Platelet receptors and signaling in the dynamics of thrombus formation

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 α2β1 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 αIIbβ3, increasing their ligand affinity. Binding of αIIbβ3 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 αIIbβ3, 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.Citation: Rivera J, Lozano ML, Navarro-Núñez L, Vicente V. Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 2009; 94:700-711. doi:10.3324/haematol.2008 This is an open-access paper. ABSTRACT Platelet receptors and signaling in the dynamics of thrombus formationJosé Rivera, María Luisa Lozano, Leyre Navarro-Núñez, and Vicente Vicente Unit of Hematology and Clinical Oncology, Centro Regional de Hemodonación, University of Murcia, Spain © F e r r a t a S t o r t i F o u n d a t i o nand metastasis, or immunological host defense. 1Internally, platelets contain a cytoskeleton, a dense tubular system, few mitochondrias, glycogen granules, dense (δ) and α storage granules and peroxisomes. The α-granules retain relevant proteins for the hemostatic function of platelets, such as von Willebrand factor (VWF), fibrinogen, P-selectin,...

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“…Formation of an occlusive thrombus is a dynamic processes which requires a coordinated series of events involving the coagulation system, the fibrinolytic system and platelet activation [26]. Thus, delaying platelet activation can impair thrombus formation by disturbing the timing required for the coordinated action of the above cited systems [11].…”

“…Initiation of a luminal thrombosis involves both activation of the coagulation cascade by TF and factor VII [18,22,23,33], and platelet activation [13,26].…”

Plaquetas: Papéis tradicionais e não tradicionais na hemostasia, na inflamação e no câncer

“…Plaquetas estão envolvidas em processos dinâmicos como a hemostasia, inflamação, imunidade e câncer, processos que necessitam de uma série coordenada de eventos que envolvem receptores de membrana, sinais bidirecionais intracelulares com liberação de proteínas e de fatores inflamatórios 1,15,16 .…”

“…Estudos in vitro e in vivo, principalmente em modelos animais, sobre as funções dos receptores de superfície plaquetária, incluindo a inibição farmacológica por antagonistas específicos, têm ajudado a revelar novos mecanismos de como a propensão trombótica e hemorrágica das plaquetas é controlada em processos fisiopatológicos 15 .…”

“…Uma grande variedade de receptores transmembranares cobre a membrana das plaquetas, incluindo muitas integrinas (α IIb β 3 , α 2 β 1 , α 5 β 1 , α 6 β 1 , α v β 3 ), receptores ricos em leucina (LRR) (glicoproteína [GP] Ib/IX/V, receptores Toll-like ), receptores acoplados à proteína G com sete domínios transmembrânicos (GPCR) (PAR-1, PAR-3 e PAR-4 receptores ativados por proteases -principalmente trombina, P2Y1 e P2Y12 receptores de ADP, receptores prostanóides -TPA, TPB -e receptores TXA2), proteínas pertencentes à superfamília das imunoglobulinas (GP VI, FcgRIIA), receptores do tipo lectina (P-selectina), receptores tirosina-quinase (receptor de trombopoietina, Gas-6, efrinas e quinases Eph) e uma variedade de outros tipos (CD63, CD36, receptor do tipo TNF, entre outros) [15][16][17][18] . e Muitos destes receptores são encontrados em outros tipos celulares, mas alguns são apenas expressos em plaquetas, como a P-selectina (C-type lectin receptors).…”