Local delivery of soluble platelet collagen receptor glycoprotein VI inhibits thrombus formation in vivo

Summary

Platelet-mediated thrombus formation at the site of vascular injury isa major trigger for thrombo-ischemic complications after coronary interventions. The platelet collagen receptor glycoprotein VI (GPVI) plays a critical role in the initiation of arterial thrombus formation. Endothelial denudation of the right carotid artery in rabbits was induced through balloon injury. Subsequently, local delivery of soluble, dimeric fusion protein of GPVI (GPVI-Fc) (n=7) or control Fc (n=7) at the site of vascular injury was performed with a modified double-balloon drugdelivery catheter.Thrombus area within the injured carotid artery was quantified using a computer-assisted image analysis and was used as index of thrombus formation.The extent of thrombus formation was significantly reduced in GPVI-Fc- compared with control Fc-treated carotid arteries (relative thrombus area, GPVI-Fc vs. Fc: 9.3 ± 4.2 vs. 2.3 ± 1.7, p<0.001). Local delivery of soluble GPVI resulted in reduced thrombus formation after catheter-induced vascular injury.These data suggest a selective pharmacological modulation of GPVI-collagen interactions to be important for controlling onset and progression of pathological arterial thrombosis, predominantly or even exclusively at sites of injured carotid arteries in the absence of systemic platelet therapy.

Keywords

Angioplasty - glycoprotein VI - platelets - thrombosis - collagen

• References

• 1 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 08: 1227-34.
• 2 Clemetson KJ, Clemetson JM. Platelet collagen receptors. Thromb Haemost 2001; 86: 189-97.
• 3 Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor?. Blood 2003; 102: 449-61.
• 4 Massberg S, Gawaz M, Gruner S. et al. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo . J Exp Med 2003; 197: 41-9.
• 5 Massberg S, Konrad I, Bultmann A. et al. Soluble glycoprotein VI dimer inhibits platelet adhesion and aggregation to the injured vessel wall in vivo . FASEB J 2004; 18: 397-9.
• 6 Gawaz M, Konrad I, Hauser AI. et al. Non-invasive imaging of glycoprotein VI binding to injured arterial lesions. Thromb Haemost 2005; 93: 910-3.
• 7 Herdeg C, Oberhoff M, Baumbach A. et al. Local paclitaxel delivery for the prevention of restenosis: biological effects and efficacy in vivo . J Am Coll Cardiol 2000; 35: 1969-76.
• 8 Herdeg C, Oberhoff M, Baumbach A. et al Effects of local all-trans-retinoic acid delivery on experimental atherosclerosis in the rabbit carotid artery. Cardiovasc Res 2003; 57: 544-53.
• 9 Cabeza N, Li Z, Schulz C. et al. Surface expression of collagen receptor Fc receptor-γ/glycoprotein VI is enhanced on platelets in type 2 diabetes and mediates release of CD40 ligand and activation of endothelial cells. Diabetes 2004; 53: 2117-21.
• 10 Torsney E, Mayr U, Zou Y. et al. Thrombosis and neointima formation in vein grafts are inhibited by locally applied aspirin through endothelial protection. Circ Res 2004; 94: 1466-73.
• 11 Naghavi M, Libby P, Falk E. et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003; 108: 1664-72.
• 12 Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005; 111: 3481-8.
• 13 Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov 2003; 02: 15-28.
• 14 Clemetson JM, Polgar J, Magnenat E. et al. The platelet collagen receptor glycoprotein VI isa member of the immunoglobulin superfamily closely related to FcαR and the natural killer receptors. J Biol Chem 1999; 274: 29019-24.
• 15 Jandrot-Perrus M, Busfield S, Lagrue AH. et al. Cloning, characterization, and functional studies of human and mouse glycoprotein VI: a platelet-specific collagen receptor from the immunoglobulin superfamily. Blood 2000; 96: 1798-1807.
• 16 Moroi M, Jung SM, Okuma M. et al. A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion. J Clin Invest 1989; 84: 1440-5.
• 17 Kehrel B, Wierwille S, Clemetson KJ. et al. Glycoprotein VI isa major collagen receptor for platelet activation: it recognizes the platelet-activating quaternary structure of collagen, whereas CD36, glycoprotein IIb/ IIIa, and von Willebrand factor do not. Blood 1998; 91: 491-9.
• 18 Chen H, Locke D, Liu Y. et al. The platelet receptor GPVI mediates both adhesion and signaling responses to collagen in a receptor density-dependent fashion. J Biol Chem 2002; 277: 3011-9.
• 19 Nieswandt B, Schulte V, Bergmeier W. et al. Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice. J Exp Med 2001; 193: 459-69.