American Journal of Cardiovascular Drugs

, Volume 5, Issue 5, pp 279–290

Inhibition of Factor Xa

A Potential Target for the Development of New Anticoagulants
Leading Article

Abstract

Anticoagulant therapy plays an important role in the prevention and treatment of pathologic arterial and venous thrombosis. There is increasing enthusiasm in the inhibition of Factor Xa as a target to achieve therapeutic anticoagulation because of its central and ‘upstream’ position in the coagulation process.

The indirect, selective, parenteral Factor Xa inhibitor fondaparinux sodium (synthetic pentasaccharide) has been studied extensively in the prevention and treatment of venous thromboembolism. In an overview of four studies in patients undergoing major orthopedic surgery, fondaparinux sodium was associated with a 55% reduction in recurrent thromboembolism, albeit with a modest increase in bleeding. Preliminary results from phase II studies of fondaparinux sodium in patients with ST-elevation and non-ST-elevation acute coronary syndromes have been promising and have led to the initiation of two large phase III trials, which are currently underway. Idraparinux sodium, a long-acting synthetic pentasaccharide, is currently being investigated as a once-weekly alternative to other long-term anticoagulants.

DX-9065a and razaxaban are two of many direct selective Factor Xa inhibitors currently in development. DX-9065a has been studied in phase II trials in patients undergoing percutaneous coronary intervention and in those with non-ST-elevation acute coronary syndromes. Razaxaban has been studied in a phase II trial in patients who have undergone orthopedic surgery. Data from these trials, although preliminary and based on small numbers of patients, suggest that direct selective Factor Xa inhibition may provide effective anticoagulation, perhaps without excessive bleeding.

Inhibition of Factor Xa is a promising target for the prevention and treatment of thrombosis in both the venous and arterial circulation. Ongoing investigation with numerous oral and parenteral inhibitors of Factor Xa will establish the potential of Factor Xa as a target for therapeutic anticoagulation.

References

  1. 1.
    Hirsh J. Heparin. N Engl J Med 1991; 324: 1565–74.PubMedCrossRefGoogle Scholar
  2. 2.
    Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991; 324: 1865–75.PubMedCrossRefGoogle Scholar
  3. 3.
    Granger CB, Becker R, Tracy RP, et al. Thrombin generation, inhibition and clinical outcomes in patients with acute myocardial infarction treated with thrombolytic therapy and heparin: results from the GUSTO-I trial. J Am Coll Cardiol 1998; 31: 497–505.PubMedCrossRefGoogle Scholar
  4. 4.
    Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337: 688–98.PubMedCrossRefGoogle Scholar
  6. 6.
    Rosenberg RD, Aird WC. Vascular-bed-specific hemostasis and hypercoagulable states. N Engl J Med 1999; 340: 1555–64.PubMedCrossRefGoogle Scholar
  7. 7.
    Butenas S, Mann KG. Kinetics of human factor VII activation. Biochemistry 1996; 36: 1904–10.CrossRefGoogle Scholar
  8. 8.
    Vinazzer H. Hereditary and acquired antithrombin deficiency. Semin Thromb Hemost 1999; 25: 257–63.PubMedCrossRefGoogle Scholar
  9. 9.
    Lindahl U, Backstrom G, Thunberg L, et al. Evidence for a 3-0 sulfated-D-glucosamine residue in the antithrombin-binding sequence of heparin. Proc Natl Acad Sci U S A 1980; 77: 6551–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Marcum JA, Rosenberg RD. Anticoagulantly active heparin-like molecules from vascular tissue. Biochemistry 1984; 23: 1730–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Broze GJ, Warren LA, Novotny WF, et al. The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits Factor Xa: insight into its possible mechanism of action. Blood 1988; 71: 335–43.PubMedGoogle Scholar
  12. 12.
    Leytus SP, Foster DC, Kurachi K, et al. Gene for human Factor X: a blood coagulation factor whose gene organization is essentially identical with that of factor IX and protein C. Biochemistry 1986; 25: 5098–102.PubMedCrossRefGoogle Scholar
  13. 13.
    Becker RC. The evolution of Factor Xa antagonists in cardiovascular disease. Daiichi Symposium. XIX Congress of the International Society of Thrombosis and Hemostasis; 2003 Jul 15; Birmingham, UK.Google Scholar
  14. 14.
    Choay J, Petitou M, Lormeau JC, et al. Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-Factor Xa activity. Biochem Biophys Res Commun 1983; 116(2): 492–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Holmer E, Kurachi K, Soderstrom G. The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, Factor Xa, factor IXa, Factor XIa, Factor XIIa and kallikrein by antithrombin. Biochem J 1981; 193: 395–400.PubMedGoogle Scholar
  16. 16.
    Olson ST, Bjork I, Sheffer R, et al. Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions: resolution of the antithrombin conformational change contribution to heparin rate enhancement. J Biol Chem 1992; 267(18): 12528–38.PubMedGoogle Scholar
  17. 17.
    Gettins P, Choay J. Examination, by 1H-n.m.r. spectroscopy, of the binding of a synthetic, high-affinity heparin pentasaccharide to human antithrombin III. CarbohydrRes 1989; 185(1): 69–76.PubMedCrossRefGoogle Scholar
  18. 18.
    Bauer KA. New pentasaccharides for prophylaxis of deep vein thrombosis: pharmacology. Chest 2003; 124 (6 Suppl.): 364S–70S.PubMedCrossRefGoogle Scholar
  19. 19.
    GlaxoSmithKline, Research Triangle Park, NC, USA. Arixtra® (fondaparinux sodium) prescribing information, May 2005 [online]. Available from URL: http://us.gsk.com [Accessed 2005 Jul 4].
  20. 20.
    Donat F, Duret JP, Santoni A, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet 2002; 41 Suppl. 2: 1–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Turpie AG, Bauer KA, Eriksson BI, et al. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. The PENTATHALON 2000 Study Steering Committee. Lancet 2002; 359: 1721–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Lassen MR, Bauer KA, Eriksson BI, et al. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. The European PentasaccHaride Elective SUrgery Study (EPHESUS) Steering Committee. Lancet 2002; 359: 1715–20.PubMedCrossRefGoogle Scholar
  23. 23.
    Bauer KA, Erikkson BI, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery: the Steering Committee of the Pentasaccharide in Major Knee Surgery Study. N Engl J Med 2001; 345: 1305–10.PubMedCrossRefGoogle Scholar
  24. 24.
    Eriksson BI, Bauer KA, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345: 1298–304.PubMedCrossRefGoogle Scholar
  25. 25.
    Turpie AG, Bauer KA, Eriksson BI, et al. Fondaparinux versus enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002; 162: 1833–40.PubMedCrossRefGoogle Scholar
  26. 26.
    Center for Drug Evaluation and Research. Final printed labelling: Arixtra™ injection [online]. Available from URL: http://www.fda.gov/cder/foi/nda/2001/21-345_Arixtra_prntlbl.pdf [Accessed 2005 Jun 20].
  27. 27.
    Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (3 Suppl.): 338S–400S.PubMedCrossRefGoogle Scholar
  28. 28.
    Agnelli G, Bergqvist D, Cohen A, et al. A randomized double-blind study to compare the efficacy and safety of fondaparinux with dalteparin in the prevention of venous thromboembolism after high-risk abdominal surgery: the Pegasus study. J Thromb Haemost 2003; 1 Suppl. 1 July: OC396.Google Scholar
  29. 29.
    Cohen AT, Gallus AS, Lassen MR, et al. Fondaparinux vs. placebo for the prevention of venous thromboembolism in acutely ill medical patients (ARTEMIS). J Thromb Haemost 2003; 1 (Suppl. 1 July): P2046.CrossRefGoogle Scholar
  30. 30.
    Buller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism: the MATISSE investigators. N Engl J Med 2003; 349: 1695–702.PubMedCrossRefGoogle Scholar
  31. 31.
    Buller HR, Davidson BL, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. The MATISSE investigators. Ann Intern Med 2004; 140(11): 867–73.PubMedGoogle Scholar
  32. 32.
    Coussement PK, Bassand JP, Convens C, et al. A synthetic Factor-Xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction: the PENTALYSE study. Eur Heart J 2001; 22: 1716–24.PubMedCrossRefGoogle Scholar
  33. 33.
    Simoons ML, Bobbink IWG, Boland J, et al. A dose-finding study of fondaparinux in patients with non-ST-segment elevation acute coronary syndromes: the PENTasaccharide in Unstable Angina (PENTUA) study. The PENTUA investigators. J Am Coll Cardiol 2004; 43: 2183–90.PubMedCrossRefGoogle Scholar
  34. 34.
    The MICHELANGELO studies: OASIS 5 (UA/NSTEMI) [online]. Available from URL: http://www.phri.ca/oasis5/index.htm [Accessed 2005 Jul 4].
  35. 35.
    Vuillemenot A, Schiele F, Meneveau N, et al. Efficacy of a synthetic pentasaccharide, a pure Factor Xa inhibitor, as an antithrombotic agent: a pilot study in the setting of coronary angioplasty. Thromb Haemost 1999; 81: 214–20.PubMedGoogle Scholar
  36. 36.
    Mehta SR, Steg PG, Granger CB, et al. Randomized, blinded trial comparing fondaparinux with unfractionated heparin in patients undergoing contemporary percutaneous coronary intervention: ASPIRE investigators. Circulation 2005; 111: 1390–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Bijsterveld NR, Moons AH, Boekholdt SM, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Herbert JM, Herault JP, Bernat A, et al. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide. Blood 1998; 91(11): 4197–205.PubMedGoogle Scholar
  39. 39.
    The Persist investigators. A novel long-acting synthetic Factor Xa inhibitor (SanOrg34006) to replace warfarin for secondary prevention in deep vein thrombosis: a phase II evaluation. J Thromb Haemost 2004; 2: 47–53.CrossRefGoogle Scholar
  40. 40.
    Rezaie AR. DX-9065a inhibition of Factor Xa and the prothrombinase complex: mechanism of inhibition and comparison with therapeutic heparins. Thromb Haemost 2003; 89: 112–21.PubMedGoogle Scholar
  41. 41.
    Brandstetter H, Kuhne A, Bode W, et al. X-ray structure of active site-inhibited clotting Factor Xa: implications for drug design and substrate recognition. J Biol Chem 1996; 271: 29988–92.PubMedCrossRefGoogle Scholar
  42. 42.
    Dyke CK, Becker RC, Kleiman NS, et al. First experience with direct Factor Xa inhibition in patients with stable coronary disease. Circulation 2002; 105: 2382–8.CrossRefGoogle Scholar
  43. 43.
    Yamazaki M, Asakura H, Aoshima K, et al. Effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of Factor Xa, against experimental disseminated intravascular coagulation in rats. Thromb Haemost 1994; 72: 392–6.PubMedGoogle Scholar
  44. 44.
    Rogers KL, Chi L, Rapundalo ST, et al. Effects of a Factor Xa inhibitor, DX-9065a, in a novel rabbit model of venous thrombosis. Basic Res Cardiol 1999; 94: 15–22.PubMedCrossRefGoogle Scholar
  45. 45.
    Herbert JM, Bernat A, Dol F, et al. DX 9065A, a novel, synthetic, selective and orally active inhibitor of Factor Xa: in vitro and in vivo studies. J Pharmacol Exp Ther 1996; 276: 1030–8.PubMedGoogle Scholar
  46. 46.
    Yokoyama T, Kelly AB, Marzec UM, et al. Antithrombotic effects of orally active synthetic antagonist of activated Factor X in nonhuman primates. Circulation 1995; 92: 485–91.PubMedCrossRefGoogle Scholar
  47. 47.
    Kim DI, Kambayashi J, Shibuya T, et al. In vivo evaluation of DX-9065a, a synthetic Factor Xa inhibitor, in experimental vein graft. J Atheroscler Thromb 1996; 2: 110–6.PubMedGoogle Scholar
  48. 48.
    Shimbo D, Osende J, Chen J, et al. Antithrombotic effects of DX-9065a, a direct Factor Xa inhibitor: a comparative study in humans versus low molecular weight heparin. Thromb Haemost 2002; 88: 733–8.PubMedGoogle Scholar
  49. 49.
    Alexander JH, Becker RC, Hasselblad V, et al. Effect of the direct Factor Xa inhibitor, DX-9065a, on thrombin generation in patients with stable coronary artery disease. J Thromb Haemost 2003; 1 Suppl. 1 July: P2017.Google Scholar
  50. 50.
    Alexander JH, Dyke CK, Yang H, et al. Initial experience with factor-Xa inhibition in percutaneous coronary intervention: the XaNADU-PCI Pilot. J Thromb Hemost 2004; 2: 234–41.CrossRefGoogle Scholar
  51. 51.
    Alexander JH, Yang H, Becker RC, et al. First experience with direct, selective Factor XA inhibition in patients with non-ST-elevation acute coronary syndromes: results of the XaNADU-ACS trial. J Thromb Haemost 2005 Mar; 3(3): 439–47.PubMedCrossRefGoogle Scholar
  52. 52.
    Morishima Y, Tanabe K, Terada Y, et al. Antithrombotic and hemorrhagic effects of DX-9065a, a direct and selective Factor Xa inhibitor: comparison with a direct thrombin inhibitor and antithrombin III-dependent anticoagulants. Thromb Haemost 1997; 78: 1366–71.PubMedGoogle Scholar
  53. 53.
    Ieko M, Tarumi T, Takeda M, et al. Synthetic selective inhibitors of coagulation Factor Xa strongly inhibit thrombin generation without affecting initial thrombin forming time necessary for platelet activation in hemostasis. J Thromb Haemost 2004; 2: 612–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Abbenante G, Fairlie DP. Protease inhibitors in the clinic. Med Chem 2005; 1: 71–104.PubMedCrossRefGoogle Scholar
  55. 55.
    Lassen MR, Davidson BL, Gallus A, et al. A phase II randomized, double-blind, five-arm, parallel-group, dose-response study of a new oral directly-acting Factor Xa inhibitor, razaxaban, for the prevention of deep vein thrombosis in knee replacement surgery: on behalf of the Razaxaban investigators [abstract]. Blood 2003; 102(11): 41.Google Scholar
  56. 56.
    Marmur JD, Anand SX, Bagga RS, et al. The activated clotting time can be used to monitor the low molecular weight heparin dalteparin after intravenous administration. J Am Coll Cardiol 2003; 41: 394–402.PubMedCrossRefGoogle Scholar
  57. 57.
    Moliterno DJ, Hermiller JB, Kereiakes DJ, et al. A novel point-of-care enoxaparin monitor for use during percutaneous coronary intervention results of the Evaluating Enoxaparin Clotting Times (ELECT) Study: the ELECT Investigators. J Am Coll Cardiol 2003; 42: 1132–9.PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Duke University Medical Center and the Duke Clinical Research InstituteDurhamUSA

Personalised recommendations