Activating effects of GPIIb/IIIa blockers: an intrinsic consequence of ligand-mimetic properties.

Intrinsic Consequence of LigandMimetic Properties To the Editor: An intrinsic activating property of GPIIb/IIIa blockers as first described by us in 19981 is widely discussed as one potential contributing factor for the disappointing outcome of trials with oral GPIIb/IIIa blockers. In a recent article in Circulation, Frelinger et al2 question the existence of an activating property of GPIIb/IIIa blockers. However, several research groups were able to extend our knowledge about the activating effects of GPIIb/IIIa blockers,3,4 a fact that was not discussed by Frelinger et al.2 In addition, the authors’ own data2 provide evidence for the existence of an intrinsic activating property of GPIIb/IIIa blockers. In Figure 3, fibrinogen binding is induced by abciximab with a dose dependency typical for the intrinsic activating property of GPIIb/IIIa blockers, revealing maximal induction of fibrinogen binding at low concentrations of abciximab. The intrinsic activating effect of GPIIb/IIIa blockers may be more prominent if platelets are preactivated, as for example, by thrombin.2 Indeed, preactivation by low concentrations of ADP has been shown to reveal the platelet-activating effect of GPIIb/IIIa blockers.3 During the use of oral GPIIb/IIIa blockers, antithrombins are generally not given and thus platelet activation by GPIIb/IIIa blockers may be unmasked. Indeed, platelet activation has been reported in patients receiving oral GPIIb/IIIa blockers.4 As in other integrins, outside-in signaling by binding of ligands or ligand-mimetics to GPIIb/IIIa is expected and has indeed been described.5 Activation of the GPIIb/IIIa integrin by ligand binding, including ligand-mimetic agents, is well in line with established integrin-signaling mechanisms. Our finding of a conformational change of the GPIIb/IIIa molecule transforming it to a receptor competent for fibrinogen binding, after association and dissociation of GPIIb/IIIa blockers, was confirmed by Frelinger et al2 (Figure 5) for 2 of the 3 commercially available agents. The most important question that has to be addressed now is whether there is a reverse conformational change of GPIIb/IIIa to a receptor not competent to bind fibrinogen. This reversibility may be dependent on temperature, ion concentrations (prone to experimental differences based on the variance of anticoagulants used), comedications, and platelet activation status. These issues have to be addressed before a conclusion on the potential role of the intrinsic activating effect of GPIIb/IIIa blockers for the clinical situation can be drawn.