The relative importance of platelet integrins in hemostasis, thrombosis and beyond

Abstract

Integrins are heterodimeric transmembrane receptors composed of α and β chains, with an N-terminal extracellular domain forming a globular head corresponding to the ligand binding site. Integrins regulate various cellular functions including adhesion, migration, proliferation, spreading and apoptosis. On platelets, integrins play a central role in adhesion and aggregation on subendothelial matrix proteins of the vascular wall, thereby ensuring hemostasis. Platelet integrins belong either to the β1 family (α2β1, α5β1 and α6β1) or to the β3 family (αIIbβ3 and αvβ3). On resting platelets, integrins can engage their ligands when the latter are immobilized but not in their soluble form. The effects of various agonists promote an inside-out signal in platelets, increasing the affinity of integrins for their ligands and conveying a modest signal reinforcing platelet activation, called outside-in signaling. This outside-in signal ensures platelet adhesion, shape change, granule secretion and aggregation. In this review, we examine the role of each platelet integrin in hemostatic plug formation, hemostasis and arterial thrombosis and also beyond these classical functions, notably in tumor metastasis and sepsis.

Research and Clinical Approaches to Assess Platelet Function in Flowing Blood

“…52 Consequently, the alterations in platelet cytoskeleton driven by GPIb-IX-V mechanotrasduction along with signaling from GPIb-IX-V result in upregulation of integrin affinity for their respective ligands. 7 These changes in integrin affinity are crucial for the maintenance of platelet adhesion to a site of vascular injury in flowing blood (via platelet-ECM interactions), as well as recruitment of additional platelets to the thrombus (via platelet-platelet interactions). Arginine-glycine-aspartic acid sequences within the Aα chain of fibrinogen, as well as a dodecapeptide sequence within the γ-chain of fibrinogen engage with active αIIbβ3.…”

“…Arginine-glycine-aspartic acid sequences within the Aα chain of fibrinogen, as well as a dodecapeptide sequence within the γ-chain of fibrinogen engage with active αIIbβ3. 7 Because of the dimeric nature of fibrinogen, 53,54 platelet binding sequences are available at each terminal of this large and extended molecule, facilitating platelet-platelet interactions.…”

“…Injury exposes the subendothelial ECM (extracellular matrix) proteins, including collagen, laminin, fibrinogen, fibronectin, and VWF (von Willebrand factor), which are prothrombotic and highly adhesive for platelets. Platelet adhesion is mediated by several specialized transmembrane adheso-signaling receptors, or receptor complexes, including integrins αIIbβ3, α2β1, α5β1, and α6β1, 7 as well as nonintegrin receptors GPIb-IX-V (glycoprotein) and GPVI, which bind components of the subendothelial matrix and to coagulation products. 8 The function and signaling of these receptors have been comprehensively reviewed.…”

The Novel Role of Noncoding RNAs in Modulating Platelet Function: Implications in Activation and Aggregation

“…This is not a surprise since upon activation, a substantial change in platelets' shape occurs [27]. It is well known that integrins play a key role in the adhesion and aggregation of the subendothelial matrix proteins of the vascular wall, thus ensuring hemostasis [57]. Five different integrins, belonging to the β1 and β3 families, (α2β1, α5β1, α6β1, αvβ3, and αIIbβ3, whose main ligands are collagen, fibronectin, laminins, vitronectin, and fibrinogen, respectively) are expressed at platelet surface [57].…”

“…Recently, the importance of α5β1 in hemostasis under normal and inflammatory conditions has also been better defined [59]. Various agonists may modulate the affinity of integrins for their ligands, thereby reinforcing platelet activation [57]. Integrins' expression, as well as the intracellular integrin-related pathway, are highly regulated [60].…”