SummaryThe goal of the present study was to investigate the effect of 7 and 14 days of daily oral administration of 75 mg clopidogrel on collagen-induced thrombogenesis in flowing non-anticoagulated human blood. Blood was drawn directly from an antecubital vein over immobilised collagen type III fibrils positioned in a parallel-plate perfusion chamber. The wall shear rates at the collagen surface were those characteristic for veins (100 s−1), and for medium sized (650 s−1) and moderately stenosed (2600 s−1) arteries.Clopidogrel ingestion reduced the thrombus volume significantly (p <0.05) at 100 and 2600 s−1 (39 and 51% respectively). The β-thromboglobulin plasma levels were reduced concomitantly. However, it was not possible to measure accurately the thrombus volume at 650 s−1, due to loose packing of the platelet thrombi. Transmission electron micros-copy substantiated this observation and showed that clopidogrel profoundly reduced the platelet degranulation process (p <0.005). The inhibitory effect of clopidogrel on platelet consumption by the growing thrombi resulted apparently in higher platelet concentration at the collagen surface, which enhanced the platelet-collagen adhesion at all three shear rates (p <0.05). Despite the low deposition of fibrin on collagen, clopidogrel reduced significantly the fibrinopeptide A plasma levels and the fibrin deposition at shear rates below 650 s−1. This was apparently a consequence of the reduced platelet recruitment and the lower activation of platelets, since activated platelets in thrombi promote deposition of fibrin.Thus, it appears that clopidogrel inhibits thrombus formation in human blood primarily by interfering with platelet-platelet binding and the inhibition is effective independently of the wall shear rate.
SummaryIn 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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