Identification of a new dysfunctional platelet P2Y12 receptor variant associated with bleeding diathesis

Lecchi, Anna; Razzari, Cristina; Paoletta, Silvia; Dupuis, Arnaud; Nakamura, Lea; Ohlmann, Philippe; Gachet, Christian; Zieger, Barbara; Cattaneo, Marco

doi:10.1182/blood-2013-07-517896

Cited by 38 publications

(35 citation statements)

References 30 publications

(51 reference statements)

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“…The majority of lesions are nonsense and missense mutations, the latter 73,82 Most of the qualitative defects identified (eg, the recently described P2RY12 H187Q mutation that impairs ADP binding 83 ) have shed new light on P2Y12 structure-function relationships.…”

Section: 8081mentioning

confidence: 99%

Genomic landscape of megakaryopoiesis and platelet function defects

Bianchi

Norfo

Pennucci

et al. 2016

Blood

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Megakaryopoiesis is a complex, stepwise process that takes place largely in the bone marrow. At the apex of the hierarchy, hematopoietic stem cells undergo a number of lineage commitment decisions that ultimately lead to the production of polyploid megakaryocytes. On average, megakaryocytes release 1011 platelets per day into the blood that repair vascular injuries and prevent excessive bleeding. This differentiation process is tightly controlled by exogenous and endogenous factors, which have been the topics of intense research in the hematopoietic field. Indeed, a skewing of megakaryocyte commitment and differentiation may entail the onset of myeloproliferative neoplasms and other preleukemic disorders together with acute megakaryoblastic leukemia, whereas quantitative or qualitative defects in platelet production can lead to inherited platelet disorders. The recent advent of next-generation sequencing has prompted mapping of the genomic landscape of these conditions to provide an accurate view of the underlying lesions. The aims of this review are to introduce the physiological pathways of megakaryopoiesis and to present landmark studies on acquired and inherited disorders that target them. These studies have not only introduced a new era in the fields of molecular medicine and targeted therapies but may also provide us with a better understanding of the mechanisms underlying normal megakaryopoiesis and thrombopoiesis that can inform efforts to create alternative sources of megakaryocytes and platelets.

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Section: 8081mentioning

confidence: 99%

Genomic landscape of megakaryopoiesis and platelet function defects

Bianchi

Norfo

Pennucci

et al. 2016

Blood

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“…1) [70]. Crystallographic data and molecular modeling studies indicated that His187 in TM5 is important for agonist and nucleotide antagonist binding and located in a region undergoing conformational changes.…”

Section: Role Of P2y 12 R In Platelet Responses To Agonists Other Thamentioning

confidence: 99%

P2Y12 receptors: structure and function

Cattaneo

2015

Journal of Thrombosis and Haemostasis

115

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To cite this article: Cattaneo M. P2Y 12 receptors: structure and function. J Thromb Haemost 2015; 13 (Suppl. 1): S10-S6.Summary. The platelet P2Y 12 receptor (P2Y 12 R) for adenosine 5 0 diphosphate (ADP) plays a central role in platelet function, hemostasis, and thrombosis. Patients with inherited P2Y 12 R defects display mild-to-moderate bleeding diatheses. Defects of P2Y 12 R should be suspected when ADP, even at high concentrations (≥ 10 lM), is unable to induce full, irreversible platelet aggregation. P2Y 12 R also plays a role in inflammation: its role in the pathogenesis of allergic asthma has been well characterized. In addition, inhibition or genetic deficiency of P2Y 12 R has antitumor effects. Drugs inhibiting P2Y 12 R are potent antithrombotic drugs. Clopidogrel is the P2Y 12 R antagonist that is most widely used in the clinical setting. Its most important drawback is its inability to inhibit adequately P2Y 12 R-dependent platelet function in about onethird of patients. New drugs, such as prasugrel and ticagrelor, which effectively inhibit P2Y 12 R in the vast majority of patients, have proved to be more efficacious than clopdidogrel in preventing major adverse cardiovascular events.

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“…Platelet integrin α IIb β 3 plays a crucial role in platelet aggregation, and it was claimed that phosphatidylinositol 3-kinase is essential for ADP-stimulated α IIb β 3 -mediated platelet activation and calcium oscillations [250]. Continuous interaction between ADP and P2Y 12 receptors is critical for the maintenance of α IIb β 3 activation [251][252][253]. Evidence was presented that P2Y 12 receptors potentiate platelet shape change induced by P2Y 1 receptor activation by a Rho kinase-dependent mechanism [254].…”

Section: Pathologymentioning

confidence: 99%

Blood cells: an historical account of the roles of purinergic signalling

Burnstock

2015

Purinergic Signalling

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The involvement of purinergic signalling in the physiology of erythrocytes, platelets and leukocytes was recognised early. The release of ATP and the expression of purinoceptors and ectonucleotidases on erythrocytes in health and disease are reviewed. The release of ATP and ADP from platelets and the expression and roles of P1, P2Y 1 , P2Y 12 and P2X1 receptors on platelets are described. P2Y 1 and P2X1 receptors mediate changes in platelet shape, while P2Y 12 receptors mediate platelet aggregation. The changes in the role of purinergic signalling in a variety of disease conditions are considered. The successful use of P2Y 12 receptor antagonists, such as clopidogrel and ticagrelor, for the treatment of thrombosis, myocardial infarction and stroke is discussed.

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Identification of a new dysfunctional platelet P2Y12 receptor variant associated with bleeding diathesis

Cited by 38 publications

References 30 publications

Genomic landscape of megakaryopoiesis and platelet function defects

Genomic landscape of megakaryopoiesis and platelet function defects

P2Y12 receptors: structure and function

Blood cells: an historical account of the roles of purinergic signalling

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