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Thromb Haemost 2019; 119(08): 1332-1346
DOI: 10.1055/s-0039-1692174
Stroke, Systemic or Venous Thromboembolism
Georg Thieme Verlag KG Stuttgart · New York

Potential Involvement of Osteopontin in Inflammatory and Fibrotic Processes in Pulmonary Embolism and Chronic Thromboembolic Pulmonary Hypertension

Sebastian Kölmel
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
,
Lukas Hobohm
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
2   Cardiology I, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
,
Anja Käberich
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
2   Cardiology I, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
,
Valentin J. Krieg
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
,
Magdalena L. Bochenek
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
2   Cardiology I, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
3   DZHK (German Centre for Cardiovascular Research), partner site Rhine-Main, Germany
,
Philip Wenzel
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
2   Cardiology I, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
3   DZHK (German Centre for Cardiovascular Research), partner site Rhine-Main, Germany
,
Christoph B. Wiedenroth
4   Department of Thoracic Surgery, Kerckhoff Heart and Lung Center, Bad Nauheim, Germany
,
Christoph Liebetrau
3   DZHK (German Centre for Cardiovascular Research), partner site Rhine-Main, Germany
5   Department of Cardiology, Kerckhoff Heart and Lung Center, Bad Nauheim, Germany
6   Division of Cardiology, Department of Internal Medicine I, University of Giessen, Giessen, Germany
,
Gerd Hasenfuß
7   Clinic of Cardiology and Pneumology, Heart Centre, University Medicine Göttingen, Göttingen, Germany
8   DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany
,
Eckhard Mayer
4   Department of Thoracic Surgery, Kerckhoff Heart and Lung Center, Bad Nauheim, Germany
,
Stavros V. Konstantinides
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
9   Department of Cardiology, Democritus University of Thrace, Alexandroupoli, Greece
,
Katrin Schäfer
2   Cardiology I, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
3   DZHK (German Centre for Cardiovascular Research), partner site Rhine-Main, Germany
,
Stefan Guth   *
4   Department of Thoracic Surgery, Kerckhoff Heart and Lung Center, Bad Nauheim, Germany
,
Mareike Lankeit   *
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
7   Clinic of Cardiology and Pneumology, Heart Centre, University Medicine Göttingen, Göttingen, Germany
10   Department of Internal Medicine and Cardiology, Campus Virchow Klinikum (CVK), Charité–University Medicine, Berlin, Germany
11   DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
› Author Affiliations
Funding This study was supported by the German Federal Ministry of Education and Research (BMBF 01EO1003 and BMBF 01EO1503). The authors are responsible for the contents of this publication. The work is part of the medical doctoral thesis of Sebastian Kölmel and his work was supported by a Doctoral Candidate Fellowship 2016 of the Center for Thrombosis and Hemostasis (CTH) of the University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
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Publication History

11 December 2018

11 April 2019

Publication Date:
10 June 2019 (online)

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Abstract

Background Inflammation and incomplete thrombus resolution leading to obstructive fibrotic remodelling are considered critical mechanisms for the development of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE). Osteopontin (OPN) is involved in a variety of biological processes including inflammation and tissue fibrosis.

Methods OPN plasma concentrations were measured in 70 CTEPH and 119 PE patients. Tissue material from 6 CTEPH patients removed during pulmonary endarterectomy and murine venous thrombi induced by subtotal ligation of the inferior vena cava in C57BL/6 mice were analysed by (immuno)histochemistry.

Results CTEPH patients had higher OPN plasma concentrations (median, 106.9 [interquartile range, 75.6–155.9]) compared to PE patients (90.4 [53.3–123.9] ng/mL, p = 0.001). OPN- and matrix metalloproteinase (MMP)-9-positive cells were predominantly present in myofibroblast-rich and profibrotic areas of CTEPH tissue material. Early stages of murine thrombus resolution were characterised by high numbers of OPN- and MMP-2-positive cells while OPN was almost absent in fresh thrombi of CTEPH tissue material. PE patients with OPN plasma concentrations of < 55 ng/mL had a 15.2-fold (95% confidence interval, 1.7–135.5, p = 0.015) increased risk for a diagnosis of CTEPH during follow-up.

Conclusion The results of the present observational translational study point to a possible involvement of OPN in the pathogenesis of CTEPH by affecting early inflammatory and late fibrotic processes.

Keywords

thrombus resolution - fibrosis - inflammation - osteopontin - chronic thromboembolic pulmonary hypertension

* The authors contributed equally and share last authorship.


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