HN-11500 - A NOVEL THROMBOXANE-A(2) RECEPTOR ANTAGONIST WITH ANTITHROMBOTIC ACTIVITY IN HUMANS AT ARTERIAL BLOOD-FLOW CONDITIONS

In the present study we have investigated the effect of a 100 mg singl e oral dose of a newly developed thromboxane A2 receptor antagonist on collagen-induced thrombogenesis in flowing human non-anticoagulated b lood. Blood was drawn directly from an antecubital vein over immobilis ed collagen type III fibrils on a cover slip placed in a parallel-plat e perfusion chamber. Shear rates at the collagen surface were characte ristic for medium sized (650 s-1) and moderately stenosed (2,600 s-1) arteries. Blood-collagen interactions were morphologically quantified as platelet-collagen adhesion, fibrin deposition and thrombus volume. Activation peptides of coagulation, fibrinopeptide A (FPA), and of pla telets, beta-thromboglobulin (beta-TG), were measured immediately dist al to the perfusion chamber. HN-11500 ingestion reduced significantly the thrombus volume by 32% at 2,600 s-1, but not at 650 s-1. However, transmission electron microscopy revealed loosely packed and less degr anulated platelets at 650 s-1. The beta-TG plasma levels were also red uced at both shear rates by the HN-11500 ingestion. The platelet-colla gen adhesion was significantly enhanced at both shear rates. This was apparently a consequence of higher platelet concentrations at the coll agen surface, because fewer platelets were consumed by the thrombi aft er the drug ingestion. In contrast, the coagulation, as measured by fi brin deposition and FPA plasma levels, was not significantly affected by HN-11500. Thus, it appears that the thromboxane A2 receptor antagon ist HN-11500 reduces the thrombotic response by primarily impairing th e platelet function at arterial blood flow conditions, and particularl y at high wall shear rates.