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      Factor XIa and Thrombin Generation Are Elevated in Patients with Acute Coronary Syndrome and Predict Recurrent Cardiovascular Events

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          Abstract

          Objective

          In acute coronary syndrome (ACS) cardiac cell damage is preceded by thrombosis. Therefore, plasma coagulation markers may have additional diagnostic relevance in ACS. By using novel coagulation assays this study aims to gain more insight into the relationship between the coagulation system and ACS.

          Methods

          We measured plasma thrombin generation, factor XIa and D-dimer levels in plasma from ACS (n = 104) and non-ACS patients (n = 42). Follow-up measurements (n = 73) were performed at 1 and 6 months. Associations between coagulation markers and recurrent cardiovascular events were calculated by logistic regression analysis.

          Results

          Thrombin generation was significantly enhanced in ACS compared to non-ACS patients: peak height 148±53 vs. 122±42 nM. There was a significantly diminished ETP reduction (32 vs. 41%) and increased intrinsic coagulation activation (25 vs. 7%) in ACS compared to non-ACS patients. Furthermore, compared to non-ACS patients factor XIa and D-dimer levels were significantly elevated in ACS patients: 1.9±1.1 vs. 1.4±0.7 pM and 495(310–885) vs. 380(235–540) μg/L. Within the ACS spectrum, ST-elevated myocardial infarction patients had the highest prothrombotic profile. During the acute event, thrombin generation was significantly increased compared to 1 and 6 months afterwards: peak height 145±52 vs. 100±44 vs. 98±33 nM. Both peak height and factor XIa levels on admission predicted recurrent cardiovascular events (OR: 4.9 [95%CI 1.2–20.9] and 4.5 [1.1–18.9]).

          Conclusion

          ACS patients had an enhanced prothrombotic profile, demonstrated by an increased thrombin generation potential, factor XIa and D-dimer levels. This study is the first to demonstrate the positive association between factor XIa, thrombin generation and recurrent cardiovascular events.

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          Most cited references 34

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            Inflammation, atherosclerosis, and coronary artery disease.

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              ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).

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                Author and article information

                Affiliations
                [1 ]Laboratory for Clinical Thrombosis and Haemostasis, Departments of Internal Medicine and Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
                [2 ]Departments of Clinical Chemistry & Hematology, Atrium Medical Center Parkstad, Heerlen, The Netherlands
                [3 ]Department Of Cardiology, Atrium Medical Center Parkstad, Heerlen, The Netherlands
                [4 ]Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
                University Hospital Medical Centre, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RL RvO HS HtC. Performed the experiments: RL RvO. Analyzed the data: RL HS. Contributed reagents/materials/analysis tools: ML RvO HS. Wrote the paper: RL RvO HS ML JK HC HtC.

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 July 2016
                2016
                : 11
                : 7
                27419389 4946779 10.1371/journal.pone.0158355 PONE-D-15-52942
                © 2016 Loeffen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                Figures: 4, Tables: 3, Pages: 16
                Product
                Funding
                Funded by: CTMM, the Center for Translational Molecular Medicine, project INCOAG (grant 01C-201),and the Dutch Heart Foundation
                Award Recipient :
                This research was performed within the framework of CTMM, the Center for Translational Molecular Medicine ( www.ctmm.nl), project INCOAG (grant 01C-201), and supported by the Dutch Heart Foundation.
                Categories
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                Biochemistry
                Proteins
                Thrombin
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