ABSTRACT
Thrombin plays a central role in thrombus formation through its conversion of fibrinogen to fibrin and activation of platelets as well as amplifying its own generation by feedback activation via factors V, VIII, and XI. Consequently, thrombin represents a logical and promising target for therapeutic interventions against arterial and venous thromboembolic disorders. Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors and is rapidly absorbed and bioconverted to the active moiety, melagatran, which inhibits fluid-phase and clot-bound thrombin with similar high potency. Binding to the active site of thrombin is direct and competitive and does not require the presence of co-factors. Inhibition of thrombin generation and platelet activation has been demonstrated in vitro with melagatran as well as ex vivo after oral administration of ximelagatran to healthy human volunteers. Oral ximelagatran dose dependently reduced the total thrombus area in an ex vivo flow chamber model of arterial thrombosis, reflecting the cumulative effect of inhibition of thrombin activity, thrombin generation, and platelet activation. Melagatran has also been shown to reduce thrombin-mediated inflammation in vitro. The combination of antithrombotic and anti-inflammatory activity with the practicality of oral dosing provided by ximelagatran represents an important new option for the treatment of arterial and venous thromboembolic disorders.
KEYWORDS
Oral direct thrombin inhibitors - ximelagatran - mechanism of action
REFERENCES
-
1
Van Aken H, Bode C, Darius H et al..
Anticoagulation: the present and future.
Clin Appl Thromb Hemost.
2001;
7
195-204
-
2
Linkins L A, Weitz J I.
New anticoagulants.
Semin Thromb Hemost.
2003;
29
619-631
-
3
Narayanan S.
Multifunctional roles of thrombin.
Ann Clin Lab Sci.
1999;
29
275-280
-
4
Nesheim M, Wang W, Boffa M, Nagashima M, Morser J, Bajzar L.
Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis.
Thromb Haemost.
1997;
78
386-391
-
5
Lorand L, Chenoweth D, Gray A.
Titration of the acceptor cross-linking sites in fibrin.
Ann NY Acad Sci.
1972;
202
155-171
-
6
Furie B, Furie B C, Flaumenhaft R.
A journey with platelet P-selectin: the molecular basis of granule secretion, signalling and cell adhesion.
Thromb Haemost.
2001;
86
214-221
-
7
Hughes P E, Pfaff M.
Integrin affinity modulation.
Trends Cell Biol.
1998;
8
359-364
-
8
Dore M, Korthuis R J, Granger D N, Entman M L, Smith C W.
P-selectin mediates spontaneous leukocyte rolling in vivo.
Blood.
1993;
82
1308-1316
-
9
Ueno A, Murakami K, Yamanouchi K, Watanabe M, Kondo T.
Thrombin stimulates production of interleukin-8 in human umbilical vein endothelial cells.
Immunology.
1996;
88
76-81
-
10
Colotta F, Sciacca F L, Sironi M, Luini W, Rabiet M J, Mantovani A.
Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin.
Am J Pathol.
1994;
144
975-985
-
11
Mutch N J, Robbie L A, Booth N A.
Human thrombi contain an abundance of active thrombin.
Thromb Haemost.
2001;
86
1028-1034
-
12
Granger C B, Miller J M, Bovill E G et al..
Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes.
Circulation.
1995;
91
1929-1935
-
13
Direct Thrombin Inhibitor Trialists' Collaborative Group .
Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients' data.
Lancet.
2002;
359
294-302
-
14
Eriksson U G, Bredberg U, Hoffmann K J et al..
Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans.
Drug Metab Dispos.
2003;
31
294-305
-
15
Gustafsson D, Antonsson T, Bylund R et al..
Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes.
Thromb Haemost.
1998;
79
110-118
-
16
Nilsson T, Sjoling-Ericksson A, Deinum J.
The mechanism of binding of low-molecular-weight active site inhibitors to human alpha-thrombin.
J Enzyme Inhib.
1998;
13
11-29
-
17
Elg M, Gustafsson D, Deinum J.
The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis.
Thromb Haemost.
1997;
78
1286-1292
-
18
Sarich T C, Eriksson U G, Mattsson C et al..
Inhibition of thrombin generation by the oral direct thrombin inhibitor ximelagatran in shed blood from healthy male subjects.
Thromb Haemost.
2002;
87
300-305
-
19
Sarich T C, Wolzt M, Eriksson U G et al..
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
-
20
Mattsson C, Björkman J A, Ulvinge J C.
Melagatran, hirudin and heparin as adjuncts to tissue-type plasminogen activator in a canine model of coronary artery thrombolysis.
Fibrinolysis Proteolysis.
1997;
11
121-128
-
21
Mattsson C, Björkman J A, Abrahamsson T et al..
Local proCPU (TAFI) activation during thrombolytic treatment in a dog model of coronary artery thrombosis can be inhibited with a direct, small molecule thrombin inhibitor (melagatran).
Thromb Haemost.
2002;
87
557-562
-
22
Klement P, Carlsson S, Rak J et al..
The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model.
J Thromb Haemost.
2003;
1
587-594
-
23
Mattsson C, Menschik-Lundin A, Nylander S, Gyzander E, Deinum J.
Effect of different types of thrombin inhibitors on thrombin/thrombomodulin modulated activation of protein C in vitro.
Thromb Res.
2001;
104
475-486
-
24
Hemker H C, Wielders S, Kessels 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
-
25
Boström S L, Hansson G F, Kjaer M, Sarich T C.
Effects of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and dalteparin on the endogenous thrombin potential in venous blood from healthy male subjects.
Blood Coagul Fibrinolysis.
2003;
14
457-462
-
26
Boström S L, Dagnelid E, Hansson G FH, Ulvinge J C.
Inhibition of thrombin-induced feedback activation of factor V: a potential pathway for inhibition of thrombin generation by melagatran.
Blood Coagul Fibrinolysis.
2004;
15
25-30
-
27
Lindhout T, Blezer R, Hemker H C.
The anticoagulant mechanism of action of recombinant hirudin (CGP 39393) in plasma.
Thromb Haemost.
1990;
64
464-468
-
28
Sandset P M, Bendz B, Hansen J B.
Physiological function of tissue factor pathway inhibitor and interaction with heparins.
Haemostasis.
2000;
30(Suppl 2)
48-56
-
29
Boström S L, Hansson G F, Sarich T C, Wolzt M.
The inhibitory effect of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, compared with enoxaparin and r-hirudin on ex vivo thrombin generation in human plasma.
Thromb Res.
2004;
113
85-91
-
30
Kahn M L, Nakanishi-Matsui M, Shapiro M J, Ishihara H, Coughlin S R.
Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin.
J Clin Invest.
1999;
103
879-887
-
31
Hagberg I A, Lyberg T.
Evaluation of circulating platelet-leukocyte conjugates: a sensitive flow cytometric assay well suited for clinical studies.
Platelets.
2000;
11
151-160
-
32
Nylander S, Mattsson C.
Thrombin-induced platelet activation and its inhibition by anticoagulants with different modes of action.
Blood Coagul Fibrinolysis.
2003;
14
159-167
-
33
Sarich T C, Osende J I, Eriksson U G et al..
Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis.
J Thromb Haemost.
2003;
1
999-1004
-
34
Eriksson U G, Bredberg U, Gislén K et al..
Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects.
Eur J Clin Pharmacol.
2003;
59
35-43
-
35
Carlsson S C, Mattsson C, Eriksson U G et al..
A review of the effects of the oral direct thrombin inhibitor ximelagatran on coagulation assays.
Thromb Res.
2005;
115
9-18
-
36
Eriksson B I, Arfwidsson A C, Frison L et al..
A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I MElagatran for THRombin inhibition in Orthopaedic surgery.
Thromb Haemost.
2002;
87
231-237
-
37
Gustafsson D, Nystrom J, Carlsson S et al..
The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects.
Thromb Res.
2001;
101
171-181
-
38
Eriksson B I, Carlsson S, Halvarsson M, Risberg B, Mattsson C.
Antithrombotic effect of two low molecular weight thrombin inhibitors and a low-molecular weight heparin in a caval vein thrombosis model in the rat.
Thromb Haemost.
1997;
78
1404-1407
-
39
Scherstén F, Wahlund G, Bjornheden T, Carlsson S, Mattsson C, Grip L.
Melagatran attenuates fibrin and platelet deposition in a porcine coronary artery over-stretch injury model.
Blood Coagul Fibrinolysis.
2003;
14
235-241
-
40
Fuentes-Prior P, Iwanaga Y, Huber R et al..
Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex.
Nature.
2000;
404
518-525
-
41
Elg M, Gustafsson D, Carlsson S.
Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat.
Thromb Res.
1999;
94
187-197
-
42
Gustafsson D, Elg M.
The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review.
Thromb Res.
2003;
109(Suppl 1)
9-15
-
43
Esmon C T.
Crosstalk between inflammation and thrombosis.
Maturitas.
2004;
47
305-314
-
44
Özmen L, Ekdahl K N, Elgue G, Larsson R, Korsgren O, Nilsson B.
Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: possible application of the thrombin inhibitor melagatran in clinical islet transplantation.
Diabetes.
2002;
51
1779-1784
-
45
Malhotra O P, Nesheim M E, Mann K G.
The kinetics of activation of normal and gamma-carboxyglutamic acid-deficient prothrombins.
J Biol Chem.
1985;
260
279-287
-
46
Franco V, Polanczyk C A, Clausell N, Rohde L E.
Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols.
Am J Med.
2004;
116
651-656
-
47
Lubetsky A, Dekel-Stern E, Chetrit A, Lubin F, Halkin H.
Vitamin K intake and sensitivity to warfarin in patients consuming regular diets.
Thromb Haemost.
1999;
81
396-399
-
48
Blanchard R A, Furie B C, Jorgensen M, Kruger S F, Furie B.
Acquired vitamin K-dependent carboxylation deficiency in liver disease.
N Engl J Med.
1981;
305
242-248
-
49
White R H, McKittrick T, Hutchinson R, Twitchell J.
Temporary discontinuation of warfarin therapy: changes in the international normalized ratio.
Ann Intern Med.
1995;
122
40-42
-
50
Cushman M, Booth S L, Possidente C J, Davidson K W, Sadowski J A, Bovill E G.
The association of vitamin K status with warfarin sensitivity at the onset of treatment.
Br J Haematol.
2001;
112
572-577
-
51
Chan Y C, Valenti D, Mansfield A O, Stansby G.
Warfarin induced skin necrosis.
Br J Surg.
2000;
87
266-272
-
52
Bendayan P, Boccalon H, Dupouy D, Boneu B.
Dermatan sulfate is a more potent inhibitor of clot-bound thrombin than unfractionated and low molecular weight heparins.
Thromb Haemost.
1994;
71
576-580
-
53
Weitz J I, Hudoba M, Massel D, Maraganore J, Hirsh J.
Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors.
J Clin Invest.
1990;
86
385-391
-
54
Agnelli G, Pascucci C, Cosmi B, Nenci G G.
The comparative effects of recombinant hirudin (CGP 39393) and standard heparin on thrombus growth in rabbits.
Thromb Haemost.
1990;
63
204-207
-
55
Serruys P W, Herrman J P, Simon R et al..
A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. Helvetica Investigators.
N Engl J Med.
1995;
333
757-763
-
56
Weitz J I, Hirsh J.
New anticoagulant drugs.
Chest.
2001;
119
95S-107S
Stefan C CarlssonPh.D.
Integrative Pharmacology, DISCOVERY, AstraZeneca R&D Mölndal
SE 431 83 Mölndal, Sweden
