adenosine diphosphate platelet aggregation
A noteworthy side-effect of ticlopidine and clopidogrel is thrombotic thrombocytopenic purpura (TTP). The loading dose is 300–600 mg, and the maintenance dose is 75–150 mg/d orally. In the presence of 25 μM MRS 2216, ADP did not induce platelet shape change, indicating that the antagonist completely abolished the function of P2Y1. Ticlopidine carries excessive hematological side-effect risk. Kumaran Kolandaivelu, Deepak L. Bhatt, in Platelets (Third Edition), 2013, Key Potential Benefits: Higher potency, Faster action, Reversible effect, Uniform inhibition, IV/oral availability. ADP is stored in platelet dense granules and released upon platelet activation. Resistance to disseminated thrombosis initiated with collagen plus epinephrine. Filkova AA, Martyanov AA, Garzon Dasgupta AK, Panteleev MA, Sveshnikova AN. Platelet Phenotypes of GPCR Knockout Mice. Drugs that block platelet ADP P2Y12 receptors have proved to be effective antiplatelet agents (Chapter 54) despite the fact that ADP, when added alone, is a less potent platelet agonist than thrombin. ADP induces an increase in the cytoplasmic free calcium level … Existing evidence suggests that there may be two receptors on the platelet for ADP: one responsible for mediating platelet aggregation that is coupled to the G protein and the other responsible for calcium influx and shape change. Prasugrel (Effient) is an irreversible P2Y12 receptor inhibitor. We use cookies to help provide and enhance our service and tailor content and ads. 2020 Apr 28;20(1):159. doi: 10.1186/s12883-020-01703-6. In CHAMPION PCI, 8,877 patients were randomized to cangrelor infusion or clopidogrel 600 mg loading dose 30 minutes prior to PCI, while in CHAMPION PLATFORM, 5,362 patients undergoing PCI were randomized to cangrelor or placebo followed by a clopidogrel 600 mg load at the end of the procedure. Adenosine diphosphate (ADP) released from platelet dense granules triggers the binding of fibrinogen to platelet receptor GPIIb-IIIa, resulting in the formation of fibrinogen bridges that link platelets into a loose aggregate. P2X1 functions as a ligand-gated ion channel, allowing rapid calcium influx upon binding of ADP [26]. Two trials, CHAMPION PCI64 and CHAMPION PLATFORM,65 compared the efficacy of cangrelor to clopidogrel in different settings. P2Y12, a new platelet ADP receptor, target of clopidogrel. Diadenosine tetraphosphate (Ap4A) is a naturally occurring compound in platelet dense granules and inhibits ADP-mediated activation of both P2Y1 and P2Y12 receptors.68 A series of modified Ap4A derivatives were tested and their effects on P2Y1 and P2Y12 measured by cytosolic Ca2+ and VASP, respectively. It also inhibits cAMP formation. Quantitative dynamics of reversible platelet aggregation: mathematical modelling and experiments. As such, it only induces shape change and reversible aggregation in human platelets, whereas the secretion of platelet-dense granule constituents and the ensuing secondary aggregation that are sometimes observed after stimulation with ADP of normal platelet-rich plasma (PRP) are triggered by thromboxane (TX) A2, the synthesis of which is stimulated by platelet aggregation.5 This phenomenon can be observed with the PRP of only a minority of normal individuals when the con centration of Ca2+ in plasma is maintained at physiological levels,6 but it is greatly enhanced and can be observed in most individuals when the concentration of plasma Ca2+ is artifactually decreased to the micromolar level, such as in citrated PRP.6–9 Although itself a weak agonist, ADP plays a key role in platelet function because, when it is secreted from the platelet-dense granules where it is stored, it amplifies the platelet responses induced by other platelet agonists8,10 and stabilizes platelet aggregates.11–13 Transduction of the ADP-induced signal involves inhibition of adenylyl cyclase and a concomitant transient increase in the concentration of cytoplasmic Ca2+, resulting from both Ca2+ influx and mobilization of internal stores (see Chapter 16). Abbreviations: AC, adenylyl cyclase; ADP, adenosine diphosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; COX-1, cyclooxygenase 1; DAG, diacylglycerol; PI3K, phosphatidylinositol 3-kinase; PLCβ, phospholipase Cβ; GDP, guanosine 5’-diphosphate; GTP, guanosine 5’-triphosphate; PG, prostaglandin; PIP2, phosphatidylinositol-4,5-bisphosphate; PKC, protein kinase C; TXA2, thromboxane A2. Association of clopidogrel high on-treatment reactivity with clinical outcomes and gene polymorphism in acute ischemic stroke patients: An observational study. ATP, being an antagonist of both P2Y1 and P2Y12, inhibits platelet activation by ADP36,37 However, through its interaction with P2X1, it can also activate platelets by inducing a very rapid influx of Ca2+ from the extracellular medium, which is associated with a transient platelet shape change.38 Platelet activation by ATP amplifies the platelet responses to other agonists, especially during flow conditions that are characterized by high shear stress.39–42, The effects of ADP and ATP on platelet function are modulated in vivo by CD39, a nucleoside triphosphate diphosphohydrolase (NTPDase-1), and another ectonucleotidase, CD39L1/NTPDase-2.43–46 NTPDase-1, which is mainly expressed by endothelial cells and vascular smooth muscle cells, hydrolyes both triphosphonucleotides and diphosphonucleotides, and inhibits ADP-induced platelet aggregation.

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