Tissue factor (TF) exposed during mechanical vascular injury is postulated to initiate thrombin production, vascular thrombosis and neointimal lesion formation. We have tested this hypothesis in baboons by measuring the effects of inactivating TF during interventional vascular procedures using recombinant human activated Factor VII that has been irreversibly inactivated by D-Phe-Phe-Arg chloromethyl ketone (FFR-rFVIIa). FFR-rFVIIa dose-response inhibition of TF expressed on segments of freshly endarterectomized homologous aorta was determined in vitro, and after interposition in chronic exteriorized femoral arteriovenous shunts. Subsequently, antithrombotic dosing of FFR-rFVIIa (1 mg/kg) was administered during three clinically relevant vascular procedures 1) surgical carotid endarterectomy, 2) femoral balloon catheter angioplasty, and 3) arteriovenous vascular graft implantation. Measurements of FFR-rFVIIa blood levels, hemostasis, surgical bleeding, 111In-platelet depositi on, and 30-day vascular lesion formation were compared for treated vs control groups. FFR-rFVIIa inhibited the formation of vascular thrombosis on endarterectomized aortic segments in a dose-dependent manner (intermediate effects using 0.05 mg/kg, and complete interruption by 1.0 mg/kg). FFR-rFVIIa was cleared from blood with an -phase T50 of approximately 110 min and a a-phase T50 of about 7 hrs. During the interventional procedures FFR-rFVIIa levels were >6 fg/mL for the initial 6 hrs, and >1 fg/mL for 24 hrs. FFR-rFVIIa therapy decreased 111In-platelet deposition at sites of endarterectomy and implanted vascular grafts for at least 24 hrs postoperatively (p<0.05). FFR-rFVIIa therapy did not significantly prolong bleeding times (p>0.2), or increase surgical blood loss (p>0.2). Injections of rFFR-rFVIIa (1 mg/kg) at the time of vascular injury significantly reduced morphometric measurements of 30-d neointimal vascular lesions induced by femoral balloon catheter angioplasty (p=0.003). Transient inactivation of tissue factor activity by FFR-rFVIIa (1 mg/kg) during mechanical vascular injury markedly reduces vascular thrombosis and decreases subsequent intimal proliferative lesion formation in baboons without increasing surgical bleeding. FUNDING NIH / HL41619 No cost extension 12/01/97 - 11/30/02 PUBLICATIONS Harker, L.A., Marzec, U.M., Kelly, A.B., Lumsden, A.B., Yokoyama, T., Hedner, U., Ezban, M. and Hanson, S.R. Prevention of vascular thrombosis and neointimal lesion formation by tissue factor antagonist effects of intravenous bolus recombinant human factor VIIa inactivated by D-phe-phe-arg chloromethyl ketone (FFR-rFVIIa) in baboons undergoing interventional vascular procedures. Circulation (In press). PR51RR00165-38 1/1/98 - 12/31/98 Yerkes Regional Primate Research Center
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