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Platelet-Derived Inhibitors of Platelet Activation

Unsworth, AJ and Bye, AP and Gibbins, JM (2017) Platelet-Derived Inhibitors of Platelet Activation. In: Platelets in Thrombotic and Non-Thrombotic Disorders: Pathophysiology, Pharmacology and Therapeutics: an Update. Springer, pp. 541-556. ISBN 9783319474625

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Abstract

When blood vessels are damaged, circulating platelets come into contact with activating stimuli that trigger aggregation and enable them to form a haemostatic plug. This process is subject to both positive and negative feedback to ensure that platelets respond appropriately to damage and do not form thrombi that totally occlude the vessel. Dysregulation of negative feedback mechanisms is believed to contribute to the increased risk of thrombosis associated with some diseases. Despite the association with thrombosis, platelet derived negative regulators of platelet activation are relatively poorly understood in comparison to mediators of platelet activation. However, it is increasingly apparent that the mechanisms by which platelets restrain activation are diverse and of equal complexity to those that mediate positive signalling. Some regulators, such as RASA3 and JAM-A, act as gatekeepers that must be deactivated for platelet activation to occur. In contrast, regulators that contain ITIMs, such as PECAM-1, are activated following stimulation and mediate negative regulation via phosphatases that restrain activation. Wnt3a and ESAM are thought to directly limit plateletplatelet adhesion by blocking activation of the fibrinogen receptor, integrin αIIbβ3. The various isoforms of PKC expressed by platelets provide a diverse and complex array of inhibitory effects including receptor desensitisation. Many platelet derived inhibitors have been identified but not fully characterised and so questions remain regarding the mechanisms that underlie their effects on platelet activity following their activation, inhibition or genetic disruption. In this chapter the current understanding and recent developments in the field of platelet-derived inhibitors of platelet activation will be discussed.

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