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Long-term treatment with ximelagatran, an oral direct thrombin inhibitor, persistently reduces the coagulation activity after a myocardial infarction
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2005 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 3, no 10, 2245-53 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: In the ESTEEM study, patients with a recent myocardial infarction were treated with aspirin and randomized to one of four doses (24-60 mg b.i.d) of the oral direct thrombin inhibitor ximelagatran or placebo for 6 months. Ximelagatran and aspirin reduced the risk of recurrent ischemic events compared with aspirin alone. In the present substudy we evaluated the different doses of ximelagatran on pharmacokinetics as measured by plasma concentration of the active compound melagatran and activated partial thromboplastin time (APTT) and pharmacodynamics as related by markers for coagulation activity, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer. METHODS AND RESULTS: Plasma samples from 518 patients were collected before, during and after the treatment period. There was a linear dose-concentration relation at peak and trough and a linear relation between concentration and APTT (P < 0.001). F1 + 2 and D-dimer were decreased by 25% and 52% at 1 week (P < 0.001) in the ximelagatran groups compared with the placebo group and the reductions were maintained during the 6 months treatment. There were no differences detected in F1 + 2 or D-dimer levels between the different ximelagatran dosages. There was no correlation between the melagatran concentration and the change in F1 + 2 and D-dimer levels. After cessation of ximelagatran F1 + 2 and D-dimer levels returned to the initial levels. CONCLUSION: The dose of ximelagatran and APTT are linearly related to the plasma concentration of melagatran. Ximelagatran induces a sustained and stable reduction of thrombin generation and fibrin turnover without any relation to dose above 24 mg b.i.d. These properties indicate that long-term treatment with a low dose of ximelagatran may provide valuable depression of coagulation activity in aspirin treated post myocardial infarction patients.

Place, publisher, year, edition, pages
2005. Vol. 3, no 10, 2245-53 p.
Keyword [en]
Aged, Azetidines/administration & dosage/*pharmacokinetics, Benzylamines, Biological Markers/blood, Blood Coagulation/*drug effects, Dose-Response Relationship; Drug, Female, Fibrin/metabolism, Glycine/analogs & derivatives/blood, Humans, Male, Myocardial Infarction/blood/*drug therapy, Partial Thromboplastin Time, Pharmacokinetics, Thrombin/antagonists & inhibitors/biosynthesis, Time Factors
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-10329DOI: 10.1111/j.1538-7836.2005.01557.xPubMedID: 16194202OAI: oai:DiVA.org:uu-10329DiVA: diva2:38097
Available from: 2007-04-16 Created: 2007-04-16 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Regulation of Tissue Factor and Coagulation Activity: Translation Studies with Focus on Platelet-Monocyte Aggregates and Patients with Acute Coronary Syndrome
Open this publication in new window or tab >>Regulation of Tissue Factor and Coagulation Activity: Translation Studies with Focus on Platelet-Monocyte Aggregates and Patients with Acute Coronary Syndrome
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Myocardial infarction (MI) is often caused by a disruption of an atherosclerotic plaque with activation of coagulation, platelets and inflammation. The aims were; to investigate whether the oral direct thrombin inhibitor, ximelagatran affected markers for coagulation, platelet and inflammation in a patient cohort with recent MI and if the coagulation markers could identify patients with increased risk of new ischemic events; to evaluate some of the mechanisms involved in formation of platelet-monocyte aggregates (PMAs).

In a biomarker substudy patients with recent MI were randomized to 24-60 mg of ximelagatran or placebo for six months. There was a persistent dose-independent reduction of coagulation markers (F1+2, D-dimer) by ximelagatran treatment. 60 % reduced their D-dimer levels after one week and that group had less ischemic events during treatment. There was an early increase of the platelet activation marker and ximelagatran in higher doses attenuated these increased levels. Both in vivo and in vitro the direct thrombin inhibitor diminished procoagulant activity and tissue factor (TF) presenting microparticles. In contrast, the inflammatory markers increased after six months of ximelagatran treatment. The PMA-levels were elevated for long-term after MI. In vitro thrombin inhibition diminished formation of PMAs. Formation of PMAs in stimulated whole blood was P-selectin dependent and induced TF expression through phosphorylation of the Src-family member Lyn in monocytes.

Addition of an oral direct thrombin inhibitor reduces coagulation and platelet activation markers for long-term after a MI together with reduced procoagulant activity which may contribute to the clinical benefit of the drug. Early reduction of D-dimer levels seems to be suitable to identify patients with reduced risk of new ischemic events independent of antithrombotic treatment. Circulating PMAs persist after a MI connecting coagulation to inflammation. Within these aggregates P-selectin induces TF, the main initiator of coagulation, partly through phosphorylation of Lyn.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 87 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 341
Keyword
Internal medicine, Myocardial infarction, Coagulation, Platelet-monocyte aggregates, Tissue factor, Thrombin inhibition, Invärtesmedicin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-8669 (URN)978-91-554-7177-4 (ISBN)
Public defence
2008-05-17, Enghoffsalen, Ingång 50 bv, Uppsala Universitets Sjukhus, Uppsala, 10:00
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Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2012-03-06Bibliographically approved

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Christersson, ChristinaOldgren, JonasWallentin, LarsSiegbahn, Agneta

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