The mechanism of action of rivaroxaban - An oral, direct Factor Xa inhibitor - Compared with other anticoagulants

Thrombosis Research

Volumn 127, Issue 6, 2011, Pages 497-504

  Samama, Meyer Michel ^a,b  

^a HÔTEL DIEU   (France)

^b Biomnis Laboratory   (France)

Author keywords

Anticoagulants; Direct Factor Xa inhibitors; Direct thrombin inhibitors; Rivaroxaban

Indexed keywords

APIXABAN; BETRIXABAN; BLOOD CLOTTING FACTOR 10A; DABIGATRAN ETEXILATE; DAREXABAN; EDOXABAN; ENOXAPARIN; FONDAPARINUX; RIFAMPICIN; RIVAROXABAN; SERINE PROTEINASE; WARFARIN;

ACUTE CORONARY SYNDROME; ANTICOAGULATION; AREA UNDER THE CURVE; BINDING AFFINITY; BLEEDING; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG EXCRETION; DRUG HALF LIFE; DRUG SAFETY; DRUG SELECTIVITY; DRUG STRUCTURE; EMBOLISM; GASTROINTESTINAL SYMPTOM; HUMAN; MAXIMUM PLASMA CONCENTRATION; PRIORITY JOURNAL; PROTHROMBIN TIME; REVIEW; STROKE; VENOUS THROMBOEMBOLISM;

ANIMALS; ANTICOAGULANTS; BLOOD COAGULATION; BLOOD COAGULATION TESTS; FACTOR XA; HUMANS; MORPHOLINES; THIOPHENES;

EID: 79957606320     PISSN: 00493848     EISSN: 18792472     Source Type: Journal    
DOI: 10.1016/j.thromres.2010.09.008     Document Type: Review

References (105)

1. Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008;451: 914-8. (Pubitemid 351301746)
2. Heit JA, Cohen AT, Anderson FA, on behalf of the VTE Impact Assessment Group. Estimated annual number of incident and recurrent, non-fatal and fatal venous thromboembolism (VTE) events in the US. Blood (ASH Annual Meeting Abstracts) 2005;106:910.
3. Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007;98:756-64.
4. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:454S-545S.
5. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism:American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:381S-453S.
6. Gross PL, Weitz JI. New anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol 2008;28:380-6.
7. Hirsh J, Warkentin TE, Raschke R, Granger C, Ohman EM, Dalen JE. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1998;114:489S-510S.
8. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:160S-98S.
9. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008;359: 938-49.
10. Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol 2003;23:17-25. (Pubitemid 36091621)
11. Maurissen LF, Castoldi E, Simioni P, Rosing J, Hackeng TM. Thrombin generation-based assays to measure the activity of the TFPI-protein S pathway in plasma from normal and protein S-deficient individuals. J Thromb Haemost 2010;8:750-8.
12. Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843-53. (Pubitemid 41716571)
13. Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. N Engl J Med 2005;353:1028-40. (Pubitemid 41262337)
14. Weitz JI. Emerging anticoagulants for the treatment of venous thromboembolism. Thromb Haemost 2006;96:274-84. (Pubitemid 44377809)
15. Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI, et al. Parenteral anticoagulants: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:141S-59S.
16. Walenga JM, Jeske WP, Samama MM, Frapaise FX, Bick RL, Fareed J. Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent. Expert Opin Investig Drugs 2002;11:397-407. (Pubitemid 34213393)
17. Tersteegen A, Schmidt S, Burkhardt N. Rivaroxaban - an oral, direct Factor Xa inhibitor - binds rapidly to Factor Xa. J Thromb Haemost 2007;5(Suppl 2):P-W-651.
18. Roehrig S, Straub A, Pohlmann J, Lampe T, Pernerstorfer J, Schlemmer KH, et al. Discovery of the novel antithrombotic agent 5-chloro-N-([(5S)-2-oxo-3-[4- (3-oxomorpholin-4-yl)phenyl]-1, 3-oxazolidin-5-yl]methyl)thiophene-2-carboxamide (BAY 59-7939): an oral, direct Factor Xa inhibitor. J Med Chem 2005;48:5900-8. (Pubitemid 41324601)
19. Straub A, Roehrig S, Hillisch A. Entering the era of non-basic P1 site groups: Discovery of Xarelto (Rivaroxaban). Curr Top Med Chem 2010;10:257-69.
20. Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer KH, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 - an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514-21.
21. Duggan ST, Scott LJ, Plosker GL. Rivaroxaban: a review of its use for the prevention of venous thromboembolism after total hip or knee replacement surgery. Drugs 2009;69:1829-51.
22. Mueck W, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost 2008;100:453-61.
23. Graff J, von Hentig N, Misselwitz F, Kubitza D, Becka M, Breddin HK, et al. Effects of the oral, direct Factor Xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol 2007;47:1398-407. (Pubitemid 47624591)
24. Depasse F, Busson J, Mnich J, Le Flem L, Gerotziafas GT, Samama MM. Effect of BAY 59-7939 - a novel, oral, direct Factor Xa inhibitor - on clot-bound Factor Xa activity in vitro. J Thromb Haemost 2005;3(Suppl 1):P1104.
25. Fareed J, Hoppensteadt D, Maddenini J, Schultz J, Neville B, Iqbal O, et al. Antithrombotic mechanism of action of BAY 59-7939 - a novel, oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3(Suppl 1):P0518.
26. Gerotziafas GT, Elalamy I, Depasse F, Perzborn E, Samama MM. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct Factor Xa inhibitor rivaroxaban. J Thromb Haemost 2007;5:886-8.
27. Perzborn E, Harwardt M, Huetter J. Inhibition of thrombin generation by rivaroxaban (BAY 59-7939) - an oral, direct Factor Xa inhibitor-in human plasma. Hamostaseologie 2007;27:A47.
28. Varin R, Mirshahi S, Mirshahi P, Chidiac J, Kierzek G, Marie JP, et al. Effect of rivaroxaban, an oral direct Factor Xa inhibitor, on whole blood clot permeation and thrombolysis: critical role of red blood cells. Blood (ASH Annual Meeting Abstracts) 2009;114:1064.
29. Biemond BJ, Perzborn E, Friederich PW, Levi M, Buetehorn U, Büller HR. Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 59-7939) - an oral, direct Factor Xa inhibitor. Thromb Haemost 2007;97:471-7. (Pubitemid 46437811)
30. Perzborn E, Arndt B, Fischer E, Harwardt M, Lange U, Trabandt A. Antithrombotic effects of rivaroxaban - an oral, direct Factor Xa inhibitor - in animal models of arterial and venous thrombosis: comparison with enoxaparin, an antithrombindependent anticoagulant. Eur Heart J 2006;27(Suppl):762:P4571.
31. Haertlein B, Parry TJ, Chen C, Perzborn E, Andrade-Gordon P, Damiano BP. Rivaroxaban - an oral, direct Factor Xa inhibitor - prevents arterial thrombotic occlusion in electrolytically injured rat carotid arteries. Blood (ASH Annual Meeting Abstracts) 2007;110:3.
32. Perzborn E, Arndt B, Harwardt M, Lange U, Fischer E, Trabant A. Antithrombotic efficacy of BAY 59-7939 - an oral, direct Factor Xa inhibitor - compared with fondaparinux in animal arterial thrombosis and thromboembolic death models. Eur Heart J 2005;26(Suppl):481:P2943.
33. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412-21. (Pubitemid 41393676)
34. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 - an oral, direct Factor Xa inhibitor - after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873-80. (Pubitemid 41803696)
35. Bayer Schering Pharma. Xarelto® Summary of Product Characteristics. Available at: http://www.xarelto.com/html/downloads/Xarelto-Summary-of-Product- Characteristics-May2009.pdf. 2009.
36. Mueck W, Becka M, Kubitza D, Voith B, Zuehlsdorf M. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct Factor Xa inhibitor - in healthy subjects. Int J Clin Pharmacol Ther 2007;45:335-44. (Pubitemid 46895052)
37. Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct factor Xa inhibitor - in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008;47:203-16.
38. Halabi A, Maatouk H, Klause N, Lufft V, Kubitza D, Zuehlsdorf M, et al. Effect of renal impairment on the pharmacology of rivaroxaban (BAY 59-7939) - an oral, direct Factor Xa inhibitor. Blood (ASH Annual Meeting Abstracts) 2006;108:913.
39. Kubitza D, Becka M, Roth A, Mueck W. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008;24:2757-65.
40. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct Factor Xa inhibitor, in healthy subjects. J Clin Pharmacol 2006;46: 549-58.
41. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban - an oral, direct Factor Xa inhibitor - are not affected by aspirin. J Clin Pharmacol 2006;46:981-90. (Pubitemid 44215062)
42. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Rivaroxaban (BAY 59-7939) - an oral, direct Factor Xa inhibitor - has no clinically relevant interaction with naproxen. Br J Clin Pharmacol 2007;63:469-76. (Pubitemid 46426627)
43. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Co-administration of rivaroxaban - a novel, oral, direct Factor Xa inhibitor - and clopidogrel in healthy subjects. Eur Heart J 2007;28(Suppl 1):189:P1272.
44. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. No interaction between the novel, oral direct Factor Xa inhibitor BAY 59-7939 and digoxin. J Clin Pharmacol 2006;46:702:11.
45. Kubitza D, Mueck W, Becka M. No interaction between rivaroxaban - a novel, oral, direct factor Xa inhibitor - and atorvastatin. Pathophysiol Haemost Thromb 2008;36:A40.
46. Kubitza D, Mueck W, Becka M. Randomized, double-blind, crossover study to investigate the effect of rivaroxaban on QT-interval prolongation. Drug Saf 2008;31:67-77.
47. Weinz C, Radtke M, Schmeer K, Kern A, Pleiss U. In vitro metabolism of BAY 59-7939 - an oral, direct Factor Xa inhibitor. Drug Metab Rev 2004;36(Suppl 1):195.
48. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765-75. (Pubitemid 351930851)
49. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, 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;372:31-9.
50. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776-86. (Pubitemid 351930852)
51. Turpie AGG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009;373:1673-80.
52. Turpie AGG, Lassen MR, Kakkar AK, Eriksson BI, Misselwitz F, Bandel TJ, et al. A pooled analysis of four pivotal studies of rivaroxaban for the prevention of venous thromboembolism after orthopaedic surgery: effect on symptomatic venous thromboembolism and death, and bleeding. Haematologica 2009;94 (Suppl 2):212:0522.
53. Hull R, Yusen RD, Bergqvist D. Variation in major bleeding definitions in phase III orthopedic VTE prophylaxis trials and the impact on major bleeding frequency. J Thromb Haemost 2009;7:171.
54. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29-38.
55. Luettgen JM, Bozarth TA, Bozarth JM, Barbera FA, Lam PY, Quan ML, et al. In vitro evaluation of apixaban, a novel, potent, selective and orally bioavailable Factor Xa inhibitor. Blood (ASH Annual Meeting Abstracts) 2006;108:4130.
56. Pinto DJ, OrwatMJ, Koch S, Rossi KA, Alexander RS, Smallwood A, et al. Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4, 5, 6, 7-tetrahydro-1H-pyrazolo[3, 4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation Factor Xa. J Med Chem 2007;50:5339-56.
57. Luettgen JM, Wang Z, Seiffert DA, Rendina AR, Knabb RM, Ogletree ML. Inhibition of measured thrombin generation in human plasma by apixaban: a predictive mathematical model based on experimentally determined rate constants. J Thromb Haemost 2007;5(Suppl 1):P-T-633.
58. He K, He B, Grace JE, Xin B, Zhang D, Pinto DJ, et al. Preclinical pharmacokinetic and metabolism of apixaban, a potent and selective Factor Xa inhibitor. Blood (ASH Annual Meeting Abstracts) 2006;108:910.
59. Frost C, Yu Z, Moore K, Nepal S, Barrett R, Mosqueda-Garcia R, et al. Apixaban, an oral direct factor Xa inhibitor: multiple-dose safety, pharmacokinetics, and pharmacodynamics in healthy subjects. J Thromb Haemost 2007;5(Suppl 2):P-M-664.
60. Lassen MR, Gallus AS, Pineo GF, Raskob GE, ADVANCE-1 Investigators. Randomized double-blind comparison of apixaban with enoxaparin for thromboprophylaxis after knee replacement: the ADVANCE-1 trial. Blood (ASH Annual Meeting Abstracts) 2008;112:31.
61. Lassen MR, Gallus AS, Pineo GF, Raskob GE. The ADVANCE-2 study: a randomized double-blind trial comparing apixaban with enoxaparin for thromboprophylaxis after total knee replacement. J Thromb Haemost 2009;7(Suppl 2):1203-4:LB-MO-005.
62. Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009;119:2877-85.
63. Morishima Y, Furugohri T, Isobe K, Honda Y, Matsumoto C, Shiozaki Y, et al. In vitro characteristics, anticoagulant effects and in vivo antithrombotic efficacy of a novel, potent and orally active direct factor Xa inhibitor, DU-176b. Blood (ASH Annual Meeting Abstracts) 2004;104:1862.
64. Zafar MU, Vorchheimer DA, Gaztanaga J, Velez M, Yadegar D, Moreno PR, et al. Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber. Thromb Haemost 2007;98:883-8. (Pubitemid 47555083)
65. Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, et al. DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost 2008;6:1542-9.
66. Ogata K, Mendell-Harary J, Tachibana M, Matsumoto H, Oguma T, Kojima M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel Factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010;50:743-53.
67. Fuji T, Fujita S, Tachibana S, Kawai Y. Randomized, double-blind, multi-dose efficacy, safety and biomarker study of the oral Factor Xa inhibitor DU-176b compared with placebo for prevention of venous thromboembolism in patients after total knee arthroplasty. Blood (ASH Annual Meeting Abstracts) 2008;112:34.
68. Raskob G, Cohen A, Eriksson B, Macdonald A, Puskas D, Shi M, et al. Randomized double-blind multi-dose trial of the oral factor-Xa inhibitor DU-176b versus LMW Heparin (Dalteparin) for prevention of venous thromboembolism after total hip replacement. Eur Heart J 2008;29(Suppl 1):602:P3712.
69. Weitz JI, Connolly SJ, Kunitada S, Jin J, Patel I. Randomized, parallel group, multicenter, multinational study evaluating safety of DU-176b compared with warfarin in subjects with non-valvular atrial fibrillation. Blood (ASH Annual Meeting Abstracts) 2008;112:33.
70. Turpie AGG, Bauer KA, Davidson BL, Fisher WD, Gent M, Huo MH, et al. A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb Haemost 2009;101:68-76.
71. Eriksson BI, Turpie AGG, Lassen M, Prins MH, Agnelli G, Kälebo P, et al. Once daily YM150, an oral direct Factor Xa inhibitor, for prevention of venous thromboembolism in patients undergoing elective primary hip replacement. Blood (ASH Annual Meeting Abstracts) 2007;112:309.
72. Gruber A, Marzec UM, Buetehorn U, Hanson S, Perzborn E. Potential of activated prothrombin complex concentrate and activated Factor VII to reverse the anticoagulant effects of rivaroxaban in primates. Blood (ASH Annual Meeting Abstracts) 2008;112:3825.
73. Perzborn E, Tinel H. FEIBA reverses the effects of a high dose of rivaroxaban in rats. Pathophysiol Haemost Thromb 2008;36:A40:P061.
74. Lu G, DeGuzman FR, Lakhotia S, Hollenbach SJ, Phillips DR, Sinha U. Recombinant antidote for reversal of anticoagulation by Factor Xa inhibitors. Blood (ASH Annual Meeting Abstracts) 2008;112:983.
75. Eriksson BI, Smith H, Yasothan U, Kirkpatrick P. Dabigatran etexilate. Nat Rev Drug Discov 2008;7:557-8. (Pubitemid 351927721)
76. Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002;45: 1757-66. (Pubitemid 34415371)
77. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthymale subjects. Br J Clin Pharmacol 2007;64:292-303. (Pubitemid 47283865)
78. Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008;36:386-99. (Pubitemid 351185753)
79. Stangier J, Stähle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008;47:47-59. (Pubitemid 350260888)
80. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008;47:285-95. (Pubitemid 351508116)
81. Boehringer Ingelheim. Pradaxa® Summary of Product Characteristics. Available at:http://www.pradaxa.com/Include/media/pdf/Pradaxa-SPC-EMEA.pdf. 2008.
82. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007;370:949-56. (Pubitemid 47393577)
83. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:2178-85. (Pubitemid 47617868)
84. The RE-MOBILIZE Writing Committee. The oral thrombin inhibitor dabigatran etexilate vs the North American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009;24:1-9.
85. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
86. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52.
87. Rezaie AR. Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin-antithrombin complex. Blood 2001;97:2308-13. (Pubitemid 32291476)
88. Brufatto N, Ward A, Nesheim ME. Factor Xa is highly protected from antithrombin-fondaparinux and antithrombin-enoxaparin when incorporated into the prothrombinase complex. J Thromb Haemost 2003;1:1258-63.
89. Orfeo T, Butenas S, Brummel-Ziedins KE, Gissel M, Mann KG. Anticoagulation by factor Xa inhibitors. J Thromb Haemost 2010;8:1745-53.
90. Jiang X, Crain EJ, Luettgen JM, Schumacher WA, Wong PC. Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb Haemost 2009;101:780-2.
91. Eisenberg PR, Sobel BE, Jaffe AS. Activation of prothrombin accompanying thrombolysis with recombinant tissue-type plasminogen activator. J Am Coll Cardiol 1992;19:1065-9.
92. Eisenberg PR, Siegel JE, Abendschein DR, Miletich JP. Importance of factor Xa in determining the procoagulant activity of whole-blood clots. J Clin Invest 1993;91:1877-83. (Pubitemid 23141454)
93. Prager NA, Abendschein DR, McKenzie CR, Eisenberg PR. Role of thrombin compared with factor Xa in the procoagulant activity of whole blood clots. Circulation 1995;92:962-7.
94. Laurent M, Varin R, Joimel U, Li H, Lu H, Blot E, et al. A novel mechanism of action of rivaroxaban: inhibition of monocyte and macrophage procoagulant activity and consequence on inflammatory process. Blood (ASH Annual Meeting Abstracts) 2009;114:3124.
95. Weitz JI. Factor Xa or thrombin: is thrombin a better target? J Thromb Haemost 2007;5(Suppl 1):65-7.
96. Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemost 2007;5(Suppl 1):60-4.
97. Brummel KE, Paradis SG, Butenas S, Mann KG. Thrombin functions during tissue factor-induced blood coagulation. Blood 2002;100:148-52. (Pubitemid 35177440)
98. Friedman RJ, Gallus AS, Cushner FD, Fitzgerald G, Anderson Jr FA, Global Orthopaedic Registry Investigators. Physician compliance with guidelines for deep-vein thrombosis prevention in total hip and knee arthroplasty. Curr Med Res Opin 2008;24:87-97.
99. Mismetti P, Laporte S. New oral antithrombotics: a need for laboratory monitoring. J Thromb Haemost 2010;8:621-6.
100. Weitz JI. Neworal anticoagulants in development. Thromb Haemost 2010;103:62-70.
101. Haas S. Facts and artefacts of coagulation assays for Factor Xa inhibitors. Thromb Haemost 2010;103:686-8.
102. Walenga JM, Hoppensteadt DA. Monitoring the new antithrombotic drugs. Semin Thromb Hemost 2004;30:683-95. (Pubitemid 40041604)
103. Samama MM, Le Flem L, Guinet C, Perzborn E, Amiral J, Depasse F. Suitability of chromogenic anti-FXa methods to measure rivaroxaban in human plasma. J Thromb Haemost 2009;7(Suppl):693:PP-WE-199.
104. Perzborn E, Harwardt M, Samama M. Assessment of Factor Xa chromogenic assays for measuring the pharmacodynamics of rivaroxaban - an oral, direct Factor Xa inhibitor. J Thromb Haemost 2009;7(Suppl 2):379:PP-MO-185.
105. Samama MM, Amiral J, Celine G, Perzborn E, Depasse F. A new and specific rapid chromogenic "anti-Xa" assay for testing rivaroxaban in plasma. Pathophysiol Haemost Thromb 2010;37(Suppl 1):A49.