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Thromb Haemost 2017; 117(04): 769-783
DOI: 10.1160/TH16-10-0790
Stroke, Systemic or Venous Thromboembolism
Schattauer GmbH

From thrombosis to fibrosis in chronic thromboembolic pulmonary hypertension

Magdalena L. Bochenek
1   Center for Cardiology, Cardiology I, University Medical Center Mainz, Germany
2   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany
3   Deutsches Zentrum für Herz-Kreislauf-Forschung e. V., partner site RheinMain (Mainz), Germany
,
Nico S. Rosinus
1   Center for Cardiology, Cardiology I, University Medical Center Mainz, Germany
3   Deutsches Zentrum für Herz-Kreislauf-Forschung e. V., partner site RheinMain (Mainz), Germany
,
Mareike Lankeit
2   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany
,
Lukas Hobohm
1   Center for Cardiology, Cardiology I, University Medical Center Mainz, Germany
2   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany
,
Felix Bremmer
4   Department of Pathology, Medical University of Göttingen, Germany
,
Eva Schütz
1   Center for Cardiology, Cardiology I, University Medical Center Mainz, Germany
,
Frederikus A. Klok
2   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany
,
Sven Horke
2   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany
5   Department of Pharmacology, University Medical Center Mainz, Germany
,
Christoph B. Wiedenroth
6   Thoracic Surgery, Kerckhoff-Clinic, Bad Nauheim, Germany
,
Thomas Münzel
1   Center for Cardiology, Cardiology I, University Medical Center Mainz, Germany
3   Deutsches Zentrum für Herz-Kreislauf-Forschung e. V., partner site RheinMain (Mainz), Germany
,
Irene M. Lang
7   Department of Internal Medicine, Division of Cardiology, Medical University of Vienna, Vienna, Austria
,
Eckhard Mayer
6   Thoracic Surgery, Kerckhoff-Clinic, Bad Nauheim, Germany
,
Stavros Konstantinides
2   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany
8   Department of Cardiology, Democritus University of Thrace, Greece
,
Katrin Schäfer
1   Center for Cardiology, Cardiology I, University Medical Center Mainz, Germany
3   Deutsches Zentrum für Herz-Kreislauf-Forschung e. V., partner site RheinMain (Mainz), Germany
› Author Affiliations Financial support: This study was supported by the Bundesministerium für Bildung und Forschung (BMBF 01E01003; Virchow fellowship to MLB) and the Deutsches Zentrum für Herz-Kreislaufforschung (DZHK Doktorandenstipendium to NSR).
Further Information

Publication History

Received: 17 October 2016

Accepted after major revision: 29 February 2016

Publication Date:
13 November 2017 (online)

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Summary

The pathomechanisms underlying the development of thrombofibrotic pulmonary artery occlusions in Chronic Thromboembolic Pulmonary Hypertension (CTEPH) are largely unknown. The aim of this study was to allocate distinct cellular processes playing a role in thrombus resolution, such as inflammation, hypoxia, proliferation, apoptosis and angiogenesis, to different stages of thrombofibrotic remodelling. A total of 182 pulmonary endarterectomy (PEA) specimens were collected from 31 CTEPH patients. To facilitate co-localisation, Tissue MicroArrays were prepared and processed for (immuno)-histochemistry and confocal fluorescence microscopy. Murine venous thrombus formation and resolution was examined after inferior vena cava ligation. PEA tissues exhibited five morphologically distinct regions predominantly consisting of either fibrin-, erythrocyte- or extracellular matrix-rich thrombus, myofibroblasts, vessels or fibrotic tissue, and were found to resemble chronological stages of thrombus resolution in mice. Cellularity was highest in vessel-rich regions, and numerous cells were strongly positive for HIF1α or HIF2α as well as markers of activated VEGF signalling, including endothelial nitric oxide synthase. On the other hand, negative regulators of angiogenic growth factor signalling and reactive oxygen species were also highly expressed. Immune cells, primarily macrophages of the M2 subtype and CD117 haematopoietic progenitors were detected and highest in vascularised regions. Our findings demonstrate the simultaneous presence of different stages of thrombus organisation and suggest that hypoxia-induced endothelial, mesenchymal and immune cell activation may contribute to thrombofibrosis in CTEPH. This systematic histological characterisation of the material obstructing pulmonary vessels in CTEPH may provide a valuable basis for further studies aimed at determining causal factors underlying this disease.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Chronic thromboembolic pulmonary hypertension - fibrosis - histological classification - venous thrombosis

 

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