Published Online
on October 21, 2002

A more recent version of this article appeared on November 12, 2002

This Article Full Text (PDF) All Versions of this Article: 106/20/2550    most recent 01.CIR.0000038501.87442.02v1 Alert me when this article is cited Alert me if a correction is posted 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 Bijsterveld, N. R. Articles by Levi, M. Search for Related Content PubMed PubMed Citation Articles by Bijsterveld, N. R. Articles by Levi, M. Related Collections Arterial thrombosis Deep vein thrombosis Coagulation Thrombin Coagulation inhibitors Other anticoagulants Coagulation and fibronolysis

Submitted on July 1, 2002
Revised on August 30, 2002
Accepted on September 2, 2002

Ability of Recombinant Factor VIIa to Reverse the Anticoagulant Effect of the Pentasaccharide Fondaparinux in Healthy Volunteers

Nick R. Bijsterveld MD^*, Arno H. Moons MD, S. Matthijs Boekholdt MD, Benien E. van Aken PhD, Hein Fennema PhD, Ron J.G. Peters MD, Joost C.M. Meijers PhD, Harry R. Büller MD, and Marcel Levi MD

From the Department of Cardiology (N.R.B., A.H.M., S.M.B., R.J.G.P.), Vascular Medicine (J.C.M.M., H.R.B., M.L.), and Internal Medicine (M.L.), Academic Medical Center, University of Amsterdam, the Netherlands, and N.V. Organon (B.E.v.A., H.F.), Oss, the Netherlands.

^* To whom correspondence should be addressed. E-mail: n.r.bijsterveld{at}amc.uva.nl.

Background—The novel anticoagulant fondaparinux proved to be effective and safe in the postoperative prevention of venous thrombosis. Current phase III trials with this synthetic selective factor Xa inhibitor focus on its use in the treatment of patients with venous and arterial thrombosis. As with any anticoagulant therapy, there is a risk of bleeding complications; hence, a strategy to reverse the effects of fondaparinux is desirable. The aim of this study was to investigate whether recombinant factor VIIa (rFVIIa) could neutralize the anticoagulant effects of subcutaneously administered fondaparinux.

Methods and Results—In a randomized, placebo-controlled design, 16 healthy male subjects received either a single subcutaneous dose of fondaparinux (10 mg) and a single intravenous bolus of rFVIIa (90 µg/kg; n=8), fondaparinux and placebo (n=4), or placebo and rFVIIa (n=4). Fondaparinux (or placebo) was administered 2 hours before rFVIIa (or placebo). Injection of rFVIIa after fondaparinux normalized the prolonged activated partial thromboplastin and prothrombin times and reversed the decrease in prothrombin activation fragments 1+2 (F₁₊₂), as observed with fondaparinux alone. Thrombin-generation time and endogenous thrombin potential, which were inhibited by fondaparinux, normalized up to 6 hours after rFVIIa injection.

Conclusions—rFVIIa is capable of normalizing coagulation times and thrombin generation during fondaparinux treatment. The duration of this effect ranged from 2 to 6 hours after rFVIIa injection. These results suggest that rFVIIa may be useful to reverse the anticoagulant effect of fondaparinux in case of serious bleeding complications or need for acute surgery during treatment with fondaparinux.

Key words: anticoagulants • pharmacokinetics • pharmacology • hemorrhage • thrombosis

This article has been cited by other articles:

				J. Hirsh, K. A. Bauer, M. B. Donati, M. Gould, M. M. Samama, and J. I. Weitz Parenteral Anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 141S - 159S. [Abstract] [Full Text] [PDF]

				M. A. Crowther and T. E. Warkentin Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents Blood, May 15, 2008; 111(10): 4871 - 4879. [Abstract] [Full Text] [PDF]

				J. H. Levy, K. A. Tanaka, and M. J. Hursting Reducing Thrombotic Complications in the Perioperative Setting: An Update on Heparin-Induced Thrombocytopenia Anesth. Analg., September 1, 2007; 105(3): 570 - 582. [Abstract] [Full Text] [PDF]

				J. Hirsh, M. O'Donnell, and J. W. Eikelboom Beyond Unfractionated Heparin and Warfarin: Current and Future Advances Circulation, July 31, 2007; 116(5): 552 - 560. [Full Text] [PDF]

				D. J. Carlbom and B. L. Davidson Pulmonary Embolism in the Critically Ill Chest, July 1, 2007; 132(1): 313 - 324. [Abstract] [Full Text] [PDF]

				R. De Caterina, S. Husted, L. Wallentin, G. Agnelli, F. Bachmann, C. Baigent, J. Jespersen, S. D. Kristensen, G. Montalescot, A. Siegbahn, et al. Anticoagulants in heart disease: current status and perspectives Eur. Heart J., April 10, 2007; (2007) ehl492v1. [Full Text] [PDF]

				D. E. Gerber, S. A. Grossman, and M. B. Streiff Management of Venous Thromboembolism in Patients With Primary and Metastatic Brain Tumors J. Clin. Oncol., March 10, 2006; 24(8): 1310 - 1318. [Abstract] [Full Text] [PDF]

				J. H. Levy Overview of clinical efficacy and safety of pharmacologic strategies for blood conservation Am. J. Health Syst. Pharm., September 15, 2005; 62(18_Supplement_4): S15 - S19. [Abstract] [Full Text] [PDF]

				V Pengo New trends in anticoagulant treatments Lupus, September 1, 2005; 14(9): 789 - 793. [Abstract] [PDF]

				M. O'Donnell, G. Agnelli, and J. I. Weitz Emerging therapies for stroke prevention in atrial fibrillation Eur. Heart J. Suppl., May 1, 2005; 7(suppl_C): C19 - C27. [Abstract] [Full Text] [PDF]

				S. Schulman and R. J. Beyth Risk of bleeding with long-term antithrombotic therapy in atrial fibrillation Eur. Heart J. Suppl., May 1, 2005; 7(suppl_C): C34 - C40. [Abstract] [Full Text] [PDF]

				J. M. Hoffman, N. D. Shah, L. C. Vermeulen, R. J. Hunkler, and K. M. Hontz Projecting future drug expenditures--2005 Am. J. Health Syst. Pharm., January 15, 2005; 62(2): 149 - 167. [Abstract] [Full Text] [PDF]

				J. Hirsh, M. O'Donnell, and J. I. Weitz New anticoagulants Blood, January 15, 2005; 105(2): 453 - 463. [Abstract] [Full Text] [PDF]

				J. I. Weitz, J. Hirsh, and M. M. Samama New Anticoagulant Drugs: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 265S - 286S. [Abstract] [Full Text] [PDF]

				J. I. Weitz New Anticoagulants for Treatment of Venous Thromboembolism Circulation, August 31, 2004; 110(9_suppl_1): I-19 - I-26. [Abstract] [Full Text] [PDF]

				T. Bombeli and D. R. Spahn Updates in perioperative coagulation: physiology and management of thromboembolism and haemorrhage Br. J. Anaesth., August 1, 2004; 93(2): 275 - 287. [Abstract] [Full Text] [PDF]

				H. R. Buller, B. L. Davidson, H. Decousus, A. Gallus, M. Gent, F. Piovella, M. H. Prins, G. Raskob, A. E.M. Segers, R. Cariou, et al. Fondaparinux or Enoxaparin for the Initial Treatment of Symptomatic Deep Venous Thrombosis: A Randomized Trial Ann Intern Med, June 1, 2004; 140(11): 867 - 873. [Abstract] [Full Text] [PDF]

				A. H Tran and G. Lee Fondaparinux for Prevention of Venous Thromboembolism in Major Orthopedic Surgery Ann. Pharmacother., November 1, 2003; 37(11): 1632 - 1643. [Abstract] [Full Text] [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]

				D. W. Branch and G. M. Rodgers Recombinant Activated Factor VII: A New Weapon in the Fight Against Hemorrhage Obstet. Gynecol., June 1, 2003; 101(6): 1155 - 1156. [Full Text] [PDF]