Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica

Centro Regional de Hemodonación, Universidad de Murcia, C/ Ronda de Garay s/n., Murcia, Spain.
Haematologica (Impact Factor: 5.81). 04/2009; 94(5):700-11. DOI: 10.3324/haematol.2008.003178
Source: PubMed

ABSTRACT 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(2)beta(1) 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, TxA(2), 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(IIb)beta(3), increasing their ligand affinity. Binding of alpha(IIb)beta(3) 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 alphaIb beta(3), 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.

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Available from: Maria L Lozano, Sep 28, 2015
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    • "Platelets are the cellular effectors of primary hemostasis, as they contribute to thrombus formation at sites of vascular injury, a fundamental tenet in physiology and medicine [49] [50] [51] [52] [53] [54] [55]. Platelets are anucleated circulating cells in mammals approximately 2 í µí¼‡m in diameter and are derived from megakaryocytes within the bone marrow [56, 57]. "
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    • "These receptors play an important role in inside–outside signaling in the course of PLT activation and the release reaction. As outlined in a review by Rivera et al. in 2009 [100], many types of mobile transmembrane receptors are present at the PLT membrane, including many integrins (αIIbβ3, α2β1, α5β1, α6β1, αVβ3), leucine-rich repeat (LRR) receptors (glycoprotein [GP] Ib/IX/V, toll-like receptors), G-protein coupled seven-transmembrane receptors (GPCR) (PAR-1 and PAR-4, thrombin receptors, P2Y1 and P2Y12 ADP receptors, TPα and TPβ (TxA2 receptors), proteins belonging to the immunoglobulin superfamily (GP VI, FcγRIIA), C-type lectin receptors (P-selectin), tyrosine kinase receptors (thrombopoietin receptor, Gas-6, ephrins, and Eph kinases), and a miscellaneous of other types (CD63, CD36, P-selectin glycoprotein ligand 1, TNF receptor type, etc.). Many of these receptors have been character‐ ized using immune electron microscopy [30] [33] [73] [74] [79] [80]. "
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