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Treatment with an Oral Direct Thrombin Inhibitor Decreases Platelet Activity but Increases Markers of Inflammation in Patients with 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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
2011 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 270, no 3, 215-223 p.Article in journal (Refereed) Published
Abstract [en]

Background: Thrombin has a role not only in the coagulation process but also in inflammatory responses. Oral direct thrombin inhibitors (DTIs) are currently being evaluated in patients with thromboembolic diseases. Objectives:  To investigate whether an oral DTI affects markers for platelet and inflammatory activity after myocardial infarction (MI). Methods:  A total of 518 patients with MI were randomly assigned to ximelagatran treatment (four different dose groups) in combination with aspirin, or aspirin alone for 6 months. The levels of soluble (s) P-selectin, soluble tissue factor, C-reactive protein (CRP), interleukin (IL)-10 and IL-18 were analysed in serial blood samples.

Results: sP-selectin concentration increased after 1 week and persisted at an elevated level for 6 months in all study groups (p<0.001). In the two highest ximelagatran dose groups, there was a reduced increase in sP-selectin compared to treatment with lower doses of ximelagatran and aspirin alone (p=0.01 and p=0.002, respectively). IL-18 levels did not change in the aspirin alone treatment group. By contrast, there was an elevation in IL-18 level in the lower and higher ximelagatran dose groups after 6 months (p=0.006 and p<0.001, respectively). Ximelagatran increased IL-10 levels (p=0.002) and reduced the decrease in CRP levels after 6 months compared to treatment with aspirin alone (p=0.002).

Conclusion: A persistent elevation of platelet activity is found in patients with a recent MI after the cessation of acute antithrombotic treatment, and the addition of an oral DTI at higher doses decreases the activity. By contrast, long-term treatment with a DTI increases the levels of several markers of inflammation. Further studies with prolonged exposure of oral DTIs are needed for evaluation of the effect on inflammatory processes and to determine whether these agents influence clinical outcomes.

Place, publisher, year, edition, pages
2011. Vol. 270, no 3, 215-223 p.
Keyword [en]
anticoagulation treatment, antithrombotic treatment, inflammation, myocardial infarction, platelets
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-144009DOI: 10.1111/j.1365-2796.2011.02354.xISI: 000293793600003PubMedID: 21255134OAI: oai:DiVA.org:uu-144009DiVA: diva2:392081
Available from: 2011-01-26 Created: 2011-01-26 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
Opponent
Supervisors
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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