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      Combination Therapy With Abciximab Reduces Angiographically Evident Thrombus in Acute Myocardial Infarction : A TIMI 14 Substudy

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          Abstract

          Background —Use of abciximab in combination with administration of thrombolytics has been shown to improve epicardial and microvascular coronary blood flow in acute myocardial infarction (AMI). As a potential mechanism, we hypothesized that combination therapy would reduce angiographically evident thrombus (AET) and would increase lumen diameter compared with thrombolytic monotherapy.

          Methods and Results —Patients who received combination therapy in TIMI 14 (low-dose thrombolytic plus abciximab, n=732) were compared with patients who received thrombolytic monotherapy without abciximab in the TIMI 4, 10A, 10B, and 14 trials (n=1662). Thrombus burden was assessed 90 minutes after treatment, and quantitative angiography was performed in an angiographic core laboratory by investigators blinded to treatment assignment. The frequency of AET was reduced in patients who received abciximab combination therapy compared with thrombolytic monotherapy (26.6% versus 35.4%, P <0.001). Similar findings were observed when the analysis was restricted to patients with patent arteries (14.7% versus 20.8%, P =0.001). Residual percent diameter stenosis at 90 minutes was also improved in the abciximab therapy group both in patent arteries (64.6±16.6 versus 68.3±14.8, P <0.001) and between patent and occluded arteries (69.3±19.5 versus 73.8±17.9, P <0.001). The absence of AET was associated with an increased frequency of >70% ST-segment resolution by 90 minutes (37.2%, 110/296 versus 18.9%, 54/286, P <0.001).

          Conclusions —Compared with thrombolytic monotherapy, combination therapy with abciximab reduces AET, which in turn is associated with reduced residual stenosis and improved ST-segment resolution in AMI. These data provide a pathophysiological link between platelet inhibition, reduced thrombus, and improvements in both epicardial and microvascular perfusion in AMI.

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          The Thrombolysis in Myocardial Infarction (TIMI) Trial: Phase I Findings

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            Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and "clinical restenosis".

            The murine/human chimeric monoclonal antibody fragment (c7E3 Fab) blocks GPIIb/IIIa and alpha v beta 3 receptors, inhibits platelet aggregation, and decreases the frequency of ischemic events after coronary artery angioplasty in patients at high risk of suffering such events. Although inhibition of platelet aggregation is likely to be the major mechanism of c7E3 Fab's effects, since activated platelets facilitate thrombin generation, it is possible that c7E3 Fab also decreases thrombin generation. To test this hypothesis, the effects of c7E3 Fab and other antiplatelet agents were tested in a thrombin generation assay triggered by tissue factor. c7E3 Fab produced dose-dependent inhibition of thrombin generation, reaching a plateau of 45-50% inhibition at concentrations > or = 15 micrograms/ml. It also inhibited thrombin-antithrombin complex formation, prothrombin fragment F1-2 generation, platelet-derived growth factor and platelet factor 4 release, incorporation of thrombin into clots, and microparticle formation. Antibody 6D1, which blocks platelet GPIb binding of von Willebrand factor, had no effect on thrombin generation, whereas antibody 10E5, which blocks GPIIb/IIIa but not alpha v beta 3 receptors decreased thrombin generation by approximately 25%. Combining antibody LM609, which blocks alpha v beta 3 receptors, with 10E5 increased the inhibition of thrombin generation to approximately 32-41%. The platelets from three patients with Glanzmann thrombasthenia, who lacked GPIIb/IIIa receptors but had normal or increased alpha v beta 3 receptors, supported approximately 21% less thrombin generation than normal platelets. We conclude that thrombin generation initiated by tissue factor in the presence of platelets is significantly inhibited by c7E3 Fab, most likely in part through both GPIIb/IIIa and alpha v beta 3 blockade, and that this effect may contribute to its antithrombotic properties.
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              St-segment resolution and infarct-related artery patency and flow after thrombolytic therapy

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                Author and article information

                Journal
                Circulation
                Circulation
                Ovid Technologies (Wolters Kluwer Health)
                0009-7322
                1524-4539
                May 29 2001
                May 29 2001
                : 103
                : 21
                : 2550-2554
                Affiliations
                [1 ]From Harvard Clinical Research Institute, Boston, Mass (C.M.G., S.A.M., S.J.M.); the University of Texas Southwestern Medical Center, Dallas, Tex (J.A.d.L.); and the Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (C.H.M., C.P.C., E.M.A., E.B.).
                Article
                10.1161/01.CIR.103.21.2550
                11382722
                f802bd7f-834c-4bd4-a775-9f9d74c7b3fa
                © 2001
                History

                Quantitative & Systems biology,Biophysics
                Quantitative & Systems biology, Biophysics

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