Summary
Platelets are central mediators of haemostasis at sites of vascular injury, but they
also mediate pathologic thrombosis. Activated platelets stimulate thrombus formation
in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting
atherothrombotic disease. They also interact with endothelial cells and leukocytes
to promote inflammation, which contributes to atherosclerosis. Multiple pathways contribute
to platelet activation, and current oral antiplatelet therapy with aspirin and a P2Y12 adenosine diphosphate (ADP) receptor antagonist target the thromboxane A2 and ADP pathways, respectively. Both can diminish activation by other factors, but
the extent of their effects depends upon the agonist, agonist strength, and platelet
reactivity status. Although these agents have demonstrated significant clinical benefit,
residual morbidity and mortality remain high. Neither agent is effective in inhibiting
thrombin, the most potent platelet activator. This lack of comprehensive inhibition
of platelet function allows continued thrombus formation and exposes patients to risk
for recurrent thrombotic events. Moreover, bleeding risk is a substantial limitation
of antiplatelet therapy, because these agents target platelet activation pathways
critical for both protective haemostasis and pathologic thrombosis. Novel antiplatelet
therapies that provide more complete inhibition of platelet activation without increasing
bleeding risk could considerably decrease residual risk for ischemic events. Inhibition
of the protease-activated receptor (PAR)-1 platelet activation pathway stimulated
by thrombin is a novel, emerging approach to achieve more comprehensive inhibition
of platelet activation when used in combination with current oral antiplatelet agents.
PAR-1 inhibition is not expected to increase bleeding risk, as this pathway does not
interfere with haemostasis.
Keywords
Antiplatelet therapy - haemostasis - inflammation - platelet activation - thrombosis
