The roles of αIIbβ3-mediated outside-in signal transduction, thromboxane A2, and adenosine diphosphate in collagen-induced platelet aggregation

111

Modulation of the proteins released during activation is one mechanism whereby aspirin may influence platelet-mediated human disease. We investigated the effect of aspirin on the platelet releasate using mass spectrometry and found that different agonists evoked different releasate profiles, with aspirin having a general moderating effect on the amount of protein released regardless of the agonist.These observations were confirmed for several cytokines using an antibody array approach. (Blood. 2007;109: [4786][4787][4788][4789][4790][4791][4792]

Section: Discussionmentioning

confidence: 98%

Moderation of the platelet releasate response by aspirin

Coppinger

O'Connor

Wynne

et al. 2007

111

“…34 These authors speculated that the PLC␥2-independent route of activation was mediated through a novel, uncharacterized signaling pathway. The results of the present study demonstrate that this pathway involves activation of PLC␥1 downstream of GPVI.…”

Section: Discussionmentioning

confidence: 99%

Murine GPVI stimulates weak integrin activation in PLCγ2–/– platelets: involvement of PLCγ1 and PI3-kinase

Suzuki‐Inoue

Ito

Frampton

et al. 2003

109

Collagen stimulates platelet activation through a tyrosine kinase-based pathway downstream of the glycoprotein VI (GPVI)-Fc receptor (FcR) ␥-chain complex. Genetic ablation of FcR ␥-chain results in a complete inhibition of aggregation to collagen. In contrast, a steady increase in light transmission is induced by collagen in phospholipase C␥2-deficient (PLC␥2 ؊/؊ ) platelets in a Born aggregometer, indicating a weak level of activation. This increase is inhibited partially in the presence of an ␣ 2 ␤ 1 -blocking antibody or an ␣ IIb ␤ 3 antagonist and completely by a combination of the 2 inhibitors. It is also abolished by the Src kinase inhibitor PP1 and reduced in the presence of the phosphatidylinositol (PI) 3-kinase inhibitor wortmannin. The GPVIspecific agonists convulxin and collagenrelated peptide (CRP) also stimulate weak aggregation in PLC␥2 ؊/؊ platelets, which is inhibited by wortmannin and PP1. Collagen and CRP stimulate tyrosine phosphorylation of PLC␥1 at its regulatory site, Tyr 783, in murine but not in human platelets through a Src kinase-dependent pathway. Adhesion of PLC␥2 ؊/؊ platelets to a collagen monolayer is severely reduced at a shear rate of 800 s ؊1 , relative to controls, whereas it is abolished in FcR ␥-chain ؊/؊ platelets. These results provide strong evidence that engagement of GPVI stimulates limited integrin activation in PLC␥2 ؊/؊ platelets via PLC␥1 and PI3-kinase.

“…71 Thus, the robust aggregation induced by collagen is blocked in the presence of inhibitors of secondary mediators and is replaced by a slow increase in light transmission, which most likely represents a combination of ␣ 2 ␤ 1 -mediated adhesion and ␣ IIb ␤ 3 -dependent aggregation. 72 It is important to consider why collagen but not GPVI-specific agonists are dependent on the release of these mediators to induce aggregation. There are likely to be several factors that contribute to this: (1) Collagen is unable to induce the same strength of intracellular signal as that induced by powerful GPVI-specific agonists such as CRP-XL, convulxin, and cross-linked antibodies, 5,61,73 most likely because of the infrequent spacing of GPO throughout its sequence.…”

Section: Role Of Secondary Mediators In Platelet Aggregation By Collagenmentioning

confidence: 99%

Platelet-collagen interaction: is GPVI the central receptor?

Nieswandt

Watson

2003

984

955

At sites of vascular injury, platelets come into contact with subendothelial collagen, which triggers their activation and the formation of a hemostatic plug. Besides glycoprotein Ib (GPIb) and ␣ IIb ␤ 3 integrin, which indirectly interact with collagen via von Willebrand factor (VWF), several collagen receptors have been identified on platelets, most notably ␣ 2 ␤ 1 integrin and the immunoglobulin (Ig) superfamily member GPVI. Within the last few years, major advances have been made in understanding platelet-collagen interactions including the molecular cloning of GPVI, the generation of mouse strains lacking individual collagen receptors, and the development of collagen receptor-specific antibodies and synthetic peptides. It is now recognized that platelet adhesion to collagen requires prior activation of integrins through "inside-out" signals generated by GPVI and reinforced by released second-wave mediators adenosine diphosphate (ADP) and thromboxane A 2 . These developments have led to revision of the original "2-site, 2-step" model, which now places GPVI in a central position in the complex processes of platelet tethering, activation, adhesion, aggregation, degranulation, and procoagulant activity on collagen. This review discusses these recent developments and proposes possible mechanisms for how GPVI acts in concert with other receptors and signaling pathways to initiate hemostasis and arterial thrombosis. IntroductionVessel wall injury triggers sudden platelet activation and platelet plug formation, followed by coagulant activity and the formation of fibrin-containing thrombi that occlude the site of injury. These events are crucial to limit blood loss at sites of tissue trauma but may also block diseased vessels, leading to ischemia and infarction of vital organs. One of the major clinical problems in the developed world is arterial thrombosis caused by rupture or erosion of an atherosclerotic plaque, leading to platelet adhesion and subsequent thrombus formation in coronary and cerebral arteries causing myocardial infarction and stroke, respectively. Therefore, a detailed understanding of the mechanisms underlying the formation of the atherosclerotic plaque as well as (arterial) thrombosis is required in order to control ischemic cardiovascular diseases while retaining hemostasis.The first step in the hemostatic cascade is platelet interaction with the exposed extracellular matrix (ECM) at sites of injury. Among the macromolecular constituents of the ECM, collagen is considered to play a major role in this process, as in vitro it not only supports platelet adhesion through direct and indirect pathways but it also directly activates the cells initiating aggregation and coagulant activity. 1 Platelet adhesion and aggregation on collagen is an integrated process that involves several platelet agonists that act through a variety of surface receptors, including integrins, immunoglobulin (Ig)-like receptors, and G-protein-coupled receptors. Over the last 20 years, immense effort has been spent on the ident...