COMPARISON OF SUSTAINED ANTITHROMBOTIC EFFECTS OF INHIBITORS OF THROMBIN AND FACTOR XA IN EXPERIMENTAL THROMBOSIS

Background In the pathogenesis of (recurrent) thrombosis, clot-associa ted thrombin appears to play an important role. Antithrombin III-indep endent thrombin inhibitors have been shown to neutralize clot-bound th rombin effectively. We compared the sustained antithrombotic effects a nd the effects on endogenous fibrinolysis of several of these agents w ith recombinant tick anticoagulant peptide (rTAP), a selective factor Xa inhibitor, and low-molecular-weight heparin (LRWH) in an experiment al venous thrombosis model. Methods and Results Rabbits received eithe r recombinant hirudin (rHir), Hirulog-1, CVS#995 (a novel direct inhib itor of thrombin), rTAP, LMWH, or saline. The effect on thrombus growt h was assessed by measuring the accretion of I-125-labeled fibrinogen onto preformed nonradioactive thrombi, and the effect on endogenous fi brinolysis was assessed by measuring the decline in radioactivity of p reformed I-125-labeled thrombi in rabbit jugular veins. All direct thr ombin inhibitors induced a sustained antithrombotic effect compared wi th either LMWH and rTAP. In addition, CVS#995 also further decreased t hrombus size after stopping its infusion, which was due to a significa nt enhancement of endogenous fibrinolysis. Conclusions Direct thrombin inhibition by rHir, Hirulog-1, or CVS#995 induces a sustained antithr ombotic effect compared with rTAP and LMWH, which is most likely due t o inhibition of clot-bound thrombin. CVS#995 was shown to also enhance the extent of endogenous fibrinolysis to a greater degree compared wi th rHir and might therefore be an interesting new antithrombotic agent for the treatment of venous and arterial thrombosis.