Thrombin plays an important role in promoting arterial
thrombosis by platelet activation and by catalyzing
fibrin formation. Use of
thrombin inhibitors that block both the platelet-activating and
fibrin formation properties of
thrombin are associated with hemostasis. This problem might be overcome by developing agents that block only the platelet-activating property of
thrombin. Because the platelet-activating property of
thrombin is mediated by the
thrombin receptor, antagonists of the
thrombin receptor might be efficacious and potentially safer with regard to
bleeding complications. We investigated whether a
peptide ligand (AFLARAA) of the
thrombin receptor that blocked
alpha-thrombin and
thrombin receptor activating peptide-induced platelet aggregation could inhibit
thrombosis. A partially occlusive
thrombus was generated by application of electric current in rabbit carotid artery. In control animals, the artery was completely occluded within 42+/-12 min after the current was discontinued. When the
thrombin receptor activating peptide antagonist was given (100 micromol/kg as an IV bolus followed by 900 micromol/kg infusion for a period of 180 min) starting at the time the current was stopped, blood flow remained patent throughout the infusion period and for an additional 60 min after the infusion was stopped. The antithrombotic effect of the antagonist
peptide was not associated with increased
bleeding tendency, as judged by the amount of blood adsorbed by a gauze pad placed in a
surgical incision extending to the muscle tissue and by a standard template bleeding time. These results indicate that
thrombin receptor antagonist
peptides can be used as
antithrombotic agents.