Comparison of sustained antithrombotic effects of inhibitors of thrombin and factor Xa in experimental thrombosis

• Published in: Circulation (New York, N.Y.) N.Y.), 1996, Vol.93 (1), p.153-160
• Main Authors: BIEMOND, B. J, FRIEDERICH, P. W, LEVI, M, VLASUK, G. P, BÜLLER, H. R, TEN CATE, J. W
• Format: Article
• Language: English
• Subjects: Animals; Antithrombins - pharmacokinetics; Antithrombins - therapeutic use; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Factor Xa - metabolism; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight - pharmacokinetics; Heparin, Low-Molecular-Weight - therapeutic use; Hirudin Therapy; Hirudins - pharmacokinetics; Jugular Veins - metabolism; Jugular Veins - pathology; Medical sciences; Peptide Fragments - pharmacokinetics; Peptide Fragments - therapeutic use; Pharmacology. Drug treatments; Rabbits; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use; Thrombin - antagonists & inhibitors; Thrombin - metabolism; Thrombosis - drug therapy; Thrombosis - metabolism
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.93.1.153

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. 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. 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.