Since the
antithrombin action of
heparin fails to interrupt arterial
thrombosis, a mediating role for
thrombin (EC 3.4.21.5) in the formation of high-shear platelet-dependent
thrombus has been unproven. To determine whether
thrombin is important in acute arterial
thrombus formation and to assess the therapeutic potential of inhibiting its action, the effects of the synthetic covalent
antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl
ketone (FPRCH2Cl) on arterial-flow vascular graft
thrombosis and occlusion have been studied in a nonhuman primate model. Continuous
intravenous infusion of FPRCH2Cl (100 nmol/kg per min) into vascular graft-bearing baboons (Papio anubis) abolished (i) vascular graft 111In-platelet deposition, (ii)
vascular graft occlusion, (iii)
thrombus-associated in vivo release of platelet-specific
proteins and fibrinopeptides, (iv) platelet
hemostatic plug formation, (v)
thrombin-induced platelet aggregation ex vivo, and (vi)
thrombin-induced blood clotting. The effects of FPRCH2Cl largely disappeared within 15 min after the infusion had been discontinued. FPRCH2Cl produced no detectable cardiovascular or other acute side effects. In contrast, sustained comparably anticoagulating levels of
heparin had no effect upon 111In-platelet graft deposition, graft occlusion, platelet function as measured by the bleeding time, platelet aggregation ex vivo, or release of platelet-specific
proteins in vivo. We conclude that
thrombin is the principal mediator of platelet-dependent
hemostatic plug formation and of the formation of platelet-dependent high-flow acute graft
thrombosis and occlusion. Moreover, FPRCH2Cl or other synthetic
antithrombins may provide effective antithrombotic
therapy for both arterial and
venous thrombosis by simultaneously inhibiting platelet activation and
fibrin formation.