GLYCOPROTEIN IIB IIIA BLOCKADE INHIBITS PLATELET-MEDIATED FORCE DEVELOPMENT AND REDUCES GEL ELASTIC-MODULUS/

The effects of GPIIb/IIIa blockade on clot retraction were studied uti lizing an instrument which directly measures force produced by platele ts. GPIIb/IIIa disruption by calcium chelation, and GPIIb/IIIa blockad e by peptides and anti-GPIIb/IIIa antibodies were investigated. One mM EDTA suppressed ADP-induced platelet aggregation by 72% and reduced f orce developed at 1200 s by 33%. At 234 mu M, the tetrapeptide Arg-Gly -Asp-Ser (RGDS) suppressed platelet aggregation by 74%, reduced force at 1200 s by 45% and reduced gel elastic modulus by 19%. Al 10 mu M th e peptide D-Arp-Gly-L-Asp-L-Try (D-RGDW) completely suppressed platele t aggregation, reduced force development by 38% and reduced gel elasti c modulus by 29%. At 0.133 mu M, monoclonal anti-GPIIIa antibody (AP-3 ) reduced force development by 74% and reduced gel modulus by 60%. Mur ine antiGPIIb/IIIa antibodies 10E5 and 7E3 markedly suppressed force d evelopment. At 0.133 mu M, 10E5 reduced force by 89% and reduced gel m odulus by 67%. At 0.053 mu M, 7E3 completely stopped force development and reduced gel modulus by 46%. Platelet aggregation was blocked by 0 .027 mu M 7E3. Selective GPIIb blockade by antibodies did not affect f orce development. None of the agents studied altered fibrin structure as monitored by effects on fibrin mass/length ratios. Suppression of p latelet aggregation occurred at inhibitor concentrations substantially lower than those required to suppress for ce development. Complete su ppression of platelet aggregation did not assure inhibition of clot re traction probably due to profound platelet activation by thrombin, The se results indicate that inhibition of fibrin(ogen) binding to GPIIb/I IIa, either by disruption of GPIIb/IIIa or by competitive blockade, in hibits platelet mediated force development and results in clot structu res which are substantially less resistant to deformation by outside f orces.