Future innovations in anti‐platelet therapies

Barrett, Natasha; Holbrook, Lisa-Marie; Jones, Sarah; Kaiser, William J.; Moraes, Leonardo A.; Rana, Rekha; Sage, Tanya; Stanley, Ronald G.; Tucker, Katherine L.; Wright, Bernice; Gibbins, Jonathan M.

doi:10.1038/bjp.2008.151

Cited by 140 publications

(105 citation statements)

References 280 publications

(288 reference statements)

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…Indeed, P2Y12 is the target of thienopyridine drugs (ticlopidine, clopidogrel, prasugrel) widely used and with probed efficacy in the prevention of vascular events in patients with cardiovascular disease, specially those having stent insertion. 39 Despite their likely categorized roles, co-activation of both P2Y1 and P2Y12 seems to be required for optimal ADP-induced aggregation and ADP-promoted thrombus growth. The observation that over-expressing the P2Y1 receptor results in full ADPinduced secretion and irreversible aggregation, shortened bleeding time and more susceptibility to ADP and collagen-induced thromboembolism and arterial thrombosis triggered by FeCl3 50 reinforces the physiological relevance of this receptor and the rationale for its consideration as target of new antithrombotic compounds.…”

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confidence: 99%

“…The observation that over-expressing the P2Y1 receptor results in full ADPinduced secretion and irreversible aggregation, shortened bleeding time and more susceptibility to ADP and collagen-induced thromboembolism and arterial thrombosis triggered by FeCl3 50 reinforces the physiological relevance of this receptor and the rationale for its consideration as target of new antithrombotic compounds. 39,47 In addition to P2Y1 and P2Y12, human platelets express a third purinergic receptor P2X1, with a significant role in platelet function. P2X1 is an ATP-driven calcium channel unable to trigger platelet aggregation by itself, but under high shear conditions acts as a positive regulator of platelet responses to collagen and thus plays a significant role in thrombus formation.…”

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confidence: 99%

“…Several peptide and non-peptide antagonists have been developed, and clinical studies are underway in the context of coronary artery disease and percutaneous coronary intervention. 39,61 Other potential antithrombotic strategies targeting the thrombin signaling pathway include inhibitors of cell-surface promoters of thrombin generation, or direct thrombin inhibitors.Although the contribution of catecholamines to the hemostatic/thrombotic process is generally thought to occur through its constrictive action on the vascular wall, circulating or locally secreted epinephrine also favors platelet activation in the growing platelet plug. A reduced number of epinephrine receptors has been related to mild bleeding disorders in a few patients.…”

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confidence: 99%

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Platelet receptors and signaling in the dynamics of thrombus formation

Rivera¹,

Lozano²,

et al. 2009

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Hemostasis and pathological thrombus formation are dynamic processes that require a co-ordinated series of events involving platelet membrane receptors, bidirectional intracellular signals, and release of platelet proteins and inflammatory substances. This review aims to summarize current knowledge in the key steps in the dynamics of thrombus formation, with special emphasis on the crucial participation of platelet receptors and signaling in this process. Initial tethering and firm adhesion of platelets to the exposed subendothelium is mediated by glycoprotein (GP) Ib/IX/V complex and collagen receptors, GP VI and α2β1 integrin, in the platelet surface, and by VWF and fibrillar collagen in the vascular site. Interactions between these elements are largely influenced by flow and trigger signaling events that reinforce adhesion and promote platelet activation. Thereafter, soluble agonists, ADP, thrombin, TxA2, produced/released at the site of vascular injury act in autocrine and paracrine mode to amplify platelet activation and to recruit circulating platelets to the developing thrombus. Specific interactions of these agonists with their G-protein coupled receptors generate inside-out signaling leading to conformational activation of integrins, in particular αIIbβ3, increasing their ligand affinity. Binding of αIIbβ3 to its ligands, mainly fibrinogen, supports processes such as clot retraction and platelet aggregation. Stabilization of thrombi is supported by the late wave of signaling events promoted by close contact between aggregated platelets. The best known contact-dependent signaling is outside-in signaling through αIIbβ3, but new ones are being clarified such as those mediated by interaction of Eph receptors with ephrins, or by Sema 4D and Gas-6 binding to their receptors. Finally, newly identified mechanisms appear to control thrombus growth, including back-shifting of activated integrins and actuation of compensatory molecules such as ESAM or PECAM-1. The expanding knowledge of thrombotic disease is expected to translate into the development of new drugs to help management and prevention of thrombosis.Key words: platelet, receptors, thrombus formation.Citation: Rivera J, Lozano ML, Navarro-Núñez L, Vicente V. Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 2009; 94:700-711. doi:10.3324/haematol.2008 This is an open-access paper. ABSTRACT Platelet receptors and signaling in the dynamics of thrombus formationJosé Rivera, María Luisa Lozano, Leyre Navarro-Núñez, and Vicente Vicente Unit of Hematology and Clinical Oncology, Centro Regional de Hemodonación, University of Murcia, Spain © F e r r a t a S t o r t i F o u n d a t i o nand metastasis, or immunological host defense. 1Internally, platelets contain a cytoskeleton, a dense tubular system, few mitochondrias, glycogen granules, dense (δ) and α storage granules and peroxisomes. The α-granules retain relevant proteins for the hemostatic function of platelets, such as von Willebrand factor (VWF), fibrinogen, P-selectin,...

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Platelet receptors and signaling in the dynamics of thrombus formation

Rivera¹,

Lozano²,

et al. 2009

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“…Platelets play a key role in the complex chain of events leading to the thrombotic occlusion of a coronary artery 4 . Antiplatelet therapy with aspirin and/or a variety of other agents is effective at reducing the mortality associated with incident CVD 5 and is recommended for the primary prevention of same in patients at high risk of atherothrombotic events 4 . Despite the greatly increased risk of heart disease and strokes, there are currently no antiplatelet guidelines for the primary prevention of CVD in patients with IA 3 , and platelet function remains largely uninvestigated in this patient population.…”

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confidence: 99%