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


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.
Biemond
B J
BJ
Center for Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, University of Amsterdam, Netherlands.
Friederich
P W
PW
Levi
M
M
Vlasuk
G P
GP
Büller
H R
HR
ten Cate
J W
JW
D000818:Animals; D000991:Antithrombins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight / Q000493:pharmacokinetics / Q000627:therapeutic use*; D024764:Hirudin Therapy; D006629:Hirudins / Q000493:pharmacokinetics; D007601:Jugular Veins / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy* / Q000378:metabolism
D000991:Antithrombins; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013917:Thrombin; D015951:Factor Xa; C074619:bivalirudin