Published online 13 March 2009
Haematologica, Vol 94, Issue 5, 700-711 doi:10.3324/haematol.2008.003178
Copyright © 2009 by Ferrata Storti Foundation
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Thrombosis

Platelet receptors and signaling in the dynamics of thrombus formation

José Rivera, María Luisa Lozano, Leyre Navarro-Núñez, Vicente Vicente

Unit of Hematology and Clinical Oncology, Centro Regional de Hemodonación, University of Murcia, Spain

Correspondence: Vicente Vicente García, Centro Regional de Hemodonación, Universidad de Murcia, C/ Ronda de Garay s/n., 30003 Murcia, Spain. E-mail:vicente.vicente{at}carm.es

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 {alpha}2β1 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 {alpha}IIbβ3, increasing their ligand affinity. Binding of {alpha}IIbβ3 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 {alpha}Ib β3, 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.




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