Figure 1.

The thrombo-inflammatory signaling of platelet activation and the modulatory effects of each and all NSAIDs on each platelet agonist and its associated receptors. ADP activates the P2Ys receptors’ associated signaling; AA and COX produce TxA2 that activates TP receptors’ signaling; vWF, fibrinogen and Collagen activate GPs (integrins) associated signaling; Thrombin activates PARs receptors’ signaling; PAF activates PAFR signaling that affects all the other platelet agonists’ signaling (i.e., activation of PLC for IP3 production, activation of kinases, activation of PLA2 for production of AA, etc.). Activation of each platelet agonist-receptor signaling results in processes through activation of intracellular signaling by kinases (MAPK, PKA, PKC, PIP3K, etc.), IP3 and [Ca⁺²i], AA, GFs, etc., all of which result in activation and aggregation of platelets. Each NSAID and some of their derivatives were found to modulate several of these thrombo-inflammatory signaling, apart from the PAF/PAFR pathways for which limited information exists. NSAIDs also affect the release of several agents and factors from platelet granules, such as GFs. Abbreviations: NSAID(s) = non-steroidal anti-inflammatory drug(s); AA = arachidonic acid; ADP = adenosine 5′ diphosphate; TP = Thromboxane Prostanoidreceptors; P2Ys = metabotropic P2 receptors, such as the Gq-protein-coupled P2Y1 and the Gi-protein-coupled P2Y12 receptor; PARs = protease-activated receptors (mostly PAR1 and PAR4); TxA2 = thromboxane A2; TxB2 = thromboxane B2; COXs = cyclooxygenases; GPs = glycoproteins as receptors (integrins), such as the integrin αIIbβ3 (glycoprotein GPIIbIIIa), integrin α2β1 (glycoprotein GPIa-IIa) and glycoprotein VI (GPVI); PAF platelet-activating factor; PAFR = receptor of PAF; vWF = von Willebrand factor; GFs = growth factors (i.e., GFsNGF = nerve growth factor; BDNF = brain-derived neurotrophic factor); PLA2 = phospholipase A2; PLC = phospholipase C.