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

2019 ◽  
Vol 119 (08) ◽  
pp. 1332-1346 ◽  
Author(s):  
Sebastian Kölmel ◽  
Lukas Hobohm ◽  
Anja Käberich ◽  
Valentin J. Krieg ◽  
Magdalena L. Bochenek ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Pulmonary Hypertension ◽  
Plasma Concentrations ◽  
Vena Cava ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Translational Study ◽  
Increased Risk ◽  
Immuno Histochemistry ◽  
Thromboembolic Pulmonary Hypertension ◽  
Tissue Material

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.

Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension

2005 ◽  
Vol 93 (03) ◽  
pp. 512-516 ◽  
Author(s):  
Diana Bonderman ◽  
Johannes Jakowitsch ◽  
Christopher Adlbrecht ◽  
Michael Schemper ◽  
Paul Kyrle ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Pulmonary Hypertension ◽  
Odds Ratio ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Medical Conditions ◽  
Symptomatic Pulmonary Embolism ◽  
Increased Risk ◽  
Lung Scan ◽  
Thromboembolic Pulmonary Hypertension ◽  
Inflammatory Bowel

SummaryChronic thromboembolic pulmonary hypertension (CTEPH) is characterized by organized thromboemboli that obstruct the pulmonary vascular bed. Although CTEPH is a serious complication of acute symptomatic pulmonary embolism in 4% of cases, signs, symptoms and classical risk factors for venous thromboembolism are lacking. The aim of the present study was to identify medical conditions conferring an increased risk of CTEPH. We performed a case-control-study comparing 109 consecutive CTEPH patients to 187 patients with acute pulmonary embolism that was confirmed by a high probability lung scan. Splenectomy (odds ratio=13, 95% CI 2.7–127), ventriculoatrial (VA-) shunt for the treatment of hydrocephalus (odds ratio=13, 95% CI 2.5–129) and chronic inflammatory disorders, such as osteomyelitis and inflammatory bowel disease (IBD, odds ratio=67, 95% CI 7.9–8832) were associated with an increased risk of CTEPH.

From thrombosis to fibrosis in chronic thromboembolic pulmonary hypertension

2017 ◽  
Vol 117 (04) ◽  
pp. 769-783 ◽  
Author(s):  
Magdalena Bochenek ◽  
Nico Rosinus ◽  
Mareike Lankeit ◽  
Lukas Hobohm ◽  
Felix Bremmer ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cell Activation ◽  
Immune Cell ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Tissue Microarrays ◽  
Growth Factor Signalling ◽  
Immuno Histochemistry ◽  
Thromboembolic Pulmonary Hypertension

SummaryThe 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.

Active search for chronic thromboembolic pulmonary hypertension does not appear indicated after acute pulmonary embolism

2010 ◽  
Vol 125 (5) ◽  
pp. e202-e205 ◽  
Author(s):  
Sulaiman Surie ◽  
Nadine S. Gibson ◽  
Victor E.A. Gerdes ◽  
Berto J. Bouma ◽  
Berthe L.F. van Eck – Smit ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Pulmonary Hypertension ◽  
Acute Pulmonary Embolism ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Active Search ◽  
Thromboembolic Pulmonary Hypertension

scholarly journals Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism

2017 ◽  
Vol 49 (5) ◽  
pp. 1601980 ◽  
Author(s):  
Raffaele Pesavento ◽  
Lucia Filippi ◽  
Antonio Palla ◽  
Adriana Visonà ◽  
Carlo Bova ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Pulmonary Hypertension ◽  
Venous Thromboembolism ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
First Episode ◽  
Long Term Outcome ◽  
Recurrent Venous Thromboembolism ◽  
Thromboembolic Pulmonary Hypertension ◽  
The Impact ◽  
Lung Scanning

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain.We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria.Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2–54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23–4.16).Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension.

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