The glycoprotein VI-phospholipase Cgamma2 signaling pathway controls thrombus formation induced by collagen and tissue factor in vitro and in vivo.
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.
Munnix
Imke C A
IC
Department of Biochemistry, CARIM, Maastricht University, Maastricht, The Netherlands.
Strehl
Amrei
A
Kuijpers
Marijke J E
MJ
Auger
Jocelyn M
JM
van der Meijden
Paola E J
PE
van Zandvoort
Marc A M
MA
oude Egbrink
Mirjam G A
MG
Nieswandt
Bernhard
B
Heemskerk
Johan W M
JW
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
D010718:Phosphatidylserines; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D005337:Fibrin; D003094:Collagen; D013925:Thromboplastin; D051966:Phospholipase C gamma