Abstract 12454: Elevating Local Concentrations of GPIIb-IIIa Antagonists Intensifies Platelet Thrombus Instability
Glycoprotein IIb-IIIa (GPIIb-IIIa) antagonists have established benefit for patients with acute coronary syndromes including those undergoing percutaneous coronary intervention. Improved outcomes may be related to the ability of these antagonists to destabilize coronary thrombi, reduce microembolization, and restore vessel patency. Previous work revealed the antagonists dissociate platelet-bound fibrinogen, and that drug concentration and residence time, and the extent and age of the thrombus were key factors in thrombus stability. Intracoronary (IC) administration increases local drug concentration and residence time, thereby boosting platelet aggregate dispersal. This work investigated the strategy of exposing human platelet aggregates to extremely high local levels of GPIIb-IIIa antagonists using in vitro models. Stable collagen-induced aggregates were subjected to 2ug/mL abciximab or 2uM eptifibatide to simulate parenteral therapeutic levels, to 1.6mg/mL abciximab or 1mM eptifibatide to simulate IC administration, or to respective carrier controls. IC concentrations produced significantly more disaggregation than typical circulating plasma concentrations (60.1% vs. 7.4% for abcix., 41.6% vs 17.6% for eptif. at 15min) (p<0.05). Microscopy confirmed that IC concentrations produced noticeably smaller, more dispersed aggregates. Likewise, higher doses of antagonists consistently induced more disaggregation than lower doses when aggregates were aged for 30 min prior to drug addition. Addition of P2Y12 antagonists or anticoagulants had negligible effect on stable platelet-rich thrombi. In an in vitro perfusion model, mimicking IC administration with a microporous balloon catheter (Atrium Clearway RX™) significantly cleared platelet thrombus vs. control, whereas treatment at parenteral levels was ineffective. In summary, this study revealed that delivery of high localized concentrations of a GPIIb-IIIa antagonist may more effectively disaggregate pre-existing platelet-rich thrombus thereby improving recanalization and reducing the extent of microembolization. Data also suggest that localized delivery of these agents may prove beneficial even under conditions where thrombus has become relatively stable.
- Glycoprotein iib/iiia platelet inhibitors
- Antiplatelet drugs
- Local delivery
- Interventional cardiology
- © 2011 by American Heart Association, Inc.