INHIBITION OF PLATELET-MEDIATED CLOT RETRACTION BY INTEGRIN ANTAGONISTS

The effects of the platelet alpha IIb beta 3 integrin (GPIIb/IIIa) ant agonists XV459 (non-peptide), c7E3 (Fab monoclonal antibody) and DMP72 8 (cyclic peptide) as well as the alpha v beta 3 integrin antagonists, LM609 (monoclonal antibody) and XT199 (non-peptide) on clotting and p latelet-mediated clot retraction were examined. While 30 nM of XV459 h ad no significant effect on the kinetics of coagulation, platelet-medi ated clot retraction was nearly fully inhibited at this concentration (Relative Retraction Rate = 0.09). XV459 resulted in a concentration r elated-response curve. Other experiments demonstrated that platelet ag gregation 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 cont rast, DMP728, an equally potent antiaggregatory agent with an IC50 Of 20-50 nM in inhibiting platelet aggregation induced by various agonist s, was found to be a less potent inhibitor of platelet-mediated clot r etraction 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 al pha v beta 3 integrin antagonists, LM609 or XT199 were without any sig nificant effects on either platelet-mediated clot retraction or platel et aggregation. In conclusion, these data suggest a differential effic acy among different GPIIb/IIIa antagonists in inhibiting platelet-medi ated clot retraction in spite of the equivalent anti-aggregatory poten cy. Additionally, the alpha v beta 3 integrin antagonists do not affec t platelet-mediated clot retraction or aggregation. Further studies wi th the previously described alpha IIb beta 3 integrin antagonists as w ell as others revealed a distinct correlation between the Kd to restin g and activated platelets and the efficacy in inhibiting platelet-medi ated clot retraction. (C) 1998 DuPont Merck Pharmaceutical Company. Pu blished by Elsevier Science Ltd.