Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates

• Published in: The Journal of clinical investigation 1993-10, Vol.92 (4), p.2003-2012
• Main Authors: HANSON, S. R, GRIFFIN, J. H, HARKER, L. A, KELLY, A. B, ESMON, C. T, GRUBER, A
• Format: Article
• Language: English
• Subjects: Animals; Arteriovenous Shunt, Surgical; Biological and medical sciences; Blood and lymphatic vessels; Blood Platelets - drug effects; Blood Platelets - physiology; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Factor V - metabolism; Factor VII - metabolism; Fibrin - metabolism; Fibrinogen - metabolism; Fibrinopeptide A - metabolism; Male; Medical sciences; Papio; Partial Thromboplastin Time; Polyethylene Terephthalates; Protein C - metabolism; Thrombin - pharmacology; Thrombosis - physiopathology; Thrombosis - prevention & control
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci116795

The effects on thrombosis and hemostasis of thrombin-induced activation of endogenous protein C (PC) were evaluated in baboons. Thrombosis was induced by placing into arteriovenous shunts a segment of Dacron vascular graft, which generated arterial platelet-rich thrombus, followed by an expansion region of low-shear blood flow, which in turn accumulated fibrin-rich venous-type thrombus. Thrombosis was quantified by 111In-platelet imaging and 125I-fibrinogen accumulation. Intravenous infusion of alpha-thrombin, 1-2 U/kg-min for 1 h, increased baseline activated PC levels (approximately 5 ng/ml) to 250-500 ng/ml (P < 0.01). The lower thrombin dose, which did not deplete circulating platelets, fibrinogen, or PC, reduced arterial graft platelet deposition by 48% (P < 0.05), and platelet and fibrin incorporation into venous-type thrombus by > 85% (P < 0.01). Thrombin infusion prolonged the activated partial thromboplastin clotting time, elevated fibrinopeptide A (FPA), thrombin-antithrombin III complex (T:AT III), and fibrin D-dimer plasma levels (P < 0.01), but did not affect bleeding times. Thrombin's antithrombotic effects were blocked by infusing a monoclonal antibody (HPC-4) which prevented PC activation in vivo, caused shunt occlusion, increased the consumption of platelets and fibrinogen, elevated plasma FPA and T:AT III levels, and reduced factor VIII (but not factor V) procoagulant activity (P < 0.05). We conclude that activated PC is a physiologic inhibitor of thrombosis, and that activation of endogenous PC may represent a novel and effective antithrombotic strategy.