Hypoxia, such as encountered at high altitude, promotes deep vein thrombosis in mice

Brill, Alexander; Suidan, Georgette L.; Wagner, Denisa D.

doi:10.1111/jth.12310

Cited by 53 publications

(38 citation statements)

References 21 publications

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“…Third, systemic hypoxia has been shown to accelerate thromboembolic events in mice through induction of the nucleotide‐binding domain, leucine‐rich–containing family, pyrin domain–containing 3 inflammasome complex . Fourth, severe hypoxia is also reported to increase the incidence and size of thrombi in the inferior vena cava stenosis model in mice …”

Section: Discussionsupporting

confidence: 86%

“…In addition, COPD patients had higher coagulation activation than age‐ and sex‐matched controls and exposure to short‐term hypoxia further augmented coagulation activation . Severe hypoxia was also shown to increase the incidence and size of thrombi in the inferior vena cava stenosis model in mice …”

Section: Introductionmentioning

confidence: 99%

“…19 Severe hypoxia was also shown to increase the incidence and size of thrombi in the inferior vena cava stenosis model in mice. 20 To the best of our knowledge, no study has investigated the association between oxygen saturation and future risk of VTE. The aims of the present study were to investigate whether measures of respiratory impairments, such as respiratory symptoms and oxygen saturation (SpO 2 ), individually and combined with COPD, were associated with increased risk of VTE.…”

Section: Introductionmentioning

confidence: 99%

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Impact of respiratory symptoms and oxygen saturation on the risk of incident venous thromboembolism—the Tromsø study

Børvik

Evensen

Morelli

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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Background Chronic obstructive pulmonary disease (COPD) is associated with risk of venous thromboembolism (VTE). It remains unknown whether individual respiratory symptoms and lowered oxygen saturation (SpO2), individually and in combination with COPD, affect the risk of VTE. Objectives To investigate whether measures of respiratory impairments including respiratory symptoms and SpO2, individually and combined with COPD, were associated with an increased risk of VTE. Methods Spirometry, SpO2, and self‐reported respiratory symptoms were collected in 8686 participants from the fifth (2001‐2002) and sixth (2007‐2008) surveys of the Tromsø Study. Incident VTE events were registered from the date of inclusion to December 31, 2016. Cox regression models with exposures and confounders as time‐varying covariates (for repeated measurements) were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for VTE. Results During a median follow‐up of 9.1 years, 330 participants developed incident VTE. Subjects with SpO2 ≤ 96% (lowest 20th percentile) had a 1.5‐fold higher risk of VTE (adjusted HR, 1.48; 95% CI, 1.13‐1.93) compared with those with SpO2 ≥ 98%. Severe respiratory symptoms (dyspnea, cough, and phlegm) were associated with a 1.4‐ to 2.0‐fold higher risk of VTE compared with no such symptoms. COPD, combined with respiratory symptoms or lowered SpO2, had an additive effect on the VTE risk. Conclusions Lowered SpO2 and severe respiratory symptoms were associated with increased VTE risk. COPD combined with respiratory impairments had an additive effect on VTE risk, and may suggest particular attention on VTE preventive strategies in COPD patients with respiratory impairments.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of respiratory symptoms and oxygen saturation on the risk of incident venous thromboembolism—the Tromsø study

Børvik

Evensen

Morelli

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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“…63 Low oxygen levels, such as occurring in areas of low flow behind vein valves, have been implicated in the pathophysiology of venous thrombosis (reviewed in Bovill and van der Vliet 64 ), and mice exposed to hypoxia exhibited an increased prevalence of venous thrombosis. 65 Interestingly, elevated serum levels of growth differentiation factor-15, a soluble marker of endothelial injury induced by p53, are useful for the prognostic risk assessment of patients with pulmonary embolism. 66,67 Altogether, these studies point to a role for p53-mediated endothelial damage 68 In the present study, venous thrombi of adult and aged mice did not differ with respect to the relative amount of macrophages or T cells within venous thrombi, and no effects of endothelial p53 expression on both parameters were observed.…”

Section: Discussionmentioning

confidence: 99%

The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

Bochenek

Bauer

Gogiraju³

et al. 2018

Blood Advances

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Key Points• Deletion of p53 in endothelial cells prevents venous thrombosis in aged, but not in adult, mice.• Neutralization of heparanase in aged mice using TFPI2 peptides restores the thrombotic phenotype of adult mice. End.p53-KO mice were protected from vein thrombosis. Analysis of primary endothelial cells from aged mice or human vein endothelial cells after induction of replicative senescence revealed significantly increased early growth response gene-1 (Egr1) and heparanase expression, and plasma factor Xa levels were elevated in aged End.p53-WT, but not in End.p53-KO mice. Increased endothelial Egr1 and heparanase expression also was observed after doxorubicin-induced p53 overexpression, whereas p53 inhibition using pifithrin-a reduced tissue factor (TF) expression. Importantly, inhibition of heparanase activity using TF pathway inhibitor-2 (TFPI2) peptides prevented the enhanced venous thrombus formation in aged mice and restored it to the thrombotic phenotype of adult mice.Our findings suggest that p53 accumulation and heparanase overexpression in senescent endothelial cells are critically involved in mediating the increased risk of venous thrombosis with age and that heparanase antagonization may be explored as strategy to ameliorate the prothrombotic endothelial phenotype with age.

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“…60 After a day in the hypoxic chamber, mice become highly susceptible to IVC thrombus formation. 61 Interestingly, hypoxia induces hypoxia-inducible factor 1a (HIF-1a), which is implicated in NETosis. 62 Through their histones, NETs may further enhance endothelial activation as histone infusion in combination with IVC stenosis greatly accelerated thrombus formation.…”

Section: Dvtmentioning

confidence: 99%

Thrombosis: tangled up in NETs

Martinod

Wagner

2014

Blood

696

622

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The contributions by blood cells to pathological venous thrombosis were only recently appreciated. Both platelets and neutrophils are now recognized as crucial for thrombus initiation and progression. Here we review the most recent findings regarding the role of neutrophil extracellular traps (NETs) in thrombosis. We describe the biological process of NET formation (NETosis) and how the extracellular release of DNA and protein components of NETs, such as histones and serine proteases, contributes to coagulation and platelet aggregation. Animal models have unveiled conditions in which NETs form and their relation to thrombogenesis. Genetically engineered mice enable further elucidation of the pathways contributing to NETosis at the molecular level. Peptidylarginine deiminase 4, an enzyme that mediates chromatin decondensation, was identified to regulate both NETosis and pathological thrombosis. A growing body of evidence reveals that NETs also form in human thrombosis and that NET biomarkers in plasma reflect disease activity. The cell biology of NETosis is still being actively characterized and may provide novel insights for the design of specific inhibitory therapeutics. After a review of the relevant literature, we propose new ways to approach thrombolysis and suggest potential prophylactic and therapeutic agents for thrombosis.

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Hypoxia, such as encountered at high altitude, promotes deep vein thrombosis in mice

Cited by 53 publications

References 21 publications

Impact of respiratory symptoms and oxygen saturation on the risk of incident venous thromboembolism—the Tromsø study

Impact of respiratory symptoms and oxygen saturation on the risk of incident venous thromboembolism—the Tromsø study

The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

Thrombosis: tangled up in NETs

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