This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Biemond, B. J. Articles by ten Cate, J. W. Search for Related Content PubMed PubMed Citation Articles by Biemond, B. J. Articles by ten Cate, J. W.

(Circulation. 1996;93:153-160.)
© 1996 American Heart Association, Inc.

Articles

Comparison of Sustained Antithrombotic Effects of Inhibitors of Thrombin and Factor Xa in Experimental Thrombosis

Bart J. Biemond, MD; Philip W. Friederich, MD; Marcel Levi, MD; George P. Vlasuk, PhD; Harry R. Büller, MD; Jan W. ten Cate, MD

From the Center for Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research (B.J.B., P.W.F., M.L., H.R.B., J.W.t.C.), Academic Medical Center, University of Amsterdam, Netherlands; and Corvas International Inc (G.P.V.), San Diego, Calif.

Correspondence to Bart J. Biemond, MD, Center for Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

Background In the pathogenesis of (recurrent) thrombosis, clot-associated thrombin appears to play an important role. Antithrombin III–independent thrombin inhibitors have been shown to neutralize clot-bound thrombin effectively. We compared the sustained antithrombotic effects and the effects on endogenous fibrinolysis of several of these agents with recombinant tick anticoagulant peptide (rTAP), a selective factor Xa inhibitor, and low-molecular-weight heparin (LMWH) in an experimental venous thrombosis model.

Methods and Results Rabbits received either recombinant hirudin (rHir), Hirulog-1, CVS#995 (a novel direct inhibitor of thrombin), rTAP, LMWH, or saline. The effect on thrombus growth was assessed by measuring the accretion of ¹²⁵I-labeled fibrinogen onto preformed nonradioactive thrombi, and the effect on endogenous fibrinolysis was assessed by measuring the decline in radioactivity of preformed ¹²⁵I-labeled thrombi in rabbit jugular veins. All direct thrombin inhibitors induced a sustained antithrombotic effect compared with either LMWH and rTAP. In addition, CVS#995 also further decreased thrombus size after stopping its infusion, which was due to a significant enhancement of endogenous fibrinolysis.

Conclusions Direct thrombin inhibition by rHir, Hirulog-1, or CVS#995 induces a sustained antithrombotic effect compared with rTAP and LMWH, which is most likely due to inhibition of clot-bound thrombin. CVS#995 was shown to also enhance the extent of endogenous fibrinolysis to a greater degree compared with rHir and might therefore be an interesting new antithrombotic agent for the treatment of venous and arterial thrombosis.

Key Words: anticoagulants • thrombosis • fibrinolysis

This article has been cited by other articles:

				J. M. Wilson, J. Gilbert, M. Harlan, A. Bracey, P. Allison, C. Schooley, and K. Pinto High-dose Intravenous Dalteparin Can be Monitored Effectively Using Standard Coagulation Times Clinical and Applied Thrombosis/Hemostasis, April 1, 2005; 11(2): 127 - 138. [Abstract] [PDF]

				S. M. Bates and J. I. Weitz Emerging Anticoagulant Drugs Arterioscler. Thromb. Vasc. Biol., September 1, 2003; 23(9): 1491 - 1500. [Abstract] [Full Text] [PDF]

				U. Rauch, J. I. Osende, V. Fuster, J. J. Badimon, Z. Fayad, and J. H. Chesebro Thrombus Formation on Atherosclerotic Plaques: Pathogenesis and Clinical Consequences Ann Intern Med, February 6, 2001; 134(3): 224 - 238. [Abstract] [Full Text] [PDF]

				R. M. Camire, M. Kalafatis, P. Simioni, A. Girolami, and P. B. Tracy Platelet-Derived Factor Va/VaLeiden Cofactor Activities Are Sustained on the Surface of Activated Platelets Despite the Presence of Activated Protein C Blood, April 15, 1998; 91(8): 2818 - 2829. [Abstract] [Full Text] [PDF]

				B. J. Meyer, J. J. Badimon, J. H. Chesebro, J. T. Fallon, V. Fuster, and L. Badimon Dissolution of Mural Thrombus by Specific Thrombin Inhibition With r-Hirudin : Comparison With Heparin and Aspirin Circulation, February 24, 1998; 97(7): 681 - 685. [Abstract] [Full Text] [PDF]