ROLE OF PLATELET GPIIB IIIA RECEPTORS IN THE MODULATION OF PLATELET PLASMINOGEN-ACTIVATOR INHIBITORS TYPE-1 (PAI-1) RELEASE/

This study was undertaken to determine the role of platelet glycoprote in (GP) IIb/IIIa receptors in the modulation of plasminogen activator type-1 (PAI-1) release from human platelets as compared to other plate let functions. To address this issue, the effect of various agonists o n human platelet aggregation, [I-125]fibrinogen binding and the releas e of PAI-1 was examined in normal and Glanzmann's thrombasthenic (GT) platelets. In control subjects, maximum platelet aggregation and PAI-1 secretion were observed within 5 min in response to the different ago nists including thrombin, collagen, adenosine diphosphate (ADP), and a rachidonic acid. Agonist-induced platelet GpIIb/IIIa receptor activati on was confirmed by [I-125]fibrinogen binding analysis. In contrast, p latelets from GT subjects demonstrated a lack of fibrinogen binding an d a lack of an aggregatory response to all agonists tested except to t he GPIb- mediated aggregation induced by ristocetin. However, GT plate lets demonstrated normal responsiveness in secreting PAI-1 in response to the various agonists. Similarly, when platelet GpIIb/IIIa receptor s were blocked in normal platelets by the tripeptide Arg-Gly-Asp (RGD) or the tetrapeptide Arg-Gly-Asp-Ser (RODS) at 10(-3) M, agonist-induc ed platelet aggregation and fibrinogen binding were blocked, but plate let PAI-1 release was not blocked. Furthermore, flow cytometric analys is using dual fluorescence markers for the platelet GPIIb/IIIa membran e receptors (FITC-labeled cyclic RGD analog, XL086) and for the alpha granule (PE-monoclonal antibody for P-selectin) demonstrated a dissoci ation between the platelet GPIIb/IIIa receptors and granular secretion . These results suggest a lack of a role for platelet GpIIb/IIIa recep tors in the modulation of platelet PAI-1 release.