effects on clot lysis (late phases of coagulation) as assessed by ROTEM. This is the first work to show that the addition of a novel GPVI inhibitor, glenzocimab, to aspirin and ticagrelor provides greater inhibition of multiple critical mechanisms of arterial thrombosis. This is a promising strategy for the further development of treatment for STEMI due to the minimal role of GPVI in haemostasis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):