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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1492-1499.
Prepublished online as a Blood First Edition Paper on October 26, 2004; DOI 10.1182/blood-2004-06-2391.


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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Relative antithrombotic effect of soluble GPVI dimer compared with anti-GPVI antibodies in mice

Sabine Grüner, Miroslava Prostredna, Martina Koch, Yoshiki Miura, Valerie Schulte, Stephanie M. Jung, Masaaki Moroi, and Bernhard Nieswandt

From the Rudolf Virchow Center, Deutsche Forschungsgemeinschaft (DFG) Research Center for Experimental Biomedicine, University of Würzburg, Germany; and the Department of Protein Biochemistry, Institute of Life Science, Kurume University, Japan.

Glycoprotein VI (GPVI) is an essential platelet collagen receptor; therefore, the inhibition of GPVI-collagen interactions may be an attractive antithrombotic strategy. We have previously shown that targeting of GPVI with antibodies leads to the depletion of the receptor and to long-term antithrombotic protection in mice. An alternative agent to interfere with GPVI-collagen interactions might be soluble GPVI acting as a competitive inhibitor, thereby averting undesired effects on platelets. To test this, we expressed soluble dimeric human GPVI, comprising the extracellular domain of the receptor fused to the human immunoglobulin Fc domain (GPVI-Fc), and compared its antithrombotic potential with that of anti-GPVI antibodies in mice. In contrast to a recent report, we found by intravital fluorescence microscopy and ultrasonic flow measurements that GPVI-Fc had no effect on platelet adhesion and thrombus formation at the injured arterial wall, whereas anti-GPVI antibodies profoundly inhibited these processes. Similar results were obtained with a fusion protein comprising the extracellular domain of mouse GPVI and human IgG-Fc. This indicates that direct targeting of GPVI provides significantly stronger protection against arterial thrombosis than soluble GPVI dimer.


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