Clopidogrel – a Platelet Inhibitor which Inhibits Thrombogenesis in Non-Anticoagulated Human Blood Independently of the Blood Flow Conditions

Abstract

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.

Modulation of thrombotic responses in moderately stenosed arteries by cigarette smoking and aspirin ingestion.

“…This physical effect was apparently enhancing the platelet-collagen adhesion at 2600 s" 1 and probably also at 650 s~\ even though aspirin had only marginal effect on the thrombus volume. Similar findings were previously observed in studies with the platelet inhibitors clopidogrel 16 and the reversible TxA 2 receptor antagonist HN-11500 17 in the same experimental model and at similar experimental conditions.…”

“…16 Increased urinary excretion of the stable thromboxane metabolite 2,3-dinorthromboxane R2 has been observed in smokers of both sexes, 7 suggesting that cigarette smoking may increase platelet reactivity and vasoconstnction through augmented TxA 2 formation. 28 The present study was carried out to investigate whether cigarette smoking affected collagen-induced thrombogenesis in flowing nonanticoagulated human blood and to quantify the effect of aspirin-blocked TxA 2 synthesis on thrombus formation.…”

“…The thrombus volume in blood from cigarette-smoking individuals was S everal prospective studies have demonstrated that cigarette smoking is a major risk factor for cardiovascular disease. 16 Enhanced thromboxane A 2 (TxA 2 ) synthesis in platelets has been implicated as a possible source of risk, since biochemical studies have shown increased TxA 2 production in cigarette smokers. 7 The TxA 2 molecule is a potent vasoconstrictor and platelet aggregation agonist.…”

Acute Antithrombotic Effect of a Front-Loaded Regimen of Clopidogrel in Patients With Atherosclerosis on Aspirin

“…23 Prothrombin fragment F1ϩ2 plasma levels were similar throughout the study and between the groups. This is consistent with other published data 24,25 showing that thrombin generation is not directly reduced with thienopyridines.…”

“…31 To the best of our knowledge, only 1 study focused on the inhibition of thrombogenesis by clopidogrel in humans. 24 In this study, a standard regimen of clopidogrel significantly inhibited thrombus formation in healthy male subjects after 2 weeks of a standard regimen of clopidogrel. We found that the inhibition was significant at day 8 in patients with atherosclerosis receiving chronic aspirin therapy when a standard regimen of clopidogrel was used.…”