Summary
In the present study we have investigated the effect of a 100 mg single oral dose
of a newly developed thromboxane A2 receptor antagonist on collagen-induced thrombogenesis in flowing human non-anticoagulated
blood. Blood was drawn directly from an antecubital vein over immobilised collagen
type III fibrils on a cover slip placed in a parallel-plate perfusion chamber. Shear
rates at the collagen surface were characteristic 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 platelets, β-thromboglobulin (β-TG), were measured
immediately distal 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 degranulated
platelets at 650 s−1. The β-TG plasma levels were also reduced at both shear rates by the HN-11500 ingestion.
The platelet-collagen adhesion was significantly enhanced at both shear rates. This
was apparently a consequence of higher platelet concentrations at the collagen surface,
because fewer platelets were consumed by the thrombi after the drug ingestion. In
contrast, the coagulation, as measured by fibrin deposition and FPA plasma levels,
was not significantly affected by HN-11500.
Thus, it appears that the thromboxane A2 receptor antagonist HN-11500 reduces the thrombotic response by primarily impairing
the platelet function at arterial blood flow conditions, and particularly at high
wall shear rates.
