Neena Kalia1, Jocelyn M Auger, Ben Atkinson, Steve P Watson. 1. Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham, United Kingdom. n.kalia@bham.ac.uk
Abstract
OBJECTIVE: The role of collagen receptor complex GPVI-FcR gamma-chain, PLCgamma2 and LAT in laser-induced thrombosis is unclear. Controversy surrounds whether collagen is exposed in this model or whether thrombosis is dependent on thrombin. This study hypothesized that collagen exposure plays a critical role in thrombus formation in this model, which was tested by investigating contributions of FcR gamma-chain, LAT, PLCgamma2 and thrombin. METHODS: Thrombi were monitored using intravital microscopy in anesthetized wild-type and FcR gamma-chain, LAT and PLCgamma2 knockout mice. Hirudin (thrombin inhibitor) was administered to wild-type and FcR gamma-chain knockout mice. RESULTS: Significantly reduced thrombus formation was observed in FcR gamma-chain and PLCgamma2 knockouts with a greater decrease observed in LAT knockouts. Dramatic reduction was observed in wild-types treated with hirudin, with abolished thrombus formation only observed in FcR gamma-chain knockouts treated with hirudin. CONCLUSIONS: GPVI-FcR gamma-chain, LAT and PLCgamma2 are essential for thrombus generation and stability in this laser-induced model of injury. More importantly, a greater role for LAT was identified, which may reflect a role for it downstream of a second matrix protein receptor. However, inhibition of platelet activation by matrix proteins and thrombin generation are both required to maximally prevent thrombus formation.
OBJECTIVE: The role of collagen receptor complex GPVI-FcR gamma-chain, PLCgamma2 and LAT in laser-induced thrombosis is unclear. Controversy surrounds whether collagen is exposed in this model or whether thrombosis is dependent on thrombin. This study hypothesized that collagen exposure plays a critical role in thrombus formation in this model, which was tested by investigating contributions of FcR gamma-chain, LAT, PLCgamma2 and thrombin. METHODS: Thrombi were monitored using intravital microscopy in anesthetized wild-type and FcR gamma-chain, LAT and PLCgamma2 knockout mice. Hirudin (thrombin inhibitor) was administered to wild-type and FcR gamma-chain knockout mice. RESULTS: Significantly reduced thrombus formation was observed in FcR gamma-chain and PLCgamma2 knockouts with a greater decrease observed in LAT knockouts. Dramatic reduction was observed in wild-types treated with hirudin, with abolished thrombus formation only observed in FcR gamma-chain knockouts treated with hirudin. CONCLUSIONS: GPVI-FcR gamma-chain, LAT and PLCgamma2 are essential for thrombus generation and stability in this laser-induced model of injury. More importantly, a greater role for LAT was identified, which may reflect a role for it downstream of a second matrix protein receptor. However, inhibition of platelet activation by matrix proteins and thrombin generation are both required to maximally prevent thrombus formation.
Authors: Eric Calvo; Fuyuki Tokumasu; Daniella M Mizurini; Peter McPhie; David L Narum; José Marcos C Ribeiro; Robson Q Monteiro; Ivo M B Francischetti Journal: FEBS J Date: 2009-12-15 Impact factor: 5.542
Authors: J D Welsh; I Poventud-Fuentes; S Sampietro; S L Diamond; T J Stalker; L F Brass Journal: J Thromb Haemost Date: 2017-02-06 Impact factor: 5.824
Authors: Olga Konopatskaya; Karen Gilio; Matthew T Harper; Yan Zhao; Judith M E M Cosemans; Zubair A Karim; Sidney W Whiteheart; Jeffery D Molkentin; Paul Verkade; Steve P Watson; Johan W M Heemskerk; Alastair W Poole Journal: J Clin Invest Date: 2009-01-19 Impact factor: 14.808
Authors: Michelle A Berny; Imke C A Munnix; Jocelyn M Auger; Saskia E M Schols; Judith M E M Cosemans; Peter Panizzi; Paul E Bock; Steve P Watson; Owen J T McCarty; Johan W M Heemskerk Journal: PLoS One Date: 2010-04-29 Impact factor: 3.240
Authors: Sebastian Dütting; Timo Vögtle; Martina Morowski; Sarah Schiessl; Carmen M Schäfer; Stephanie K Watson; Craig E Hughes; Jochen A Ackermann; Daniel Radtke; Heike M Hermanns; Steve P Watson; Lars Nitschke; Bernhard Nieswandt Journal: Circ Res Date: 2013-11-21 Impact factor: 17.367
Authors: Craig E Hughes; Leyre Navarro-Núñez; Brenda A Finney; Diego Mourão-Sá; Alice Y Pollitt; Steve P Watson Journal: J Thromb Haemost Date: 2010-10 Impact factor: 5.824