Inhibition of platelet-mediated clot retraction by integrin antagonists

The effects of the platelet alpha IIb beta 3 integrin (GPIIb/IIIa) antagonists XV459 (non-peptide), c7E3 (Fab monoclonal antibody) and DMP728 (cyclic peptide) as well as the alpha v beta 3 integrin antagonists, LM609 (monoclonal antibody) and XT199 (non-peptide) on clotting and platelet-mediated clot retraction were examined. While 30 nM of XV459 had no significant effect on the kinetics of coagulation, platelet-mediated clot retraction was nearly fully inhibited at this concentration (Relative Retraction Rate = 0.09). XV459 resulted in a concentration related-response curve. Other experiments demonstrated that platelet aggregation was maximally inhibited at XV459 concentrations ranging from 30-50 nM. Similarly, c7E3 demonstrated comparable inhibitory efficacy in inhibiting either clot retraction or platelet aggregation. In contrast, DMP728, an equally potent antiaggregatory agent with an IC50 Of 20-50 nM in inhibiting platelet aggregation induced by various agonists, was found to be a less potent inhibitor of platelet-mediated clot retraction with a half-maximal inhibition of clot retraction at similar to 0.7 mu M, and maximum effects at concentrations of 10 mu M. The alpha v beta 3 integrin antagonists, LM609 or XT199 were without any significant effects on either platelet-mediated clot retraction or platelet aggregation. In conclusion, these data suggest a differential efficacy among different GPIIb/IIIa antagonists in inhibiting platelet-mediated clot retraction in spite of the equivalent anti-aggregatory potency. Additionally, the alpha v beta 3 integrin antagonists do not affect platelet-mediated clot retraction or aggregation. Further studies with the previously described alpha IIb beta 3 integrin antagonists as well as others revealed a distinct correlation between the Kd to resting and activated platelets and the efficacy in inhibiting platelet-mediated clot retraction. (C) 1998 DuPont Merck Pharmaceutical Company. Published by Elsevier Science Ltd.