An insight into arterial thrombosis?

Abstract

The clinical importance of the interaction between collagen and platelets is difficult to overstate, given that collagen-induced platelet activation could be the key primary event that triggers arterial thrombosis. Investigation of this interaction is complicated not only by the diversity and complexity of the activating ligand, but also by the growing awareness that there are many surface receptors on the platelet that interact with collagen. It is currently believed that platelets adhere to collagen via the integrin α2β1 followed by activation of the platelet as a result of collagen binding to the non-integrin GPVI, a transmembrane protein and member of the immunoglobulin superfamily of receptors that signals via the FcR γ-chain. A recent report1xExpression and function of the mouse collagen receptor glycoprotein VI is strictly dependent on its association with the FcRγ<f-chain. Nieswandt, B. et al. J. Biol. Chem. 2000; 275: 23998–24002Crossref | PubMed | Scopus (150)See all References1 promises to facilitate further the dissection of this complex collagen–platelet interaction.Nieswandt et al.1xExpression and function of the mouse collagen receptor glycoprotein VI is strictly dependent on its association with the FcRγ<f-chain. Nieswandt, B. et al. J. Biol. Chem. 2000; 275: 23998–24002Crossref | PubMed | Scopus (150)See all References1 have developed an antibody ( JAQ1) to a 60 kDa murine platelet surface protein, which they claim is the first monoclonal antibody to GPVI. JAQ1 itself did not activate platelets, but it did selectively inhibit collagen-induced platelet activation, whereas crosslinking of the bound antibody resulted in rapid platelet activation. GPVI signals in response to collagen as a consequence of clustering and the bringing together of the FcR γ-chains. Hence, these data suggest that JAQ1 recognizes GPVI, and only causes activation following addition of crosslinking antibody. Not surprisingly, platelets from FcR γ-chain knockout mice, which do not aggregate in response to collagen, did not aggregate following crosslinking of the antibody either. However, it is of interest to note that JAQ1 itself failed to bind to these platelets, which suggests that the γ-chain is an absolute requirement for the expression of GPVI in normal platelets.These data are clearly of interest for those in the platelet collagen receptor field because non-activating monoclonal antibodies are valuable means for selectively blocking receptors. JAQ1 will, therefore, prove to be a powerful tool for the investigation of the role of GPVI in murine platelet activation. Although these data clearly support the view that GPVI is a major receptor mediating collagen-induced platelet activation, JAQ1 might also assist in revealing whether other collagen receptors (including α2β1, p65, a receptor specific for collagen type I, and CD36) can generate signals in response to collagen. Furthermore, the role of GPVI in models of thrombosis could be investigated using JAQ1, with the possibility of identifying it as a novel target for therapeutic intervention in thrombotic disease. It will be of interest to see if JAQ1 has a profile in human platelets similar to that in mice. If so, it will not only assist in unlocking a complex pharmacological puzzle but also potentially facilitate the identification of a more effective way of treating a major cause of death and morbidity in the Western world.