Early recovery of microvascular perfusion induced by t-PA in combination with abciximab or eptifibatide during postischemic reperfusion.

Silva Bertuglia,Andrea Giusti

doi:10.1186/1471-2261-2-10

Abstract

GPIIb/IIIa inhibitors abciximab and eptifibatide have been shown to inhibit platelet aggregation in ischemic heart disease. Our aim was to test the efficacy of abiciximab (Reo Pro) or eptifibatide (Integrilin) alone or in combination with plasminogen activator (t-PA) in an experimental model of ischemia reperfusion (I/R) in hamster cheek pouch microcirculation visualized by fluorescence microscopy. Hamsters were treated with saline, or abiciximab or eptifibatide or these drugs combined with t-PA infused intravenously 10 minutes before ischemia and through reperfusion. We measured the microvessel diameter changes, the arteriolar red blood cell (RBC) velocity, the increase in permeability, the perfused capillary length (PCL), and the platelet and leukocyte adhesion on microvessels. I/R elicited large increases in the platelet and leukocyte adhesion and a decrease in microvascular perfusion. These responses were significantly attenuated by abiciximab or eptifibatide (PCL:70 and 65% at 5-10 mins of reperfusion and 85 and 87% at 30 mins of reperfusion, respectively, p < 0.001) while t-PA combined with abiciximab or eptifibatide, was more effective and microvascular perfusion recovered immediately after postischemic reperfusion. Platelets are crucial in I/R injury, as shown by the treatment with abicixmab or eptifibatide, which decreased platelet aggregation in microvessels, and also decreased leukocyte adhesion in venules. Arterial vasoconstriction, decreased arterial RBC velocity and alterations in the endothelial barrier with increased permeability delayed the complete restoration of blood flow, while t-PA combined with inhibition of platelet aggregation speeded up the capillary perfusion after reperfusion.

Highlights

GPIIb/IIIa inhibitors abciximab and eptifibatide have been shown to inhibit platelet aggregation in ischemic heart disease
In t-PA in combination with gpIIa/IIIb inhibitors (tAB) and tEF groups there was a significant increase in arteriolar diameter compared with ischemia reperfusion (I/R) whereas in the groups treated with t-Pa combined with gpIIa/IIIb inhibitors, diameters maintained or increased its baseline value at the end of the observation period
We demonstrated that the inhibition of platelet aggregation is crucial in I/R injury as shown by the treatment with abicixmab or eptifibatide that decreased significantly, platelet aggregation in both arterioles and venules, and leukocyte adhesion in venules in the hamster cheek pouch microcirculation

Summary

Introduction

GPIIb/IIIa inhibitors abciximab and eptifibatide have been shown to inhibit platelet aggregation in ischemic heart disease. These are a chimeric monoclonal antibody (c7E3 Fab), Reo Pro or abciximab [5,6,7,8,9] and a cyclic heptapeptide, Integrilin or eptifibatide [10,11,12] containing a KGD sequence developed as a high affinity mimic of the fibrinogen RGD sequence, which binds to the gp IIb-IIIa receptor They have been shown to be specific for inhibition of platelet aggregation (and possibly adhesion) in human ischemic heart disease [10,13,14]. Injury to endothelial cells may suppress production of prostacyclin and promote production of tromboxaneA2 in the vessel wall causing platelets to become adherent to damaged vessels

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