Abstract
Platelet glycoprotein VI (GPVI) acts as a decisive collagen receptor in atherothrombosis.
Besides collagen, injured atherosclerotic plaques expose tissue factor (TF) that triggers
fibrin formation. Two recent studies reported that platelet GPVI also functions as
fibrin receptor, which would importantly widen the mode of action of GPVI-targeted
antithrombotic drugs. We studied the binding of two GPVI fusion proteins to fibrin
under static and arterial flow conditions. Fibrin was prepared from purified fibrinogen
or generated more physiologically from endogenous fibrinogen by coagulating plasma
with thrombin. Fibrin formation was also triggered by exposing TF-coated surfaces
or human atherosclerotic plaque slices to arterially flowing blood. By binding studies
and advanced optical imaging, we found that recombinant dimeric GPVI-Fc fusion proteins
with Fc from either IgG1 (GPVI-Fc1) or IgG2 (GPVI-Fc2) bound to collagen fibres, but
neither to fibrin prepared from purified fibrinogen obtained from three suppliers,
nor to physiological fibrin formed by thrombin in plasma or triggered by exposing
TF or atherosclerotic plaque slices to arterially flowing blood. Our findings do not
support a role of dimeric platelet GPVI as receptor for fibrin. This is important
for the understanding of plaque-triggered platelet thrombus formation and is clinically
relevant for future GPVI-targeting therapies with recombinant GPVI-Fc and anti-GPVI
antibodies.
Keywords
GPVI - collagen receptor - targeting drugs - GPVI-Fc - fibrin - atherothrombosis
