The Role of P2Y₁₂ Receptor and Activated Platelets During Inflammation

Abstract

Platelets play an important role not only during thrombosis, but also in modulating immune responses through their interaction with immune cells and by releasing inflammatory mediators upon activation. The P2Y12 receptor is a Gi-coupled receptor that not only regulates ADP-induced aggregation but that can also dramatically potentiate secretion, when platelets are activated by other stimuli. Considering the importance of P2Y12 receptor in platelet function, a class of anti-platelet drugs, thienopyridines, have been designed and successfully used to prevent thrombosis. This review will focus on the role of activated platelets in inflammation and the effects that P2Y12 antagonism exerts on the inflammatory process. A change in platelet functions was noted in patients treated with thienopyridines during inflammatory conditions, suggesting that platelets may modulate the inflammatory response. Further experiments in a variety of animal models of diseases, such as sepsis, rheumatoid arthritis, myocardial infarction, pancreatitis and pulmonary inflammation have also demonstrated that activated platelets influence the inflammatory state. Platelets can secrete inflammatory modulators in a P2Y12–dependent manner, and, as a result, directly alter the inflammatory response. P2Y12 receptor may also be expressed in other cells of the immune system, indicating that thienopyridines could directly influence the immune system rather than only through platelets. Overall the results obtained to date strongly support the notion that activated platelets significantly contribute to the inflammatory process and that antagonizing P2Y12 receptor can influence the immune response.

Potent irreversible P2Y12 inhibition does not reduce LPS-induced coagulation activation in a randomized, double-blind, placebo-controlled trial

“…Prasugrel is a potent inhibitor of platelet activation, with a rapid onset of action [33]. Platelets contribute not only to plasma coagulation, but also to inflammation by releasing the content of their granules [34]. We were therefore surprised that prasugrel appeared to be without effect on any of the pharmacodynamic markers used in the present study.…”

A novel approach of platelet function test for prediction of attenuated response to clopidogrel

“…Not only experimental but also growing clinical evidence support an association between CRP and activation of platelets [11]. In the non-responder subgroup, the serum concentration of CRP also showed a significant positive correlation with the percentage of H-IPF in the upper sample suggesting that more intense vascular or systemic inflammatory response may be associated to increased production of immature platelets [12][13][14]. This is in accordance with our observation that the highest H-IPF percentage was observed in the upper samples of non-responders [3,4].…”

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…The inhibition of this effect is utilized in the clinic to prevent myocardial infarction and stroke. P2Y 12 receptors, expressed on platelets, regulate various forms of inflammation and could either improve or worsen the scenario (Liverani et al, 2014a). In the CNS, P2Y 12 receptors are expressed on astrocytes, oligodendrocytes and the resting, ramified microglia executing surveillant functions (Amadio et al, 2014;Franke et al, 2004).…”