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(Circulation Research. 2002;90:428.)
© 2002 American Heart Association, Inc.

Molecular Medicine

A Structural and Dynamic Investigation of the Facilitating Effect of Glycoprotein IIb/IIIa Inhibitors in Dissolving Platelet-Rich Clots

J.Ph. Collet, G. Montalescot, C. Lesty, J.W. Weisel

From the Department of Cardiology (J.Ph.C., G.M.), Pitié-Salpêtrière Hospital, Paris; the Department of Cell and Developmental Biology (J.Ph.C., J.W.W.), University of Pennsylvania School of Medicine, Philadelphia, Pa; and the Hematology Laboratory (C.L.), Pitié-Salpêtrière Hospital, Paris.

Correspondence to J.Ph. Collet, MD, PhD, Dept of Cardiology, Centre Hospitalier Universitaire Pitié-Salpêtrière, 47, boulevard de l’Hôpital, 75013 Paris, France. E-mail jean-philippe.collet{at}psl.ap-hop-paris.fr

Glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors were shown recently to facilitate the rate and the extent of pharmacological thrombolysis. However, their synergistic potential with rtPA in dissolving thrombotic vaso-occlusions is not fully understood. We have therefore developed a dynamic and structural approach for analysis of fibrinolysis to assess the inhibiting effect of platelets and the facilitating effect of GPIIb/IIIa inhibitors in dissolving platelet-rich clots (PRCs). Fluorescent rtPA was used to study the architecture of PRCs, to follow the progression of the rtPA binding front, and to measure the lysis-front velocity using confocal microscopy. Fibrinolysis resistance of PRCs was related to a reduction of both rtPA binding and lysis-front velocities of platelet-rich areas compared with platelet-poor areas (2.4±0.2 versus 3.5±0.4 µm/min for rtPA binding velocity, P=0.04, and 1.2±0.6 versus 2.8±0.2 µm/min for lysis-front velocity, P=0.008, in platelet-rich and platelet-poor areas, respectively). Fibrinolysis appeared heterogeneous, leaving platelet-rich areas un-lysed. Adding pharmacological concentrations of abciximab (0.068 µmol/L) or eptifibatide (1 µmol/L) before clotting decreased the average surface of platelet-rich areas by 64% (P=0.0005) and 72% (P=0.0007), respectively. The resulting equalization of rtPA binding rate and rtPA binding-front velocity between platelet-rich and platelet-poor areas led to a 3-fold increase of the lysis-front velocity in platelet-rich areas of either abciximab-PRC (P=0.006) or eptifibatide-PRC (P=0.03). The overall lysis rate of treated-PRC was increased by 74% compared with control-PRC (P<0.01). These results demonstrate that fibrinolysis resistance of PRCs is related primarily to the heterogeneity in the clot structure between platelet-rich and platelet-poor areas. GP IIb/IIIa inhibitors facilitate the rate and the extent of fibrinolysis by improving rtPA binding velocity and, subsequently, the lysis rate in platelet-rich areas. These findings provide new insights on the synergistic potential of GP IIb/IIIa inhibitors and fibrinolytic agents.

Key Words: fibrin • platelets • thrombolysis • fibrinolysis • inhibitors

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