Complementary roles of platelet glycoprotein VI and integrin α2β1 in collagen‐induced thrombus formation in flowing whole blood ex vivo

Kuijpers, Marijke J. E.; Schulte, Valerie; Bergmeier, Wolfgang; Lindhout, Théo; Brakebusch, Cord; Offermanns, Stefan; Fässler, Reinhard; Heemskerk, Johan W. M.; Nieswandt, Bernhard

doi:10.1096/fj.02-0381fje

Cited by 142 publications

(183 citation statements)

References 42 publications

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“…These results closely resemble those obtained for human GPVI-deficient platelets in similar assays (Moroi et al, 1996). Similar observations have also been reported for normal platelets and a function-blocking anti-GPVI antibody (Siljander et al, 2004), suggesting that GPVI and α2β1 might play complementary roles in which α2β1 is able to bind to collagen before platelet activation and GPVI is required for thrombus formation (Kuijpers et al, 2003).…”

Section: Glycoprotein VI (Gpvi)supporting

confidence: 78%

Platelet adhesion signalling and the regulation of thrombus formation

Gibbins

2004

Journal of Cell Science

259

232

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Platelets perform a central role in haemostasis and thrombosis. They adhere to subendothelial collagens exposed at sites of blood vessel injury via the glycoprotein (GP) Ib-V-IX receptor complex, GPVI and integrin α2β1. These receptors perform distinct functions in the regulation of cell signalling involving non-receptor tyrosine kinases (e.g. Src, Fyn, Lyn, Syk and Btk), adaptor proteins, phospholipase C and lipid kinases such as phosphoinositide 3-kinase. They are also coupled to an increase in cytosolic calcium levels and protein kinase C activation, leading to the secretion of paracrine/autocrine platelet factors and an increase in integrin receptor affinities. Through the binding of plasma fibrinogen and von Willebrand Factor to integrin αIIbβ3, a platelet thrombus is formed. Although increasing evidence indicates that each of the adhesion receptors GPIb-V-IX and GPVI and integrins α2β1 and αIIbβ3 contribute to the signalling that regulates this process, the individual roles of each are only beginning to be dissected. By contrast, adhesion receptor signalling through platelet endothelial cell adhesion molecule 1 (PECAM-1) is implicated in the inhibition of platelet function and thrombus formation in the healthy circulation. Recent studies indicate that understanding of platelet adhesion signalling mechanisms might enable the development of new strategies to treat and prevent thrombosis.

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Section: Glycoprotein VI (Gpvi)supporting

confidence: 78%

Platelet adhesion signalling and the regulation of thrombus formation

Gibbins

2004

Journal of Cell Science

259

232

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“…32 Blood was perfused over coverslips coated with collagen or fibrinogen mounted on a transparent, parallel-plate flow perfusion chamber. 33 Alternatively, coverslips were coated with mouse von Willebrand factor (VWF), using a rabbit antibody against human VWF (1:500; Dako).…”

Section: Measurement Of Thrombus Formation Under Flowmentioning

confidence: 99%

Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis

Lievens

Zernecke

Seijkens

et al. 2010

Blood

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260

221

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CD40 ligand (CD40L), identified as a costimulatory molecule expressed on T cells, is also expressed and functional on platelets. We investigated the thrombotic and inflammatory contributions of platelet CD40L in atherosclerosis. Although CD40L-deficient (Cd40l ؊/؊ ) platelets exhibited impaired platelet aggregation and thrombus stability, the effects of platelet CD40L on inflammatory processes in atherosclerosis were more remarkable. Repeated injections of activated Cd40l ؊/؊ platelets into Apoe ؊/؊ mice strongly decreased both platelet and leukocyte adhesion to the endothelium and decreased plasma CCL2 levels compared with wildtype platelets. Moreover, Cd40l ؊/؊ platelets failed to form proinflammatory plateletleukocyte aggregates. Expression of CD40L on platelets was required for plateletinduced atherosclerosis as injection of Cd40l ؊/؊ platelets in contrast to Cd40l ؉/؉ platelets did not promote lesion formation. Remarkably, injection of Cd40l ؉/؉ , but not Cd40l ؊/؊ , platelets transiently decreased the amount of regulatory T cells

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“…Experiments were conducted as described 27 . Briefly, transparent flow chambers with a slit depth of 50 µm, equipped with Horm-type collagen-coated cover slips, were connected to a syringe filled with anticoagulated blood.…”

Section: Secretionmentioning

confidence: 99%

G13 is an essential mediator of platelet activation in hemostasis and thrombosis

Moers

Nieswandt

Maßberg

et al. 2003

Nat Med

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233

236

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Platelet activation at sites of vascular injury is essential for primary hemostasis, but also underlies arterial thrombosis leading to myocardial infarction or stroke 1,2 . Platelet activators such as adenosine diphosphate, thrombin or thromboxane A 2 (TXA 2 ) activate receptors that are coupled to heterotrimeric G proteins 1,3 . Activation of platelets through these receptors involves signaling through G q , G i and G z (refs. 4-6). However, the role and relative importance of G 12 and G 13 , which are activated by various platelet stimuli 7-9 , are unclear. Here we show that lack of Gα 13 , but not Gα 12 , severely reduced the potency of thrombin, TXA 2 and collagen to induce platelet shape changes and aggregation in vitro. These defects were accompanied by reduced activation of RhoA and inability to form stable platelet thrombi under high shear stress ex vivo. Gα 13 deficiency in platelets resulted in a severe defect in primary hemostasis and complete protection against arterial thrombosis in vivo. We conclude that G 13 -mediated signaling processes are required for normal hemostasis and thrombosis and may serve as a new target for antiplatelet drugs.

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Complementary roles of platelet glycoprotein VI and integrin α2β1 in collagen‐induced thrombus formation in flowing whole blood ex vivo

Cited by 142 publications

References 42 publications

Platelet adhesion signalling and the regulation of thrombus formation

Platelet adhesion signalling and the regulation of thrombus formation

Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis

G13 is an essential mediator of platelet activation in hemostasis and thrombosis

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