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Thromb Haemost 1994; 71(01): 103-109
DOI: 10.1055/s-0038-1642391
Review Article
Schattauer GmbH Stuttgart

HN-11500 – a Novel Thromboxane A2 Receptor Antagonist With Antithrombotic Activity in Humans at Arterial Blood Flow Conditions

Helge E Roald
1   The Faculty of Medicine, University of Oslo, Oslo, Norway
,
R Marius Barstad
2   The Nycomed Bioreg A/S, Oslo, Norway
,
Anne Engen
2   The Nycomed Bioreg A/S, Oslo, Norway
,
Peter Kierulf
3   The Clinical Chemistry Department, Ullevaal University Hospital, Oslo, Norway
,
Fredrik Skjørten
4   The Department of Pathology, Ullevaal University Hospital, Oslo, Norway
,
Kjell S Sakariassen
2   The Nycomed Bioreg A/S, Oslo, Norway
› Author Affiliations
Further Information

Publication History

Received: 14 May 1993

Accepted after revision 02 September 1993

Publication Date:
12 July 2018 (online)

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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.

 

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