Platelet activation agonists

The balance of opposing pro- and anti-platelet forces determines the overall hemostatic response. Successful hemostasis is achieved when assorted signal-transduction systems, mediators, white blood cells, and platelet receptors for agonists and adhesion molecules overcome the local resistance against platelet activation to generate... 

Platelets can be activated by a variety of agents including the physiologic agonists ADP, thromboxane A2, epinephrine, collagen, and thrombin. Platelet activation is generally associated with a change in platelet shape (except for epinephrine-induced platelet activation) from discs to spiny spheres with pseudopodia. Platelet pseudopod formation is dependent on actin polymerization in the activated platelets. The interaction of actin filaments with myosin, mediated by calcium (9), facilitates platelet contractile activity (e.g., clot retraction). 

Platelet activation occurs in large part via G protein-coupled agonist receptors and intracellular signaling events that involve activation of phospholipase C (PLC). PLC catalyzes the breakdown of plasma membrane inositol phospholipids, resulting in generation of 1,2-diacylglycerol (DAG) and 1,4,5-inositol triphosphate (IP3). DAG activates protein kinase C, and IP3 induces mobilization of calcium from intracellular stores (10). 

Physiological effect at the site of an endothelial damage is the conjoint activity of several agonists from exposed subendothelium, released during platelet activation, coming from red or white cells or from activation of clotting mechanisms of the surrounding plasma,... 

The above-mentioned agonists are important factors in platelets activation and in the thrombotic process and many of the receptors are targets in the development of drugs for thrombosis prevention (Table I). 

Platelet activation cascade in response to different agonists and the site of action of different antiplatelet agents. 

Cilostazol is a PDE3 inhibitor and also is a drug with multiple mechanisms of action (23,24), some of which are directly platelet-related, and others of which exert their effects indirectly via endothelial cells (Figs, 4 and 5), As a PDE inhibitor, it increases the concentration of cyclic nucleotides within platelets and inhibits platelet aggregation in response to shear forces (via ADP) and a variety of agonists. Like other inhibitors of platelet activation, it blocks the expression and release of P-selectin, a key adhesion molecule on the membrane of platelet alpha granules that externalizes with activation, and plays an important role in the interactions between platelets, endothelial cells, and leukocytes, The effect of cilostazol on P-selectin expression appears to be additive to those of aspirin and clopidogrel (25). 

It has been shown that patients with diabetes exhibit platelet activation and increased reactivity to agonists. The heightened platelet reactivity may be related to the increased prevalence of nonresponders and occurrence of ischemic events reported in patients with diabetes (106,107). It has also been reported that patients with a high body mass index (BMI) exhibited a suboptimal platelet response with the standard 300 mg loading dose (108). 

Xiao Z, Theroux R Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome. J Am Coll Cardiol 2004 43 1 982-1988. 

---