on October 27, 2005
Published online before print October 27, 2005, doi: 10.1161/01.ATV.0000193568.71980.4a
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Submitted on July 8, 2005
Accepted on October 12, 2005
The Glycoprotein VI-Phospholipase C
2 Signaling Pathway Controls Thrombus Formation Induced by Collagen and Tissue Factor In Vitro and In Vivo
Imke C.A. Munnix ;
From the Departments of Biochemistry (I.C.A.M., M.J.E.K., P.E.J.v.d.M., J.W.M.H.), Biophysics (M.A.M.v.Z.), and Physiology (M.G.A.o.E.), CARIM, Maastricht University, Maastricht, the Netherlands; Rudolf Virchow Center (A.S., B.N.), DFG Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany; and Centre for Cardiovascular Sciences Institute of Biomedical Research (J.M.A.), University of Birmingham, Birmingham, United Kingdom.
* To whom correspondence should be addressed. E-mail: jwm.heemskerk{at}bioch.unimaas.nl.
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.
Methods and 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 
-chain, Src kinases, adaptor protein LAT, and phospholipase C2 (PLC2). 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 -chain, Src kinase, LAT, and PLC2. 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 -chain, and Src kinases enhanced the formation of phosphatidylserine-exposing and fibrin-rich thrombi.
Conclusions--The GPVI-PLC2 activation pathway regulates collagen-dependent coagulation in venous and arterial thrombus formation.
Key words: glycoprotein VI • LAT • platelets • Src kinase • thrombin
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