Relative antithrombotic effect of soluble GPVI dimer compared with anti-GPVI antibodies in mice.
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.
Grüner
Sabine
S
Rudolf Virchow Center, Deutsch Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Würzburg, 97078 Würzburg, Germany.
Prostredna
Miroslava
M
Koch
Martina
M
Miura
Yoshiki
Y
Schulte
Valerie
V
Jung
Stephanie M
SM
Moroi
Masaaki
M
Nieswandt
Bernhard
B
D000818:Animals; D001666:Binding Sites, Antibody; D001667:Binding, Competitive / Q000502:physiology; D020212:Carotid Artery Injuries / Q000097:blood / Q000276:immunology / Q000628:therapy; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D019281:Dimerization; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism; D007275:Injections, Intravenous; D007518:Isoantibodies / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010973:Platelet Adhesiveness / Q000502:physiology; D010974:Platelet Aggregation / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D012995:Solubility; D013927:Thrombosis / Q000097:blood / Q000276:immunology / Q000517:prevention & control
D005343:Fibrinolytic Agents; D007141:Immunoglobulin Fc Fragments; D007518:Isoantibodies; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; C098341:platelet membrane glycoprotein VI; D003094:Collagen