Inhibition of GPVI, but not plaque tissue factor, prevented plaque-induced thrombus formation, which occurs in two discrete steps starting with rapid GPVI-mediated platelet adhesion to collagen.
OBJECTIVES: The aim of this study was to understand the initial mechanism of arterial thrombus formation induced by vulnerable human atherosclerotic plaques to re-assess and improve current antithrombotic strategies. BACKGROUND: Rupture of atherosclerotic plaques causes arterial thrombus formation that might lead to myocardial infarction and ischemic stroke. Atherothrombosis is considered as an inseparable tangle of platelet activation and coagulation processes, involving plaque components such as tissue factor (TF) and collagen as well as blood-borne TF and coagulation factor XIIa (FXIIa). A combination of anticoagulants and antiplatelet agents is the present treatment. METHODS: Human atheromatous plaque material was exposed to blood or blood components at physiological calcium/magnesium concentration. Platelet aggregation and coagulation were measured under static and arterial flow conditions by state-of-the-art microscopic and physiological techniques. Plaque TF, plaque collagen, FXIIa, and platelet glycoprotein VI (GPVI) were specifically inhibited. RESULTS: Plaques induced thrombus formation by 2 discrete steps. The rapid first phase of GPVI-mediated platelet adhesion and aggregation onto plaque collagen occurred within 1 min. The second phase of coagulation started after a delay of >3 min with the formation of thrombin and fibrin, and was driven entirely by plaque TF. Coagulation occurred only in flow niches provided by platelet aggregates, with no evidence for a role of blood-borne TF and FXIIa. Inhibition of GPVI but not plaque TF inhibited plaque-induced thrombus formation. CONCLUSIONS: The major thrombogenic plaque components--collagen and TF--induce platelet activation and coagulation, respectively, in 2 consecutive steps. Targeting specifically the first step is crucial and might be sufficient to inhibit atherothrombus formation.
“Since signal transmission by these receptors is essential for platelet activation by plaques, we suspected that inhibition of the signal pathway downstream of these receptors should also effectively suppress thrombus formation”
Reininger et al. (Mon,) conducted a other in Atherothrombosis. Inhibition of platelet glycoprotein VI (GPVI) and plaque tissue factor (TF) was evaluated on Platelet aggregation and coagulation (thrombus formation). Inhibition of GPVI, but not plaque tissue factor, prevented plaque-induced thrombus formation, which occurs in two discrete steps starting with rapid GPVI-mediated platelet adhesion to collagen.