EFFECT OF SR121566A, A POTENT GP IIB-IIIA ANTAGONIST ON PLATELET-MEDIATED THROMBIN GENERATION IN-VITRO AND IN-VIVO

The effect of SR121566A, a new non-peptide GP IIb-IIIa antagonist was studied in vitro with regard to thrombin generation in platelet rich p lasma and in vivo on stasis-induced venous thrombosis in the rabbit. S R121566A inhibited ADP-, arachidonic acid-and collagen-induced human p latelet aggregation with IC50 values of 46 +/- 7.5, 56 +/- 6 and 42 +/ - 3 nM, respectively. In the same experimental conditions, SR121566A s trongly inhibited thrombin generation triggered by low concentrations of tissue factor. SR121566A reduced in a dose-dependent manner both th e area under the curve and the thrombin peak concentration but did not affect the lag phase (defined as the time until 10 nM thrombin was ge nerated). Aspirin (100 mu g/ml) did not affect thrombin generation. On e hour after intravenous administration to rabbits, SR121566A exhibite d a potent ex vivo inhibitory effect against ADP-, arachidonic acid- a nd collagen-induced platelet aggregation. The ID50 were 0.6 +/- 0.25, 0.7 +/- 0.08 and 0.13 +/- 0.08 mg/kg, respectively. The ability of asp irin and SR121566A to affect venous stasis was determined in a stasis- induced venous thrombosis model in rabbits under high and low thrombog enic challenges. While aspirin was ineffective in both conditions, SR1 21566A significantly inhibited thrombus formation under low thrombogen ic challenge demonstrating for the first time that a potent non-peptid e platelet GP IIb-IIIa antagonist inhibits thrombin generation in vivo and exhibits a strong antithrombotic effect with regard to stasis-ind uced venous thrombosis. These results therefore confirm the existence of a close relationship between platelet activation and thrombin gener ation leading to blood coagulation but also emphasise the key role of platelets in the development of venous thrombosis, most likely through activation of the GP IIb-IIIa complex.