Subscribe to RSS
DOI: 10.1055/s-0037-1614512
Differential Inhibition of Thrombin Activity and Thrombin Generation by a Synthetic Direct Thrombin Inhibitor (Napsagatran, Ro 46-6240) and Unfractionated Heparin in Patients with Deep Vein Thrombosis
Publication History
Received
14 August 1998
Accepted after resubmission
07 January 1999
Publication Date:
09 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199904/lookinside/thumbnails/10.1055-s-0037-1614512-1.jpg)
Summary
Background: Direct thrombin inhibitors belong to a new class of antithrombotic drugs whose effects on blood coagulation in vivo in patients suffering from acute thrombotic conditions have not yet been fully explored. Methods and Results: One hundred and five patients with acute proximal deep-vein thrombosis were randomized to receive a continuous intravenous infusion of napsagatran, a novel synthetic thrombin inhibitor, at a fixed dose of 5 mg/h (n = 36) or 9 mg/h (n = 25) for five days, or APTT-adjusted unfractionated heparin (UFH, n = 44) for the same time. In these patients, thrombin activity and thrombin generation could be assessed by measuring thrombin-antithrombin III complexes (TAT) and prothrombin fragment 1+2 (F1+2), respectively, on three occasions. At baseline, TAT and F1+2 did not differ among the three groups. On Day 2 (steady state), TAT significantly decreased in all groups, and the decrease was significantly more pronounced in the patients given higher-dose napsagatran. F1+2 decreased significantly only in UFH-treated patients. Two hours after cessation of the infusion, the TAT levels increased in the two napsagatran groups but not in the UFH group, whilst F1+2 went back to the baseline levels in the napsagatran-treated patients but remained low in the UFH-treated patients. There was no rebound effect. Conclusions: The data presented suggest that direct thrombin inhibition with napsagatran at 9 mg/h is more potent than UFH in attenuating thrombin activity, but is less potent than UFH in inhibiting thrombin generation. The real significance of these findings will have to be substantiated in further trials with clinically relevant endpoints.
6 Study committees, participating centers, and investigators are listed at the end of the paper quoted as ref. 5
-
References
- 1 Lefkovits J, Topol EJ. Direct thrombin inhibitors in cardiovascular medicine. Circulation 1994; 90: 1522-36.
- 2 Weitz I J, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by heparin-antithrombin III independent inhibitors. J Clin Invest 1990; 86: 385-92.
- 3 Tschopp TB, Ackermann J, Gast A, Hilpert K, Kirchhofer S, Roux S, Schmid G, Soukup M. Napsagatran, thrombin inhibitor, Ro 46-6240. Drugs of the Future 1995; 20: 476-9.
- 4 Gast A, Tschopp TB, Schmid G, Hilpert K, Ackermann J. Inhibition of clot-bound and free (fluid-phase thrombin) by a novel synthetic thrombin inhibitor (Ro 46-6240), recombinant hirudin and heparin in human plasma. Blood Coagul Fibrinol 1994; 5: 879-87.
- 5 Bounameaux H, Ehringer H, Hulting J, Rasche H, Rapold HJ, Zultak M. An exploratory trial of two dosages of a novel synthetic thrombin inhibitor (Napsagatran, Ro 46-6240) compared with unfractionated heparin for treatment of proximal deep-vein thrombosis. Results of the European Multicenter ADVENT trial. Thromb Haemost 1997; 78: 997-1002.
- 6 Brieger D, Dawes J. Long term persistence of biological activity following administration of Enoxaparin sodium (clexane) is due to sequestration of antithrombin-binding low molecular weight fragments — Comparison with unfractionated heparin. Thromb Haemost 1996; 75: 740-6.
- 7 Gast A, Tschopp T. Inhibition of extrinsic and intrinsic thrombin generation by a novel synthetic thrombin inhibitor (Ro 46-6240), recombinant hirudin and heparin in human plasma. Blood Coagul Fibrinol 1995; 6: 553-60.
- 8 Schiele F, Vuillemot A, Kramarz P, Kieffer Y, Soria J, Soria C, Camez A, Misrahi MC, Bassand JP. A pilot study of subcutaneous recombinant hirudin (HBW 023) in the treatment of deep vein thrombosis. Thromb Haemost 1994; 71: 558-62.
- 9 Ginsberg JS, Nurmohamed MT, Gent M, MacKinnon B, Stevens P, Weitz J, Maraganore J, Hirsh J. Effect on thrombin generation of single injections of Hirulog™ in patients with calf vein thrombosis. Thromb Haemost 1994; 72: 523-5.
- 10 Elias A, Bonfils S, Daoud-Elias M, Gauthier B, SiéP et al. Influence of long term oral anticoagulants upon prothrombin fragment 1 + 2, thrombin-anti-thrombin III complex and D-Dimer levels in patients affected by proximal deep vein thrombosis. Thromb Haemost 1993; 69: 302-5.
- 11 Zoedheyli P, Bichler J, Owen WG, Grill DE, Fuster V, Mruk JS, Chesebro JH. Persistent thrombin generation in humans during specific thrombin inhibition with hirudin. Circulation 1994; 90: 2671-8.
- 12 Eichinger S, Wolzt M, Schneider M, Nieszpaur-Los M, Heinrichs H, Lech-ner K, Eichler HG, Kyrle PA. Effects of recombinant hirudin (r-hirudin, HBW 023) on coagulation and platelet activation in vivo. Comparison with unfractionated heparin and a low-molecular-weight heparin preparation (fragmin). Arterioscler Thromb Vasc Biol 1995; 15: 886-92.
- 13 Schiele F, Lindgaerde F, Eriksson H, Bassand JP, Wallmark A, Hansson PO, Grollier G, Sjo M, Moia M, Camez A, Smyth V, Walker M. for the International Multicentre Hirudin Study Group. Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective dose-ranging randomized trial. Thromb Haemost 1997; 77: 834-8.