Cell Adhesion Mechanisms in Platelets

Abstract

Abstract-At sites of vascular injury, platelets come into contact with the subendothelial extracellular matrix which triggers their activation and the formation of a hemostatic plug. This process is crucial for normal hemostasis, but may also lead to pathological thrombus formation causing diseases such as myocardial infarction or stroke. The initial capture of flowing platelets is mediated by the interaction of the glycoprotein (GP) Ib-V-IX complex with von Willebrand factor (vWF) immobilized on exposed collagens. This interaction allows the binding of the collagen receptor GPVI to its ligand and to initiate cellular activation, a process that is reinforced by locally produced thrombin and soluble mediators released from platelets. These events lead to the shift of ␤1 and ␤3 integrins on the platelet surface from a low to a high affinity state, thereby enabling them to bind their ligands and to mediate firm adhesion, spreading, coagulant activity, and aggregation. This review summarizes the most important structural and functional properties of these adhesion receptors and briefly discusses their potential as targets for antithrombotic therapy.

Engagement of αIIbβ3 (GPIIb/IIIa) with ανβ3 Integrin Mediates Interaction of Melanoma Cells with Platelets

“…Here, we confirm by intravital microscopy that platelet depletion results in significantly decreased melanoma cell adhesion to the vascular wall in vivo, demonstrating an interaction of melanoma cells with platelets in vivo. Once adherent to the vessel wall, such as after endothelial injury, the platelet fibrinogen receptor GPIIb/IIIa becomes activated and contributes to thrombus formation and wound healing (3,59). Interestingly, we observed that inhibition of GPIIb/IIIa resulted in both the reduced adhesion of melanoma cells to immobilized platelets and the reduced adhesion to endothelial cells under shear flow conditions in the presence of platelets.…”

Intracellular cyclophilin A is an important Ca2+ regulator in platelets and critically involved in arterial thrombus formation

“…1,2 In contrast, uncontrolled platelet activation can induce acute vessel occlusion, leading to myocardial infarction or stroke at areas of atherosclerotic plaque rupture. 3,4 Platelet activation and thrombus formation is a multistage process that involves different signaling pathways to trigger platelet shape change, integrin activation, and degranulation. 4,5 The signaling pathways converge in the activation of phospholipase C (PLC), leading to the formation of inositol 1,4,5-triphosphate (IP 3 ) and diacylglycerol.…”

Thrombin and Collagen Induce a Feedback Inhibitory Signaling Pathway in Platelets Involving Dissociation of the Catalytic Subunit of Protein Kinase A from an NFκB-IκB Complex

“…Many factors bind to specific platelet receptors and regulate signaling pathways, which promote or inhibit platelet adhesion, aggregation, and secretion. In vivo, circulating platelets are continually exposed to a variety of activating factors including collagen, fibrinogen, ADP, von Willebrand Factor (vWF), thrombin, and thromboxane (3)(4)(5), as well as inhibitory factors such as endothelial-derived nitric oxide (NO), prostacyclin (PG-I 2 ), and ADPase (3,(5)(6). A strong equilibrium between the two opposing processes of platelet stimulation and inhibition is thought to be essential for normal platelet and vascular function.…”

“…In the initial steps of platelet activation, the platelet receptor glycoproteins (GP) 3 1b and GPVI interact with extracellular matrix (ECM) proteins, causing platelets to tether and roll on the injured endothelium or subendothelial ECM (5). Stimulation of these receptors triggers intracellular signaling cascades that activate integrin ␣IIb␤3 and induce the release of secondary mediators like ADP and thromboxane A 2 (TXA 2 ), leading to full platelet activation and thrombus formation.…”