Clot Lysis in a Primate Model of Peripheral Arterial Occlusive Disease with Use of Systemic or Intraarterial Reteplase: Addition of Abciximab Results in Improved Vessel Reperfusion

Abstract

This study was designed to compare the ability of reteplase (a fibrinolytic agent) alone or in combination with abciximab (a monoclonal antibody antagonist of platelet glycoprotein IIb/IIIa) to achieve and sustain vessel patency in an acute model of peripheral arterial occlusive disease in cynomolgus monkeys. Total arterial occlusion was induced in the femoral arteries of 32 cynomolgus monkeys (eight groups of four) by endothelial injury and injection of thrombin-treated autologous blood. Reteplase was administered by intravenous bolus dose or by intraarterial infusion at the site of the clot. Abciximab was administered as a single weight-adjusted intravenous bolus dose. Platelet activity was measured by ex vivo platelet aggregation before and after abciximab treatment. Different groups of animals received sequential partial doses of reteplase with or without increasing doses of abciximab until either the weight-adjusted human dose equivalent of reteplase was reached or vessel recanalization was achieved. Animals receiving reteplase-only regimens demonstrated variability in the times required for reperfusion and the permanence of the effect. The coadministration of abciximab at doses of the antibody that achieved near or full inhibition of platelet function generally decreased the time to reperfusion and resulted in more consistent and sustained vessel patency. In the case of systemic intravenous reteplase, the coadministration of abciximab resulted in effective reperfusion of thrombosed vessels at decreased doses of the lytic agent. Reteplase administered systemically or at the site of thrombotic occlusion restored blood flow for periods of varying duration in monkeys with acute femoral artery thrombosis. The coadministration of systemic intravenous abciximab to intravenous or intraarterial reteplase allowed the use of lower doses of fibrinolytic agent with more accelerated and sustained reperfusion.