Glycoprotein IIb/IIIa inhibitors increase COAT-platelet production in vitro.

Platelets activated simultaneously with thrombin and collagen reveal a subpopulation of cells that express on their surfaces high levels of several alpha-granule proteins, including factor V and fibrinogen; these COAT platelets (collagen and thrombin-activated platelets) represent roughly 30% of the total population. Evidence of enhanced stability of proteins on the COAT-platelet surface was provided by the observation that PAC-1, a mAB recognizing the activated form of glycoprotein (GP) IIb/IIIa, did not inhibit fibrinogen binding to COAT-platelets. We therefore undertook a systematic evaluation of the effects of other GP IIb/IIIa inhibitors on the production of COAT platelets. Not only did GP IIb/IIIa antagonists fail to inhibit the retention of fibrinogen on COAT-platelets, but several actually increased the absolute percentage of COAT platelets produced. The increases over control values in the presence of eptifibatide, tirofiban, and DMP-802 were 1.36-, 1.20-, and 1.05-fold, respectively (P <.01 for each comparison). COAT-platelet production in the presence of abciximab was not significantly affected. However, platelet activation with thrombin plus ALB6, an Fc-receptor agonist, produces a product, referred to as FcRT platelets, that is indistinguishable from COAT platelets; all 4 GP IIb/IIIa antagonists tested potentiated formation of FcRT platelets. These findings indicate that fibrinogen binding to COAT platelets and FcRT platelets is not affected by available GP IIb/IIIa inhibitors. More importantly, our study demonstrates a potentiation of COAT-platelet production by some GP IIb/IIIa antagonists that may be relevant to the observation that long-term administration of orally available GP IIb/IIIa inhibitors not only failed to protect patients but actually increased the frequency of acute coronary events.