Abciximab, Eptifibatide, and Tirofiban Exhibit Dose-dependent Potencies to Dissolve Platelet Aggregates

Abstract

Platelet GPIIb/IIIa antagonists are not only used to prevent platelet aggregation, but also in combination with thrombolytic agents for the treatment of coronary thrombi. Recent data indicate a potential of abciximab alone to dissolve thrombi in vivo. We investigated the potential of abciximab, eptifibatide, and tirofiban to dissolve platelet aggregates in vitro. Adenosine diphosphate (ADP)-induced platelet aggregation could be reversed in a concentration-dependent manner by all three GPIIb/IIIa antagonists when added after the aggregation curve reached half-maximal aggregation. The concentrations chosen are comparable with in vivo plasma concentrations in clinical applications. Disaggregation reached a maximum degree of 72.4% using 0.5 microg/ml tirofiban, 91.5% using 3.75 microg/ml eptifibatide, and 48.4% using 50 microg/ml abciximab (P < 0.05, respectively). A potential fibrinolytic activity of the GPIIb/IIIa antagonists was ruled out by preincubation with aprotinin or by a plasma clot assay. A stable model Chinese hamster ovary (CHO) cell line expressing the activated form of GPIIb/IIIa was used to confirm the disaggregation capacity of GPIIb/IIIa antagonists found in platelets. Not only abciximab, but also eptifibatide and tirofiban have the potential to disaggregate newly formed platelet clusters in vitro. Because enzyme-dependent fibrinolysis does not appear to be involved, competitive removal of fibrinogen by the receptor antagonists is the most likely mechanism.

GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice

“…Our study extends the hierarchical model proposed by Stalker et al 30 by demonstrating that once the thrombus occludes ;50% of the artery, platelet cross-linking in its external layer occurs in a GpIba-VWF dependent manner. This model helps reconcile the lack of efficiency of GpIIb/IIIa inhibitors to treat acute occlusive thrombosis, 4 despite their efficiency to disaggregate fresh platelet aggregates 31 and nonocclusive thrombi. 6 This model also provides an explanation for the thrombolytic effect of GpIba-VWF blockade after occlusive thrombosis in guinea pigs and confirms this finding in another model of MCA thrombosis.…”

Intracoronary Eptifibatide Bolus Administration During Percutaneous Coronary Revascularization for Acute Coronary Syndromes With Evaluation of Platelet Glycoprotein IIb/IIIa Receptor Occupancy and Platelet Function

“…These studies have demonstrated that eptifibatide disaggregates thrombi more effectively at concentrations with an order of magnitude greater than that usually achieved with standard intravenous administration. 5,6 Furthermore, recent studies have shown that higher concentrations of a GP IIb/IIIa antagonist are necessary to effectively disaggregate stable, aged aggregates compared with newly formed thrombi. Figure 5.…”

“…GP IIb/IIIa antagonists at high local concentrations may enhance thrombus disaggrega-tion by disrupting platelet crosslinking. 5,6 Indeed, higher levels of platelet GP IIb/IIIa receptor occupancy (RO) with eptifibatide have been associated with improved myocardial perfusion among patients with ST-elevation myocardial infarction. 7 Thus, intracoronary administration of eptifibatide may result in a high local concentration, which may lead to increased levels of platelet GP IIb/IIIa RO, destabilization of platelet aggregates, and promotion of thrombus disaggregation in the epicardial artery and microvasculature, thereby improving myocardial perfusion.…”

Local Intra-Arterial Eptifibatide for Intraoperative Vessel Thrombosis during Aneurysm Coiling

“…As a result, emergency surgery can be performed almost immediately following the administration of eptifibatide but has to be postponed for 12-48 hours following abciximab treatment. Eptifibatide, as a lower molecular-weight compound than abciximab is able to penetrate the thrombus easier through the fibrin-fibrinogen network that is formed on the platelet aggregates, 14 and it is responsible for thrombocytopenia less often than abciximab. 16 Its antiplatelet effect is not inhibited by unfractionated heparin as is that of abciximab.…”