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Targeting Intraplatelet Signaling Pathways as Potential Antithrombotic Strategy

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Platelets in Thrombotic and Non-Thrombotic Disorders

Abstract

Platelets assume two main functions that lead to opposite outcomes. In one instance, they support hemostatic plug formation and prevent bleeding at sites of vascular breach. Alternatively, their uncontrolled recruitment at sites of plaque erosion/rupture in arteries can lead to ischemic events and death. Antiplatelet agents have been developed to successfully treat or prevent arterial thrombotic events, but their use is inevitably associated with bleeding complications. These agents target platelet receptors (i.e., P2Y12, the ADP receptor mediating aggregation and thrombus stability; αIIbβ3, the fibrinogen and vWF receptor mediating platelet aggregation/thrombus growth; PAR1, the high-affinity platelet thrombin receptor) or the cyclooxygenase 1 (COX1) enzyme that promotes TxA2 synthesis (another platelet-derived endogenous agonist of platelet aggregation). Evidences have emerged showing that these pathways are complementary as combinations of drugs provide additive protection. Signaling pathways downstream of the glycoprotein receptors have been well characterized and indicate that inhibition of effectors (specific to a pathway or ubiquitous) could provide significant protection from thrombosis. In this chapter, we will review the biology associated with genetic and pharmacologic modulation of platelet effectors and report their effects on thrombosis and primary hemostasis.

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  1. Biology Department, Pliant Therapeutics, 700 Saginaw Drive, Redwood City, CA, 94063, USA

    Patrick Andre

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  1. Department of Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia , Perugia, Italy

    Paolo Gresele

  2. Houston Methodist Hospital , Houston, Texas, USA

    Neal S. Kleiman

  3. Bloodworks Northwest, University of Washington , Seattle, Washington, USA

    José A. Lopez

  4. Sackler Inst of Pulmonary Pharmacol, King’s College London, London, United Kingdom

    Clive P. Page

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Andre, P. (2017). Targeting Intraplatelet Signaling Pathways as Potential Antithrombotic Strategy. In: Gresele, P., Kleiman, N., Lopez, J., Page, C. (eds) Platelets in Thrombotic and Non-Thrombotic Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-47462-5_90

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