Advances in antithrombotic treatment – antithrombotics with anti‑Xa effect
Authors:
A. Bátorová
Authors‘ workplace:
Národné hemofilické centrum, Klinika hematológie a transfuziológie Lekárskej fakulty UK a FN Bratislava, Slovenská republika, prednosta doc. MUDr. Martin Mistrík, Ph. D.
Published in:
Vnitř Lék 2009; 55(3): 295-301
Category:
15th Parizek's Days
Overview
The use of anticoagulants in the prophylaxis and treatment of arterial and venous thrombosis has substantially expanded during the last years. Increasing knowledge about the inherited and acquired thrombophilia and the risk factors predisposing to the recurrency of thromboembolic events result in a new indications for primary and secondary thromboprophylaxis with prolonged or even life-long duration. The limitations of classical anticoagulans, heparin and vitamin K antagonists support the development of medicaments with a specific antithrombotic action. The new generation anticoagulants inhibit in a specific way either particular coagulation enzyme or hemostasis activation step. Based on the in vitro studies and extensive clinical observations the activated factor Xa (F Xa) seems to be one of the most advantageous targets for a specific action of perspective antithrombotic agents. Two selective F Xa inhibitors have been approved for clinical use: fondaparinux is an indirect parenteral F Xa inhibitor, and most recently approved rivaroxaban is the first oral anti‑Xa inhibitor. Other anti‑Xa molecules are under development for either parenteral (idraparinux, DX-9065a) or oral use (razaxaban, apixaban, rivaroxaban, LY-51, 7717, BMS-56247 a DU-176b).
Key words:
new anticoagulants – factor Xa – selective anti‑factor Xa inhibitors
Sources
1. Rosendaal FE, Van Hylcama Vlieg A, Doggen JM. Venous thrombosis in elderly. J Thromb Haemost 2007; 5 (Suppl 1): 310–317.
2. Silverstein MD, Heit JA, Mohr DN et al. Trends in the incidence of deep venous thrombosis and pulmonary embolism: a 25 year population‑based study. Arch Intern Med 1998; 158: 585–593.
3. Heit JA. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost 2005; 3: 1611–1617.
4. Stein PD, Hull RD, Kayali F et al. Venous thromboembolism according to age; impact of an aging population. Arch Intern Med 2004; 164: 2260–2263.
5. Davie EW. Biochemical and molecular aspects of the coagulation cascade. Thromb Haemost 1995; 75: 1–6.
6. Hoffman M, Monroe DM. III A cell- -based model of hemostasis. Thromb Haemost 2001; 85: 958–965.
7. Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005; 3: 1843–1853.
8. Ansell J. Faxtor Xa or thrombin: is factor Xa a better target? J Thromb Haemost 2007; 5: (Suppl 1): 60–64.
9. Weitz JI. Factor Xa or thrombin: Is thrombin a better target? J Thromb Haemost 2007; 5 (Suppl 1): 65–67.
10. Abilgaard U. Highly purified antithrombin III with heparin cofactor activity prepared by disc electrophoresis. Scand J Clin Lab Invest 1968; 21: 89–91.
11. Rosenberg RD, Lam L. Corelations between structure and function of heparin. Proc Natl Acad Sci USA, 1979; 76: 1218–1222.
12. Lindahl U, Backtrom G, Hook M et al. Structure and antithrombin‑binding site of heparin. Proc Natl Acad Sci USA 1979; 76: 3198–3202.
13. Hirsh J. Low molecular weight heparins. 4th ed. Hamilton: BC Decker Inc 2007.
14. Johnson EA, Kirkwood TB, Stirling Y et al. Four heparin preparations: anti‑Xa potentiating effect of heparin after subcutaneous injection. Thromb Haemost 1976; 35: 586–591.
15. Carter CJ, Kelton JG, Hirsh J et al. The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. Blood 1982; 59: 1239–1245.
16. Weitz JI. Low molecular-weight heparins. N Engl J Med 1997; 337: 688–698.
17. Warkentin TE, Levine MN, Hirsh J et al. Heparin‑induced thrombocytopenia in patients treated with low-molecular weigh heparin or unfractionated heparin. N Eng J Med 1995; 3232: 1330–1335.
18. Warkentin TE, Greinacher A. Heparin‑induced thrombocytopenia. Recognition, treatment and prevention. Chest 2004; 126 (Suppl 3): 311–337.
19. Hirsh J. Fondaparinux. Hamilton: BC Decker Inc 2007.
20. Kalicki RM, Aregger F, Alberio L et al. Use of the pentasaccharide fondaparinux as an anticoagulant during haemodialysis. Thrombosis Haemost 2007; 98: 1200–1207.
21. Bijstervald NR, Moons AH, Boeckhold SM et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasacharide fondaparinux in healthy volunters. Circulation 2002; 106: 2550– 2554.
22. Turpie AGG, Eriksson BI, Bauer KA et al. Fondaparinux. J Am Acad Ortop Surg 2004; 12: 371–375.
23. Savi P, Chong BH, Greinacher A et al. Effect of fondaparinux on platelet activation in the presence of heparin. Blood 2005; 105: 139–144.
24. Warkentin TE. HIT. Lessons learned. Pathophysiol Haemos Thromb 2006; 1–2: 50–57.
25. Harenberg J, Jorg I, Fenyvesi T. Treatment of heparin‑induced thrombocytopenia with fondaparinux. Haematologica 2004; 89: 1017–1018.
26. Efird L. Fondaparinux for thromboembolic treatment and prophylaxis of heparin‑induced thrombocytopenia. Ann Pharmacother 2006; 40: 1383–1387.
27. Bátorová A, Skraková M, Labancová Aet al. Manažment heparínom-indukovanej trombocytopénie. Interná medicína 2006; 10: 31.
28. Warkentin TE, Maurer BT, Aster RH et al. Heparin‑induced thrombocytopenia associated with fondaparinux. N Engl J Med 2007; 356: 2653–2654.
29. Weitz JI, Hirsh J, Samama M. New anticoagulant drugs. Chest 2004; 126 (Suppl 3): 265–285.
30. Veyrat-Follet C, Vivier N, Trellu M et al. The pharmacokinetics of idraparinux, a long acting indirect factor xa inhibitor: population pharmacokinetic analysis from Phase III clinical trials. J Thromb Haemost 2009; Epub ahead of print.
31. Eriksson BI, Borris LC, Friedman RJ et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765–2775.
32. Kakkar AK, Brenner B, Dahl OE et al. Extended duration rivaroxaban versus short‑term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372: 31–39.
33. Lassen MR, Ageno W, Borris LC et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776–2786.
34. Abrams PJ, Emerson CR. Rivaroxaban, a novel direct oral anti Xa inhibitor. Pharmacotherapy 2009; 29: 167–181.
35. Carreiro J, Ansell J Apixaban, an oral direct Factor Xa inhibitor: awaiting the verdict. Expert Opin Investig Drugs 2008; 17: 1937–1945.
36. Turpie AG, Bauer KA, Davidson BL et al. EXPERT Study Group. A randomized evaluation of betrixaban, an oral factor X inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb Haemost 2009; 101: 68–76.
37. Agnelli G, Haas S, Ginsberg JS at al. A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost 2007; 5: 746–753.
38. Abraham E, Reinhart K, Opal S et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomised control trial. JAMA 2003; 290: 238– 247.
39. Golino P, Ragni M, Cirillo P et al. Antithrombotic effects of recombinant human, active site-blocked factor VIIa in a rabbit model of recurrent and arterial thrombosis. Circulation Res 1998; 82: 39–46.
40. Jang Y, Guzman LA, Lincoff AM et al. Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabbit atherosclerotic femoral artery injury model. Circulation 1995; 92: 3041–3050.
41. Benedict CR, Ryan J, Wolitzky B et al. Active-site blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model. J Clin Invest 1991; 88: 1760–1765.
42. Fuererstein GZ, Toomey JR, Valocik R et al. An inhibitory anti‑factor IX antibody effectively reduces thrombus formation in a rat model of venous thrombosis. Thromb Haemost 1999; 92: 1443–1450.
43. White B, Livingstone W, Murphy C et al. An open label study of the adjuvant hemostatic support with protein C replacement in purpura fulminans‑associated menongococcaemia. Blood 2000; 96: 3719–3724.
44. Bernard GR, Vincent JL, Laterre PF et al. Efficacy and safety of recombinant activated protein C for severe sepsis. N J Engl Med 2001; 344: 699–709.
45. Aoki Y, Ohishi R, Takei R et al. Effects of recombinant human soluble thrombomodulin (rhs-TM) on a rat model of disseminated intravascular coagulation with decreased levels of plasma antithrombin III. Thromb Haemost 1994; 71: 452–455.
46. Kaeron C, Comp P, Douketis JD et al. A dose‑response study of recombinant human soluble thrombomodulin (ART-123) for prevention of venous thromboembolism sfter unilateral total hip replacement. J Thromb Haemost 2003; 1 (Suppl 1): OC330.
47. Baetz BE, Spinler SA. Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases. Pharmacotherapy 2008; 28: 1354–1373.
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Internal Medicine
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