Coagulation and the Vessel Wall in Pulmonary Embolism

Alias, Sherin; Lang, Irene M.

doi:10.1086/674768

Cited by 22 publications

(24 citation statements)

References 130 publications

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“…It did not result in hemodynamically relevant pulmonary embolisms leading to PAH and only caused very mild pulmonary arterial endothelial dysfunction. This corroborates the existing evidence in literature, which has repeatedly reported on the hardships to induce PE in mice and other animals [ 20 ]. This phenomenon has best been described in dogs, which are resistant to sustained DVT or PE because of high endogenous thrombolytic activity [ 21 ], probably caused by increased plasmin and/or plasminogen activity [ 22 ].…”

Section: Discussionsupporting

confidence: 92%

Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase‐Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice

Brandt

Giokoglu

Garlapati

et al. 2018

Oxidative Medicine and Cellular Longevity

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Pulmonary embolism (PE) results from deep vein thrombosis (DVT) and can lead to chronic thromboembolic pulmonary hypertension (CTEPH) involving vascular dysfunction. Mechanisms are incompletely understood, in part due to lack of mouse models. We induced PE in C57BL/6 mice by intravenous injection of thrombin (166 U/kg BW), confirmed by a sudden bradycardia, bradypnea, and an increase in pulmonary artery (PA) pressure observed by high-frequency ultrasound. While symptoms resolved rapidly after single thrombin application, repeated PEs resulted in sustained PA-pressure increase, increased PA superoxide formation assessed by oxidative fluorescent microtopography, increased PA gp91phox expression, and endothelial dysfunction assessed by isometric tension studies of isolated PA segments after 24 hours. DVT was modeled in C57BL/6 mice by ligation of the inferior vena cava (IVC). Importantly, small pulmonary emboli could be detected along with a mild phenotype of PA endothelial dysfunction and oxidative stress in the absence of PA-pressure elevation. mRNA expression of plasminogen activator inhibitor-1 was increased in PAs of mice with recurrent PE after repetitive thrombin injections and to a lesser extent in DVT mice. In summary, our data suggest that PA endothelial dysfunction, induced by gp91phox-derived ROS, is an early event upon repetitive PE. This phenomenon might help to elucidate the mechanisms of PA dysfunction in the pathogenesis of CTEPH.

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Section: Discussionsupporting

confidence: 92%

Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase‐Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice

Brandt

Giokoglu

Garlapati

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease defined by the presence of chronic clot accompanied by vascular remodeling and pulmonary arterial hypertension. [1][2][3][4][5] Despite the introduction of pharmacologic therapies for CTEPH, 6 pulmonary thromboendarterectomy (PTE) remains the gold-standard treatment for advanced, symptomatic disease. 1 While imaging is important for both the diagnosis of CTEPH and evaluation for PTE, 7,8 interpretation of vascular morphology remains challenging.…”

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confidence: 99%

Pulmonary Vascular Morphology as an Imaging Biomarker in Chronic Thromboembolic Pulmonary Hypertension

et al. 2016

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Patients with chronic thromboembolic pulmonary hypertension (CTEPH) have morphologic changes to the pulmonary vasculature. These include pruning of the distal vessels, dilation of the proximal vessels, and increased vascular tortuosity. Advances in image processing and computer vision enable objective detection and quantification of these processes in clinically acquired computed tomographic (CT) scans. Three-dimensional reconstructions of the pulmonary vasculature were created from the CT angiograms of 18 patients with CTEPH diagnosed using imaging and hemodynamics as well as 15 control patients referred to our Dyspnea Clinic and found to have no evidence of pulmonary vascular disease. Compared to controls, CTEPH patients exhibited greater pruning of the distal vasculature (median density of small-vessel volume: 2.7 [interquartile range (IQR): 2.5-3.0] vs. 3.2 [3.0-3.8]; P = 0.008), greater dilation of proximal arteries (median fraction of blood in large arteries: 0.35 [IQR: 0.30-0.41] vs. 0.23 [0.21-0.31]; P = 0.0005), and increased tortuosity in the pulmonary arterial tree (median: 4.92% [IQR: 4.85%-5.21%] vs. 4.63% [4.39%-4.92%]; P = 0.004). CTEPH was not associated with dilation of proximal veins or increased tortuosity in the venous system. Distal pruning of the vasculature was correlated with the cardiac index (R = 0.51, P = 0.04). Quantitative models derived from CT scans can be used to measure changes in vascular morphology previously described subjectively in CTEPH. These measurements are also correlated with invasive metrics of pulmonary hemodynamics, suggesting that they may be used to assess disease severity. Further work in a larger cohort may enable the use of such measures as a biomarker for diagnostic, phenotyping, and prognostic purposes.

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“…In both PTE animal models and PTE patients, alternations of pulmonary endothelium function have been observed, such as procoagulant activity and fibrinolytic function, along with a noticeable increase in the blood concentration of plasminogen activator inhibitor type I and arginase II protein in PTE patients[51,54]. On one hand, PTE might lead to the dysfunction of endothelial cells through both mechanical and inflammatory insults, with both the lysing thrombus and mechanical effects of thrombotic occlusion damaging the endothelium of the vein[55]; while on the other hand, considering the necessity ofendothelial cells in the resolution of venous thrombi, dysfunctional endothelial cells may contribute to the further progression of the PTE diseases[56,57]. Our data confirmed previous hypothesis that PTE induced dramatic gene expression alterations in pulmonary artery.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Pulmonary Artery in a Rabbit Model of Pulmonary Thromboembolism

et al. 2016

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Acute pulmonary thromboembolism (PTE) refers to the obstruction of thrombus in pulmonary artery or its branches. Recent studies have suggested that PTE-induced endothelium injury is the major physiological consequence of PTE. And it is reasonal to use PTE-induced endothelium injury to stratify disease severity. According to the massive morphologic and histologic findings, rabbit models could be applied to closely mimic the human PE. Genomewide gene expression profiling has not been attempted in PTE. In this study, we determined the accuracy of rabbit autologous thrombus PTE model for human PTE disease, then we applied gene expression array to identify gene expression changes in pulmonary arteries under PTE to identify potential molecular biomarkers and signaling pathways for PTE. We detected 1343 genes were upregulated and 923 genes were downregulated in PTE rabbits. The expression of several genes (IL-8, TNF-α, and CXCL5) with functional importance were further confirmed in transcript and protein levels. The most significantly differentially regulated genes were related to inflammation, immune disease, pulmonary disease, and cardiovascular diseases. Totally 87 genes were up-regulated in the inflammatory genes. We conclude that gene expression profiling in rabbit PTE model could extend the understanding of PTE pathogenesis at the molecular level. Our study provides the fundamental framework for future clinical research on human PTE, including identification of potential biomarkers for prognosis or therapeutic targets for PTE.

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Coagulation and the Vessel Wall in Pulmonary Embolism

Cited by 22 publications

References 130 publications

Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase‐Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice

Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase‐Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice

Pulmonary Vascular Morphology as an Imaging Biomarker in Chronic Thromboembolic Pulmonary Hypertension

Gene Expression Profiling of Pulmonary Artery in a Rabbit Model of Pulmonary Thromboembolism

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