PLATELET DEPOSITION INDUCED BY SEVERELY DAMAGED VESSEL WALL IS INHIBITED BY A BOROARGININE SYNTHETIC PEPTIDE WITH ANTITHROMBIN ACTIVITY

Thrombin plays a key role in platelet activation and thrombosis. Speci fic inhibition of thrombin appears to be one of the best approaches to prevent thrombus formation. We have studied the effects of a syntheti c alpha-aminoboronic acid derivative - [Ac, (D) Phe-Pro-Boro-Arg-Hydro cloric acid] - on platelet deposition on severely damaged arterial wal l. Platelet deposition was evaluated under well characterized rheologi cal conditions in an original perfusion chamber and detected by autolo gous In-111-labeled platelets. The study was performed ''in vivo'' in a porcine model of arterial thrombosis triggered by severely damaged v essel wall at blood flow conditions mimicking mild stenosis (1690 s(-1 )) and patent (212 s(-1)) vessels. In addition, ex-vivo platelet aggre gation activity was evaluated by whole blood impedance aggregometry us ing collagen, ADP and thrombin as agonists. The synthetic alpha-aminob oronic peptide was intravenously administered as a bolus followed by c ontinuous infusion. Ex vivo thrombin-induced whole blood platelet aggr egation was totally abolished, while ADP- and Collagen-induced whole b lood platelet aggregation was not modified. The effects of the synthet ic antithrombin on platelet deposition were evaluated in native blood (non-anticoagulated) conditions and in combination with heparin. Under both experimental conditions, the synthetic peptide significantly inh ibited platelet deposition at local flow conditions of both high (1690 s(-1)) and low (212 s(-1)) shear rates. Our results suggest that spec ific inhibition of locally generated thrombin might be a good strategy to prevent platelet dependent arterial thrombus formation independent ly of the local flow shear rate of the area at risk.