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Table of Contents
Vol. 33, No. 2, 2003
Issue release date: November 2003
Section title: Original Paper
Pathophysiol Haemost Thromb 2003;33:68–74

Effects of the Oral Direct Thrombin Inhibitor Ximelagatran on P-Selectin Expression and Thrombin Generation in Atrial Fibrillation

Wolzt M.a · Boström S.L.b · Svensson M.b · Wåhlander K.b,c · Grind M.d · Sarich T.C.e
aDepartment of Clinical Pharmacology, University of Vienna, Vienna, Austria; bAstraZeneca R&D, Mölndal, cDepartment of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg, Sweden; dAstraZenca R&D Charnwood, Loughborough, UK; eAstraZeneca LP, Wilmington, Del., USA
email Corresponding Author

Troy C. Sarich, PhD

Experimental Medicine, AstraZeneca LP

PO Box 15347, C4C-123

Wilmington, DE 19850 (USA)

Tel. +1 302 885 8979, Fax +1 302 886 3386, E-Mail troy.sarich@astrazeneca.com


  1. Wolf PA: Prevention of stroke. Lancet 1998;352(suppl 3):SIII-15–SIII-18.
  2. Hart RG, Sherman DG, Easton JD, Cairns JA: Prevention of stroke in patients with nonvalvular atrial fibrillation. Neurology 1998;51:674–681.
  3. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, McNamara RL, Prystowsky EN, Wann LS, Wyse DG: ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. Eur Heart J 2001;22:1852–1923.
  4. Blann AD, Li-Saw-Hee F, Lip GY, Minamino T, Kitakaze M, Sanada S, Asanuma H, Kurotobi T, Koretsune Y, Fukunami M, Kuzuya T, Hoki N, Hori M: Increased membrane and soluble P-selectin in atrial fibrillation. Circulation 1999;100:e86–e87.
  5. Goette A, Ittenson A, Hoffmanns P, Reek S, Hartung W, Klein H, Ansorge S, Geller JC: Increased expression of P-selectin in patients with chronic atrial fibrillation. PACE 2000;23:1872–1875.
  6. Li-Saw-Hee FL, Blann AD, Gurney D, Lip GY: Plasma von Willebrand factor, fibrinogen and soluble P-selectin levels in paroxysmal, persistent and permanent atrial fibrillation. Effects of cardioversion and return of left atrial function. Eur Heart J 2001;22:1741–1747.
  7. Michelson AD: Platelet activation by thrombin can be directly measured in whole blood through the use of the peptide GPRP and flow cytometry: Methods and clinical applications. Blood Coagul Fibrinolysis 1994;5:121–131.
  8. Becker RC, Bovill EG, Seghatchian MJ, Samama MM: Pathobiology of thrombin in acute coronary syndromes. Am Heart J 1998;136:S19–S31.
  9. Fenton JW 2nd, Ofosu FA, Brezniak DV, Hassouna HI: Thrombin and antithrombotics. Semin Thromb Haemost 1998;24:87–91.
  10. Hauptmann J, Stürzebecher J: Synthetic inhibitors of thrombin and factor Xa: From bench to bedside. Thromb Res 1999;93:203–241.
  11. Eichinger S, Wolzt M, Schneider B, Nieszpaur-Los M, Heinrichs H, Lechner K, Eichler HG, Kyrle PA: Effects of recombinant hirudin (r-hirudin, HBW 023) on coagulation and platelet activation in vivo: Comparison with unfractionated heparin and a low-molecular-weight heparin preparation (Fragmin). Arterioscler Thromb Vasc Biol 1995;15:886–892.
  12. Prasa D, Svendsen L, Stürzebecher J: The ability of thrombin inhibitors to reduce the thrombin activity generated in plasma on extrinsic and intrinsic activation. Thromb Haemost 1997;77:498–503.
  13. Sarich TC, Wolzt M, Eriksson UG, Mattsson C, Schmidt A, Elg S, Andersson M, Wollbratt M, Fager G, Gustafsson D: Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects. J Am Coll Cardiol 2003;41:557–564.
  14. Lindhout T, Blezer R, Hemker HC: The anticoagulant mechanism of action of recombinant hirudin (CGP39393) in plasma. Thromb Haemost 1990;64:464–468.
  15. Hemker HC, Wielders S, Kessles H, Beguin S: Continuous registration of thrombin generation in plasma, its use for the determination of the thrombin potential. Thromb Haemost 1993;70:617–624.
  16. Hemker HC, Beguin S: Thrombin generation in plasma: Its assessment via the endogenous thrombin potential. Thromb Haemost 1995;74:134–138.
  17. Eriksson UG, Bredberg U, Gislen K, Johansson LC, Frison L, Ahnoff M, Gustafsson D: Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003;59:35–43.
  18. Grind M, Hamrén B, Bååthe S, Wollbratt M, Eriksson UG: Pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation receiving long-term treatment: A population analysis by nonlinear mixed effect modeling (abstract). Clin Pharmacol Ther 2002;71:P31.
  19. Larsson M, Logren U, Ahnoff M, Lindmark B, Abrahamsson P, Svennberg H, Persson BA: Determination of melagatran, a novel, direct thrombin inhibitor, in human plasma and urine by liquid chromatography-mass spectrometry. J Chromatogr B Biomed Sci Appl 2002;766:47–55.
  20. Stohlawetz P, Horvath M, Pernerstorfer T, Nguyen H, Vondrovec B, Robisch A, Eichler HG, Spitzauer S, Jilma B: Effects of nitric oxide on platelet activation during plateletpheresis and in vivo tracking of biotinylated platelets in humans. Transfusion 1999;39:506–514.
  21. Minamino T, Kitakaze M, Asanuma H, Ueda Y, Koretsune Y, Kuzuya T, Hori M: Plasma adenosine levels and platelet activation in patients with atrial fibrillation. Am J Cardiol 1999;83:194–198.
  22. Li-Saw-Hee FL, Blann AD, Edmunds E, Gibbs CR, Lip GY: Effect of acute exercise on the raised plasma fibrinogen, soluble P-selectin and von Willebrand factor levels in chronic atrial fibrillation. Clin Cardiol 2001;24:409–414.
  23. Minamino T, Kitakaze M, Sanada S, Asanuama H, Kurotobi T, Koretsune Y, Fukunami M, Kuzuya T, Hoki N, Hori M: Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: Role of nitric oxide. Circulation 1998;98:1721–1727.
  24. Pongratz C, Brandt-Pohlmann M, Henneke KH, Pohle C, Zink D, Gehling G, Bachmann K: Platelet activation in embolic and preembolic status of patients with nonrheumatic atrial fibrillation. Chest 1997;111:929–933.
  25. Li-Saw-Hee FL, Blann AD, Lip GY: A cross-sectional and diurnal study of thrombogenesis among patients with chronic atrial fibrillation. J Am Coll Cardiol 2000;35:1926–1931.
  26. Kamath S, Blann AD, Chin BS, Lip GY: A prospective randomized trial of aspirin-clopidogrel combination therapy and dose-adjusted warfarin on indices of thrombogenesis and platelet activation in atrial fibrillation. J Am Coll Cardiol 2002;40:484–490.
  27. Li-Saw-Hee FL, Blann AD, Goldsmith I, Lip GY: Indexes of hypercoagulability measured in peripheral blood reflect levels in intracardiac blood in patients with atrial fibrillation secondary to mitral stenosis. Am J Cardiol 1999;83:1206–1209.
  28. Pernerstorfer T, Eichler HG, Stohlawetz P, Speiser W, Jilma B: Effects of heparin and aspirin on circulating P-selectin. E-selectin and von Willebrand factor levels in healthy men. Atherosclerosis 2001;155:389–393.
  29. Barkalow FJ, Barkalow KL, Mayadas TN: Dimerization of P-selectin in platelets and endothelial cells. Blood 2000;96:3070–3077.
  30. Tans G, Curvers J, Middeldorp S, Thomassen MC, Meijers JC, Prins MH, Bouma BN, Buller HR, Rosing J: A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways. Thromb Haemost 2000;84:15–21.
  31. Wielders S, Mukherjee M, Michiels J, Rijkers DT, Cambus JP, Knebel RW, Kakkar V, Hemker HC, Beguin S: The routine determination of the endogenous thrombin potential, first results in different forms of hyper- and hypocoagulability. Thromb Haemost 1997;77:629–636.
  32. Bos GM, Rijkers DT, Willems HP, den Heijer M, Beguin S, Gerrits WB, Hemker HC: The elevated risk for venous thrombosis in persons with hyperhomocysteinemia is not reflected by the endogenous thrombin potential. Thromb Haemost 1999;81:467–468.
  33. Eichinger S, Weltermann A, Phillipp K, Hafner E, Kaider A, Kittl EM, Brenner B, Mannhalter C, Lechner K, Kyrle PA: Prospective evaluation of hemostatic system activation and thrombin potential in healthy pregnant women with and without factor V Leiden. Thromb Haemost 1999;82:1232–1236.
  34. Peyrou V, Lormeau JC, Herault JP, Gaich C, Pfliegger AM, Herbert JM: Contribution of erythrocytes to thrombin generation in whole blood. Thromb Haemost 1999;81:400–406.
  35. Boström SL, Sarich TC, Wolzt M: The effects of melagatran, the active form of H376/95, an oral, direct thrombin inhibitor, on thrombin generation (abstract). Blood 2000;96:56a.