Summary
The effect of SR121566A, a new non-peptide GP IIb-IIIa antagonist was studied in vitro with regard to thrombin generation in platelet rich plasma and in vivo on stasis-induced venous thrombosis in the rabbit. SR121566A inhibited ADP-, arachidonic
acid- and collagen-induced human platelet aggregation with IC50 values of 46 ± 7.5, 56 ± 6 and 42 ± 3 nM, respectively. In the same experimental
conditions, SR121566A strongly inhibited thrombin generation triggered by low concentrations
of tissue factor. SR121566A reduced in a dose-dependent manner both the 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 generated). Aspirin (100 µg/ml) did not affect
thrombin generation.
One hour after intravenous administration to rabbits, SR121566A exhibited a potent
ex vivo inhibitory effect against ADP-, arachidonic acid- and 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 aspirin
and SR121566A to affect venous stasis was determined in a stasis-induced venous thrombosis
model in rabbits under high and low thrombogenic challenges. While aspirin was ineffective
in both conditions, SR121566A significantly inhibited thrombus formation under low
thrombogenic challenge demonstrating for the first time that a potent non-peptide
platelet GP IIb-IIIa antagonist inhibits thrombin generation in vivo and exhibits a strong antithrombotic effect with regard to stasis-induced venous
thrombosis. These results therefore confirm the existence of a close relationship
between platelet activation and thrombin generation 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.
