Thromb Haemost 2010; 104(03): 504-513
DOI: 10.1160/TH09-12-0817
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Differential effects of TAK-442, a novel orally active direct factor Xa inhibitor, and ximelagatran, a thrombin inhibitor, on factor V-mediated feedback on coagulation cascade and bleeding

Noriko Konishi
1   Pharmacology Research Laboratories, Takeda Pharmaceutical Company Ltd., Osaka, Japan
,
Katsuhiko Hiroe
1   Pharmacology Research Laboratories, Takeda Pharmaceutical Company Ltd., Osaka, Japan
,
Masaki Kawamura
2   Takeda Global Research & Development Center Inc., Deerfield, Illinois, USA
› Author Affiliations
Further Information

Publication History

Received: 04 December 2009

Accepted after major revision: 24 April 2010

Publication Date:
23 November 2017 (online)

Summary

Thrombin amplifies the blood coagulation via factor V (FV)-mediated positive feedback loop. We hypothesised that factor Xa (FXa) inhibitors would interfere more gradually with this feedback activation loop than thrombin inhibitors, thereby achieving a better balance between haemostasis and prevention of thrombosis. In this study, we compared the effects of TAK-442, a novel FXa inhibitor, versus ximelagatran, a thrombin inhibitor, on FV-mediated positive feedback, venous thrombosis and bleeding. In normal plasma, TAK-442 delayed the onset of tissue factor-induced thrombin generation and prolonged prothrombin time (PT) with more gradual concentration-response curve than melagatran, the active form of ximelagatran. The effect of melagatran on the onset of thrombin generation decreased in an FVa-concentration-dependent manner in FV-deficient plasma supplemented with FVa. Furthermore, in FV-deficient plasma, the PT-prolonging potency of melagatran was markedly increased with a change in its concentration-response curve from steep to gradual. In the rat venous thrombosis model, TAK-442 (10 mg/kg, p.o.) prevented thrombus formation by 55% with 1.2 times prolongation of PT; a similar effect was observed in ximelagatran-treated (3 mg/kg, p.o.) rats. TAK-442 at 100 mg/kg prolonged PT by only 2.1 times with no change in bleeding time (BT), whereas ximelagatran at 10 mg/kg prolonged PT by 3.9 times and significantly increased BT. These results suggest that the differential effects of the two agents on FV-mediated amplification of thrombin generation may underlie the observation of a wider therapeutic window for TAK-442 than for ximelagatran.

 
  • References

  • 1 Hirsh J, Dalen J, Anderson DR. et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119: 8S-21S.
  • 2 Francis CW, Berkowitz SD, Comp PC. et al. EXULT A Study Group. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003; 349: 1703-1712.
  • 3 Schulman S, Wahlander K, Lundstrom T. et al. THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003; 349: 1713-1721.
  • 4 Olsson SB. Executive Steering Committee on behalf of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORT-IF III). Lancet 2003; 362: 1691-1698.
  • 5 Albers GW, Diener HC, Frison L. et al. SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. J Am Med Assoc 2005; 293: 690-698.
  • 6 Fiessinger JN, Huisman MV, Davidson BL. et al. THRIVE Treatment Study Investigators. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. J Am Med Assoc 2005; 293: 681-689.
  • 7 Colwell Jr CW, Berkowitz SD, Lieberman JR. et al. EXULT B Study Group. Oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty. J Bone Joint Surg Am 2005; 87: 2169-2177.
  • 8 Boos CJ, Lip GY. Ximelagatran: an eulogy. Thromb Res 2006; 118: 301-304.
  • 9 Eriksson BI, Dahl OE, Rosencher N. et al. RE-MODEL Study Group. 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: 2178-2185.
  • 10 Hara T, Yokoyama A, Tanabe K. et al. DX-9065a, an orally active, specific inhibitor of factor Xa, inhibits thrombosis without affecting bleeding time in rats. Thromb Haemost 1995; 74: 635-639.
  • 11 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: 1366-1371.
  • 12 Sato K, Kaku S, Hirayama F. et al. Antithrombotic effect of YM-75466 is separated from its effect on bleeding time and coagulation time. Eur J Pharmacol 1998; 352: 59-63.
  • 13 Wong PC, Crain EJ, Watson CA. et al. Nonpeptide factor Xa inhibitors III: effects of DPC423, an orally-active pyrazole antithrombotic agent, on arterial thrombosis in rabbits. J Pharmacol Exp Ther 2002; 303: 993-1000.
  • 14 Eriksson BI, Borris LC, Friedman RJ. et al. RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-2775.
  • 15 Lassen MR, Ageno W, Borris LC. et al. RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776-2786.
  • 16 Kakkar AK, Brenner B, Dahl OE. et al. RECORD2 Investigators. 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.
  • 17 Weitz JI. New oral anticoagulants in development. Thromb Haemost 2010; 103: 62-70.
  • 18 Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010; 103: 572-585.
  • 19 Lindhout T, Blezer R, Hemker HC. The anticoagulant mechanism of action of recombinant hirudin (CGP 39393) in plasma. Thromb Haemost 1990; 64: 464-468.
  • 20 Kretz CA, Cuddy KK, Stafford AR. et al. HD1, a thrombin- and prothrombin-binding DNA aptamer, inhibits thrombin generation by attenuating prothrombin activation and thrombin feedback reactions. Thromb Haemost 2010; 103: 83-93.
  • 21 Béguin S, Welzel D, Al Dieri R. et al. Conjectures and refutations on the mode of action of heparins. The limited importance of anti-factor xa activity as a pharmaceutical mechanism and a yardstick for therapy. Haemostasis 1999; 29: 170-178.
  • 22 Fujimoto T, Imaeda Y, Konishi N. et al. Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor. J Med Chem 2010; 53: 3517-3531.
  • 23 Kawamura M, Konishi N, Hiroe K. et al. Antithrombotic and anticoagulant profiles of TAK-442, a novel factor Xa inhibitor in a rabbit model of venous thrombosis. J Cardiovasc Pharmacol. 2010 in press.
  • 24 Hemker HC, Giesen PL, Ramjee M. et al. The thrombogram: monitoring thrombin generation in platelet-rich plasma. Thromb Haemost 2000; 83: 589-591.
  • 25 Ofosu FA, Hirsh J, Esmon CT. et al. Unfractionated heparin inhibits thrombincatalysed amplification reactions of coagulation more efficiently than those catalysed by factor Xa. Biochem J 1989; 257: 143-150.
  • 26 Pieters J, Lindhout T. The limited importance of factor Xa inhibition to the anticoagulant property of heparin in thromboplastin-activated plasma. Blood 1988; 72: 2048-2052.
  • 27 Beguin S, Lindhout T, Hemker HC. The mode of action of heparin in plasma. Thromb Haemost 1988; 60: 457-462.
  • 28 Nagashima H. Studies on the different modes of action of the anticoagulant pro-tease inhibitors DX-9065a and Argatroban. I. Effects on thrombin generation. J Biol Chem 2002; 277: 50439-50444.
  • 29 Majerus PW, Tollfeson DM, Shuman MA. The interaction of platelets with thrombin. In: Platelets in Biology and Pharmacology. North-Holland Publishing; 1976. pp. 241-260.
  • 30 Millis DCB, Macfarlene DE. Platelet receptors. In: Platelets in Biology and Pharmacology. North-Holland Publishing; 1976. pp. 160-202.
  • 31 Sambrano GR, Weiss EJ, Zheng YW. et al. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 2001; 413: 74-78.
  • 32 Covic L, Misra M, Badar J. et al. Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation. Nat Med 2002; 8: 1161-1165.
  • 33 Lassen MR, Davidson BL, Gallus A. et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007; 5: 2368-2375.
  • 34 Agnelli G, Haas S, Ginsberg JS. et 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.
  • 35 Eriksson BI, Turpie AG, Lassen MR. et al. ONYX study group. A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery. J Thromb Haemost 2007; 5: 1660-1665.