Evidence of platelet activation during treatment with a GPIIb/IIIa antagonist in patients presenting with acute coronary syndromes

Abstract

Orbofiban is both an antagonist and a partial agonist of platelet GPIIb/IIIa. At low concentrations of the drug, this partial agonist activity may enhance platelet aggregation. Along with suboptimal plasma drug levels, these findings may help explain the lack of efficacy seen with orbofiban in patients with ACS.

Impact of clinical syndrome acuity on the differential response to 2 glycoprotein IIb/IIIa inhibitors in patients undergoing coronary stenting. The TARGET trial

“…These observations may be explained by clopidogrel-mediated inhibition of stent-induced ␣ IIb␤3 receptor activation. 29 These data also collectively suggest that maximal antiplatelet activity is required in clinical syndromes associated with heightened platelet activation [15][16][17] and that the variance in pharmacodynamic potency between abciximab and tirofiban with the drug regimens used in the present study might be mitigated by the antiplatelet effects of thienopyridines.…”

“…Because protection from periprocedural events by GP IIb/IIIa receptor blockade may be dependent on the degree of platelet inhibition achieved, 21 the findings of the present study are concordant with recent reports describing lesser early pharmacodynamic potency of tirofiban relative to abciximab with the drug regimens studied in this trial, 10,22 a condition that may be exacerbated by GP IIb/IIIa receptor up-regulation in ACS. [15][16][17] A notable dissociation between periprocedural myonecrosis and 6-month mortality was observed in this large trial. Despite the fact that an additional 39 ACS patients treated with tirofiban rather than abciximab developed an MI, the 6-month mortality in these 2 groups was identical; there were 20 deaths after tirofiban versus 20 after abciximab.…”

“…[1][2][3][4][5][6][7] Individually, different GP IIb/IIIa inhibitors vary in the extent and time course of platelet inhibition achieved and in their specificity for the ␣ IIb␤3 integrin receptor. 8 -14 Furthermore, because clinical syndromes characterized by plaque rupture and thrombus formation are associated with systemic platelet activation, [15][16][17] a differential response to GP IIb/IIIa inhibitors of varying potency might be anticipated in patients with unstable angina compared with stable ischemic heart disease.…”

Integrins as therapeutic targets: lessons and opportunities

“…This has also been seen with oral α IIb β 3 antagonists, for which low doses were shown to induce platelet aggregation while higher doses were inhibitory 182 . In both cases, the problems appear to arise during trough periods.…”

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…However, subtherapeutic doses of GPIIb/IIIa antagonists especially orally active compounds have been shown to have deleterious outcomes on patients Quinn et al, 2002). While this outcome may be the result of partial agonism at sub-therapeutic concentrations (Cox et al, 2000), leading to 'platelet escape' and thrombus formation, a pro-inflammatory profile of GPIIb/IIIa antagonists is apparent. In vitro studies reveal that both monoclonal antibodies and non-peptide inhibitors increase platelet P-selectin expression and plateletleukocyte complexes (Caron et al, 2002;Klinkhardt et al, 2002), as well as the release of CD40L and tissue factor (Zhao et al, 2003) and may explain the negative clinical effects of GPIIb/IIIa antagonists.…”