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Blood, 1 August 2006, Vol. 108, No. 3, pp. 908-914.
Prepublished online as a Blood First Edition Paper on March 28, 2006; DOI 10.1182/blood-2005-07-2937.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Activation-independent, antibody-mediated removal of GPVI from circulating human platelets: development of a novel NOD/SCID mouse model to evaluate the in vivo effectiveness of anti–human platelet agents
Brian Boylan,
Michael C. Berndt,
Mark L. Kahn, and
Peter J. Newman
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; the Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia; the Division of Cardiology, Department of Medicine, University of Pennsylvania, Philadelphia, PA; the Department of Pharmacology, Medical College of Wisconsin, Milwaukee, WI; the Department of Cellular Biology, Medical College of Wisconsin, Milwaukee, WI; and the Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI.
GPVI is a 62-kDa membrane glycoprotein expressed in noncovalent association with the Fc receptor  chain on human and murine platelets and serves as the major activating receptor for collagen. GPVI-specific antibodies have the capacity to specifically deplete GPVI from mouse and human platelets in vivo, rendering them unresponsive to collagen and GPVI-specific agonists. Such antibodies do not remove GPVI from noncirculating platelets in vitro, however, making it difficult to evaluate their antithrombotic potential and mechanism of action, particularly in human platelets. We devised a model system in which human platelets are introduced into the retroorbital plexus of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, allowed to circulate, and evaluated for the effects of GPVI-specific murine monoclonal antibodies (mAbs) on platelet survival and function. GPVI-specific mAbs triggered depletion of GPVI from human, but not murine, platelets. Soluble truncated human GPVI appeared concomitantly in mouse plasma. GPVI-depleted human platelets had markedly diminished responses to GPVI-specific agonists and unexpectedly exhibited somewhat depressed responses to G-protein–coupled agonists. The ability to evaluate in living mice the in vivo function and survival of circulating human platelets may prove valuable for determining mechanisms of antibody-mediated platelet passivation and aid in the development of novel anti-platelet therapeutics.
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