© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Disaggregation of In Vitro Preformed Platelet-Rich Clots by Abciximab Increases Fibrin Exposure and Promotes Fibrinolysis
Presented in part at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8–11, 1998.
From the Department of Cardiology (J.P.C., D.T.) and the Hematology Research Center (C.L.), Pitié-Salpêtrière Hospital, Paris; Research Laboratory Sainte Marie (J.P.C., J.S.), Hotel Dieu Hospital, Paris; UPS 937 (Z.M.), CNRS, Paul Brousse Hospital, Villejuif; and Hemostasis Laboratory (C.S.), Lariboisière Hospital, Paris, France.
Correspondence to J.P. Collet, MD, PhD, Department 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
Abstract—The glycoprotein IIb/IIIa receptor inhibitor abciximab has been shown to facilitate the rate and the extent of pharmacological thrombolysis with recombinant tissue plasminogen activator (rtPA) in patients with acute myocardial infarction. However, the underlying mechanisms remain not fully determined. We sought to demonstrate that this facilitating effect of abciximab could be related to its potential to modify the clot architecture and the clot physical properties. Compared with fibrin-rich clots, platelets dramatically modified the in vitro properties of the fibrin network, leading to a significant increase of the permeability (Ks) and the viscoelasticity (G') indexes but also leading to the appearance of platelet aggregates (surface area [S.ag]). These modifications resulted in a 2.6-fold decrease of the fibrinolysis rate when rtPA (1 nmol/L) was added before the initiation of clotting. Adding aspirin (100 µg/mL) or abciximab (0.068 µmol/L) before the clotting of platelet-rich clots (PRCs) lowered Ks by 50% and 70%, respectively (P<0.01), G' by 41% and 66%, respectively (P<0.01), and S.ag by 32% and 61%, respectively (P<0.01). As a consequence, the lysis speed was increased by 21% with aspirin (P<0.01) and 45% with abciximab (P<0.01). However, unlike aspirin, permeation of preformed PRCs with abciximab (0.068 µmol/L) decreased G' (37%, P<0.01), Ks (35%, P<0.001) and S.ag (25%, P=NS) and resulted in a 27% (P<0.01) increase of the lysis speed when abciximab and rtPA (0.2 µmol/L) were simultaneously permeated. This effect was found to be time dependent and was observed only with early permeation, starting within the first 10 minutes of clotting. These changes in the physical properties of the PRC architecture suggest that fibrin is removed from the platelet-fibrin aggregates and reexposed into the surrounding fibrin network, increasing rtPA access to fibrin and therefore the fibrinolysis rate. The superiority of abciximab over aspirin in accelerating fibrinolysis of forming and preformed PRCs is related to its ability to modulate the interactions of fibrinogen and fibrin with platelets. These findings provide new mechanistic information on reperfusion therapy.
Key Words: platelets • fibrin • fibrinolysis • glycoprotein IIb/IIIa inhibitors
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