Platelets agonists

A2. Abi-Younes, S., Sauty, A., Mach, F., Sukhova, G. K., Libby, P., and Luster, A. D., The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. Circ. Res. 86, 131-138 (2000). 

Platelet agonists ligation to its specific receptors leads to production and release of several intracellular messenger molecules such as calcium, products of the PLC, and COX. 

Many platelet agonists, such as ADF) TXA2, epinephrine, serotonin, and thrombin, interact with specific transmembrane receptors that are coupled to G-proteins, initiating several signaling pathways that lead to PLC activation ending in platelets shape change and granule secretion (Fig. 4). 

Thrombin and collagen are the strongest platelet agonists. Thrombin signaling is mediated by a family of G protein-coupled receptors, termed protease-activated receptors (PARs). Four PARs have been identified (PAR-1 through PAR-4) PAR-1, PAR-3, and PAR-4 are thrombin receptors (18). PAR-2 can be activated by trypsin and tryptase, but not by thrombin (19). 

Platelet participation in normal hemostasis. The hemostatic plug is the specific response to external vessel lesion and depends on the extent of vessel wall damage, the specific interaction between endothelial cells and activated platelets, release of the contents of platelets intracellular granules in response to activation, the conjoint activity of activated factor Vll and platelet agonists, and the open conditions of blood flow. After activation, platelets also produce the external ization of membrane phosphatidylserine through the flip-flop mechanism that will support the function of the prothrombinase complex ending in thrombin generation and local clot formation. 

Adenosine, in addition to serving as a substrate for the generation of cAMP plays a physiologic role as a platelet inhibitor and a vasodilator and may attenuate neutrophil-mediated damage to endothelial cells, Adenosine diphosphate (ADP)— a potent platelet agonist—is converted to adenosine, which is taken up rapidly by cells, especially erythrocytes and endothelial cells, A small proportion is metabolized to the aforementioned cyclic nucleotides. The remainder is broken down to inosine and subsequently to xanthine. Dipyridamole inhibits the active transport of adenosine into cells, but does not interfere with the passive diffusion. Since the platelet inhibitory effects of adenosine proceed via stimulation of adenylate cyclase, these effects can also be amplified by dipyridamole, In circulating blood, the largest amount of adenosine is found in red blood cells, This may, in part, help explain why dipyridamole is much more effective in whole blood than in plasma. 

Halenda et al, 1986). PKC is believed to be activated indirectly by all platelet agonists through the DAG (Fukami and Holmsen, 1995) produced by phosphoinositide-specific PLC. 

Thrombin is the most potent physiologic platelet agonist, and induce all the platelet responses mentioned in section 9.3 and suppresses cAMP synthesis. Although thrombin is an enzyme, its ability to activate platelets depends on its concentration (Detwiler and Feinman, 1973). Harmon and Jamieson (1986) suggested that there are both high affinity... 

Adrenaline is only capable of producing platelet aggregation in the presence of other platelet agonists (Steen cr of, 1993 Lanza et al, 1988), and is therefore not a tme agonist. Platelets have stimulatory Uj adrenoreceptors and inhibitory p adrenoreceptors, but the adrenoreceptors predcnnhiates. The adrenoreceptor is coupled via G proteins to adenylyl cyclase, while ffie a, adrenoreceptor (present in about 30 %) has Ireen proposed to be... 

Clark EA, Shathl SJ, Ginsberg MH, Bolen J, Brugge JS. Regulation of the protein tyrosine kinase pp72 by platelet agonists and the int rin otjJ),. JBiol Chem 269 28859-28864, 1994a. 

Defects in Platelet-Agonist Interaction (Receptor Defects)... 

Defects in platelet-agonist interaction are exemplified by patients with impaired responses because of an abnormality at the level of platelet surface receptors for a specific agonist. Such receptor defects have been documented for epinephrine, collagert, ADP, and thromboxane A2. Hirata et al (21) have described an Arg 60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder. Evidence has been... 

---