No abstract

No abstract

Objectives-The objective of this study was to determine whether adjunctive therapy during percutaneous coronary intervention (PCI) affects markers of systemic inflammation or platelet activation. Despite different mechanisms of action, direct-thrombin inhibition with bivalirudin during PCI provided similar protection from periprocedural and chronic ischemic complications as compared with unfractionated heparin (UFH) plus planned use of GPIIb/IIIa antagonists in the REPLACE-2 and ACUITY trials. Methods and Results-Patients undergoing nonurgent PCI of a native coronary artery were randomized to receive adjunctive therapy with bivalirudin or UFHϩeptifibatide. Interleukin (IL)-6 and C-reactive protein (CRP) transiently increased in both groups after PCI. In the UFHϩeptifibatide, but not the bivalirudin group, myeloperoxidase (MPO) levels were elevated 2.3-fold above baseline (Pϭ0.004) immediately after PCI. In an in vitro assay, heparin and to a lesser extent enoxaparin, but not bivalirudin or eptifibatide, stimulated MPO release from and binding to neutrophils and neutrophil activation. A mouse model of endoluminal femoral artery denudation was used to investigate further the importance of MPO in the context of arterial injury. Key Words: platelets Ⅲ neutrophils Ⅲ myeloperoxidase Ⅲ percutaneous coronary intervention Ⅲ adjunctive therapy A ggressive antithrombotic therapy, in particular antiplatelet therapy with glycoprotein (platelet glycoprotein [GP]) IIb/IIIa antagonists, thienopyridines, and aspirin used in conjunction with unfractionated heparin, have consistently been shown to decrease the risk of periprocedural thrombotic complications associated with percutaneous coronary interventions (PCI). 1,2 Bivalirudin, a direct thrombin inhibitor, was approved for use in PCI as an alternative to heparin before to widespread use of GPIIb/IIIa antagonists. Recently, the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 and the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trials demonstrated that bivalirudin used with GPIIb/IIIa antagonists on a provisional basis provided similar protection from periprocedural ischemic and hemorrhagic complications compared with heparin plus planned use of GPIIb/IIIa antagonists. 3,4 In the REPLACE-2 trial of low-to moderate-risk patients undergoing PCI, the primary composite end point at 30 days (incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding) occurred in 9.2% of patients in the bivalirudin group versus 10.0% of patients in the unfractionated heparin (UFH) plus GPIIb/IIIa antagonist group. 3 At 1 year, a nonsignificant trend toward lower mortality with bivalirudin was observed (1.9% in bivalirudin group and 2.5% in heparin plus GPIIb/ IIIa antagonist group). 3 The results from the ACUITY trial also suggest that in patients with acute coronary syndromes undergoing PCI, routine use of bivalirudin is associated with similar ischemic outcomes as UFH or low-molecular weight...

A B S T R A C T When human, canine, or bovine factor VIII preparations are chromatographed on 4% agarose at ionic strength 0.2, the factor VIII activity elutes as a single peak in the void volume with slight tailing. Incubation of such preparations with dilute (0.01 U/ml) highly purified thrombin results in some activation of factor VIII. Chromatography of such incubation mixtures, under the same conditions as before, results in elution of two peaks of factor VIII activity, one in the void volume and one much later with marked tailing. The void volume peak has most of the protein and some factor VIII activity. These void volume fractions also contain all the von Willebrand factor activity of thrombin-treated human factor VIII preparations and all of the platelet aggregating factor activity of thrombin-treated bovine preparations. Longer treatment with thrombin, or treatment with stronger thrombin, appears to shift much more of the procoagulant activity to the later eluting peak. Also, when the peak of factor VIII activity, found in the void volume after thrombin treatment, was again incubated with dilute thrombin, an increase in factor VIII activity occurred. Chromatography of this incubation mixture demonstrated only a small amount of activity in the void volume, while the bulk of the activity was present in the second peak. On the other hand, thrombin treatment of factor VIII activity from peak 2 caused a rapid decline of activity instead of a further increase. It is proposed that the residual factor VIII activity found in the void volume represents unreacted factor