title: Platelet deposition induced by severely damaged vessel wall is inhibited by a boroarginine synthetic peptide with antithrombin activity.
abstract: Thrombin plays a key role in platelet activation and thrombosis. Specific inhibition of thrombin appears to be one of the best approaches to prevent thrombus formation. We have studied the effects of a synthetic alpha-aminoboronic acid derivative- [Ac, (D) Phe-Pro-Boro-Arg-Hydrochloric acid] - on platelet deposition on severely damaged arterial wall. Platelet deposition was evaluated under well characterized rheological conditions in an original perfusion chamber and detected by autologous 111In-labeled platelets. The study was performed "in vivo" in a porcine model of arterial thrombosis triggered by severely damaged vessel wall at blood flow conditions mimicking mild stenosis (1690 s-1) and patent (212 s-1) vessels. In addition, ex-vivo platelet aggregation activity was evaluated by whole blood impedance aggregometry using collagen, ADP and thrombin as agonists. The synthetic alpha-aminoboronic peptide was intravenously administered as a bolus followed by continuous infusion. Ex vivo thrombin-induced whole blood platelet aggregation was totally abolished, while ADP- and Collagen-induced whole blood platelet aggregation was not modified. The effects of the synthetic 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 inhibited platelet deposition at local flow conditions of both high (1690 s-1) and low (212s-1) shear rates. Our results suggest that specific inhibition of locally generated thrombin might be a good strategy to prevent platelet dependent arterial thrombus formation independently of the local flow shear rate of the area at risk.
authors.affiliation: Cardiovascular Biology Research, Massachusetts General Hospital, Harvard Medical School Boston 02114.
authors.forename: J J
authors.initials: JJ
authors.lastname: Badimon
authors.forename: D
authors.initials: D
authors.lastname: Weng
authors.forename: J H
authors.initials: JH
authors.lastname: Chesebro
authors.forename: V
authors.initials: V
authors.lastname: Fuster
authors.forename: L
authors.initials: L
authors.lastname: Badimon
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000473:pathology*; D001896:Boron Compounds / Q000494:pharmacology*; D003094:Collagen / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000293:injuries / Q000473:pathology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013552:Swine / Q000097:blood; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000517:prevention & control
chemical_list: D001896:Boron Compounds; D005343:Fibrinolytic Agents; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; C066061:acetylphenylalanyl-prolyl-boroarginine; D000244:Adenosine Diphosphate; D006493:Heparin; D003094:Collagen; D013917:Thrombin