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CLINICAL RESEARCH: PLATELET INHIBITION AND REPERFUSION

Short-term intravenous eptifibatide infusion combined with reduced dose recombinant tissue plasminogen activator inhibits platelet recruitment at sites of coronary artery injury

Mark H. Rubenstein, MD^*, Aloke V. Finn, MD^*, Robert C. Leinbach, MD, FACC^*, Stanley Hollenbach, PhD, H. Thomas Aretz, MD^*, Renu Virmani, MD and Herman K. Gold, MD, FACC^*,*

^* Cardiac Unit and the Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
Millennium Pharmaceuticals Inc., Boston, Massachusetts, USA
Armed Forces Institute of Pathology, Washington, D.C., USA

Manuscript received June 19, 2002; revised manuscript received July 10, 2003, accepted August 26, 2003.

^* Reprint requests and correspondence: Dr. Herman K. Gold, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.
hgold{at}partners.org

Presented at the 51st Scientific Session of the American College of Cardiology, March 17–20, 2002, Atlanta, Georgia.

OBJECTIVES: This study was designed to determine in a dog model of coronary thrombosis whether short-term eptifibatide (Ep) combined with low-dose plasminogen activator (rt-PA) inhibits platelet recruitment at sites of endothelial damage after normalization of platelet function.

BACKGROUND: Ep plus reduced-dose rt-PA has not previously been shown to render a recanalized coronary artery resistant to platelet recruitment after normalization of platelet function.

METHODS: Inhibition of platelet recruitment was studied by scanning electron microscopy (SEM) in a canine model of left anterior descending (LAD) thrombosis. In phase I treatment groups were: 1) Ep (n = 6); 2) Ep + rt-PA (n = 6); 3) rt-PA (n = 6); and 4) placebo (n = 4). Coronary blood flow was monitored and LAD segments excised for SEM after 90-min infusion of study drug. In phase II, dogs were randomized to Ep alone (n = 5) or to Ep + rt-PA (n = 5). Coronary blood flow was monitored during and 120 min after cessation of drug when platelet function had returned to normal and LAD segments were excised.

RESULTS: All animals except placebo showed reflow. In phase I, SEM showed an absence of platelet aggregates with Ep alone and with Ep + rt-PA, but not with rt-PA alone. In phase II, SEM showed an intimal surface devoid of mural thrombus and platelet aggregates only in Ep + rt-PA treated arteries. Ep-alone treated arteries showed new platelet aggregates at sites of residual mural thrombus.

CONCLUSIONS: Short-term infusion Ep plus low-dose rt-PA acutely neutralizes the ability of damaged endothelial surfaces to recruit new platelets by inhibiting platelet aggregation and eliminating residual mural thrombus.

Abbreviations and Acronyms   ACT = activated clotting time   Ep = eptifibatide   GP = glycoprotein   IV = intravenous   LAD = left anterior descending   MI = myocardial infarction   rt-PA = tissue plasminogen activator   SEM = scanning electron microscopy