Activated Protein C (APC) is a physiologic anticoagulant generated from plasma protein C by thrombin bound to endothelial thrombomodulin (TM). APC downregulates the production of thrombin by inactivating critical cofactor functions of coagulation factors V and VIII. This study evaluates the antithrombotic efficacy and safety of recombinant human soluble (rHs)TM in baboons. rHsTM dose responses were determined for thrombus formation, thrombin inactivation, generation of APC, hemostatic function, and pharmacokinetics. Thrombus formation was measured as the deposition of autologous 111In-platelets and accumulation of 125I-fibrin for both platelet-rich arterial-type and fibrin-rich venous-type thrombosis in a two-component thrombogenic device interposed in chronic femoral arteriovenous (AV) shunts. Ex vivo, rHsTM inactivated soluble thrombin, but not bound thrombin, and catalyzed the generation of APC by both soluble and bound thrombin. Bolus intravenous rHsTM in babo ons 1) cleared from plasma with a T50 of 6 hrs; 2) produced dose-dependent inhibition of thrombus formation (dosing rHsTM at 1 mg/kg abolished the deposition of 111In-platelets and 125I-fibrin in the formation of venous-type fibrin-rich thrombus, and 5 mg/kg rHsTM eliminated 111In-platelet and 125I-fibrin accumulation in the formation of arterial-type platelet-rich thrombus); 3) inhibited coagulation in a dose-dependent manner; 4) suppressed device-mediated increases in systemic APC levels (attributed to rHsTM-dependent inactivation of soluble thrombin with consequent reduction in APC generation by endothelial-TM); and 5) minimally impaired platelet hemostatic function, as measured by the template bleeding time. When in vivo APC generation was prevented by injecting 5 mg/kg HPC4 monoclonal antibody (MoAb) prior to administering rHsTM, thrombus formation was substantially augmented, indicating that APC generation contributed significantly to the antithrombotic effects produced by rHsTM infusi ons. rHsTM produces safe, dose-dependent, antithrombotic effects that are attributable to direct inactivation of soluble thrombin, coupled with the local generation of APC mediated by both bound and soluble thrombin. FUNDING NIH / HL53222 $287,244 8/01/98 - 7/31/99 PUBLICATIONS Harker, L.A., Marzec, U.M., Mohri, M., Fernandez, J.A., Kelly, A.B., Hanson, S.R., Esmon, C.T. and Griffin, J.H. Antithrombotic efficacy and safety of recombinant human soluble thrombomodulin in non-human primates Inactivation of thrombin and enhanced generation of activated protein C. Circulation (In press). PR51RR00165-38 1/1/98 - 12/31/98 Yerkes Regional Primate Research Center
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