Figure 1. Selective inhibition of integrin a2bb3 in thrombosis. Findings published in Nature reveal two waves in integrin a2bb3 (GPIIb/IIIa; CD41/CD61) regulation associated with distinct phases of the blood clotting process. During integrin activation by thrombin [a], talin binds to a region of integrin a2bb3 that contains an EXE motif. This first regulatory wave triggers platelet adhesion to blood vessels. Following activation, integrin a2bb3 becomes accessible to clotting factors such as fibrinogen [b]. This second wave is associated with platelet aggregation. During platelet aggregation, integrin a2bb3-fibrinogen complexes are maintained but talin is displaced by guanine nucleotide binding protein (G protein) α3 (GNA13) [c]. Inhibiting GNA13 binding with a competitive, membrane-tethered, EXE motif-based peptide prevents platelet aggregation and thrombosis without increasing the risk of bleeding. Marketed integrin a2bb3 inhibitors interfere with ligand binding and formation of integrin a2bb3-fibrinogen complexes. (Figure based on Box 2 in Shattil, S.J. et al., Nat. Rev. Mol. Cell Biol. 11, 288-300; 2010.)