title: The glycoprotein VI-phospholipase Cgamma2 signaling pathway controls thrombus formation induced by collagen and tissue factor in vitro and in vivo.
abstract: OBJECTIVE
  Both collagen and tissue factor can be initiating factors in thrombus formation. We investigated the signaling pathway of collagen-induced platelet activation in interaction with tissue factor-triggered coagulation during the thrombus-forming process.
  
  
  RESULTS
  In murine blood flowing over collagen, platelet exposure of phosphatidylserine and procoagulant activity, but not adhesion, completely relied on each of the following signaling modules: glycoprotein VI (GPVI), FcR gamma-chain, Src kinases, adaptor protein LAT, and phospholipase Cgamma2 (PLCgamma2). On flow in the presence of tissue factor, these signaling components were essential for platelet aggregation and greatly enhanced fibrin clot formation. Collagen-stimulated thrombin generation relied on the presence and activity of GPVI, FcR gamma-chain, Src kinase, LAT, and PLCgamma2. The physiological importance of this GPVI pathway was shown in a FeCl3-induced in vivo murine thrombosis model. In both venules and arterioles, signaling through GPVI, FcR gamma-chain, and Src kinases enhanced the formation of phosphatidylserine-exposing and fibrin-rich thrombi.
  
  
  CONCLUSIONS
  The GPVI-PLCgamma2 activation pathway regulates collagen-dependent coagulation in venous and arterial thrombus formation.
authors.affiliation: Department of Biochemistry, CARIM, Maastricht University, Maastricht, The Netherlands.
authors.forename: Imke C A
authors.initials: IC
authors.lastname: Munnix
authors.forename: Amrei
authors.initials: A
authors.lastname: Strehl
authors.forename: Marijke J E
authors.initials: MJ
authors.lastname: Kuijpers
authors.forename: Jocelyn M
authors.initials: JM
authors.lastname: Auger
authors.forename: Paola E J
authors.initials: PE
authors.lastname: van der Meijden
authors.forename: Marc A M
authors.initials: MA
authors.lastname: van Zandvoort
authors.forename: Mirjam G A
authors.initials: MG
authors.lastname: oude Egbrink
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Heemskerk
mesh_terms: D000818:Animals; D001160:Arterioles; D001777:Blood Coagulation / Q000502:physiology; D001792:Blood Platelets / Q000201:enzymology; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008817:Mice, Mutant Strains; D010718:Phosphatidylserines / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D011673:Pulsatile Flow; D015398:Signal Transduction / Q000502:physiology*; D013925:Thromboplastin / Q000378:metabolism*; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism*; D014699:Venules
chemical_list: D010718:Phosphatidylserines; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D005337:Fibrin; D003094:Collagen; D013925:Thromboplastin; D051966:Phospholipase C gamma