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

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          Abstract

          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 (SpO 2), individually and in combination with COPD, affect the risk of VTE.

          Objectives

          To investigate whether measures of respiratory impairments including respiratory symptoms and SpO 2, individually and combined with COPD, were associated with an increased risk of VTE.

          Methods

          Spirometry, SpO 2, 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 SpO 2 ≤ 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 SpO 2 ≥ 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 SpO 2, had an additive effect on the VTE risk.

          Conclusions

          Lowered SpO 2 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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          Most cited references32

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          Hypoxemia in patients with COPD: cause, effects, and disease progression

          Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.
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            Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE).

            We sought to assess prospectively whether higher levels of blood coagulation factors and inflammation markers are risk factors for venous thromboembolism. In two pooled population-based cohort studies, we measured levels of factor VII, factor VIII, von Willebrand factor, fibrinogen, and C-reactive protein, and white blood cell count, in samples obtained from 19,237 adults with no baseline history of venous thromboembolism, cancer, or warfarin use. The endpoint was validated venous thromboembolism during follow-up (median, 7.8 years). A total of 159 venous thromboembolism events occurred. Factor VIII and von Willebrand factor were linearly associated with increased risk of venous thromboembolism (P for trend <0.0001). As compared with those in the lowest quartile, the multivariate-adjusted hazard ratio (HR) of venous thromboembolism was 2.6 (95% confidence interval [CI]: 1.6 to 4.3) for factor VIII levels in the highest quartile and 3.8 (95% CI: 2.0 to 7.2) for the highest fifth percentile. For von Willebrand factor, the hazard ratios in middle-aged subjects were 4.6 (95% CI: 2.2 to 9.2) for the highest quartile and 7.6 (95% CI: 3.1 to 18) for the highest fifth percentile. Factor VII levels above the 95th percentile, as compared with the lowest quartile, also conveyed a higher risk of venous thromboembolism (HR = 2.4; 95% CI: 1.2 to 4.8). In contrast, there was no association of venous thromboembolism with fibrinogen or C-reactive protein levels, or white cell count. In this prospective study, elevated factor VIII and von Willebrand factor levels were common, independent, and dose-dependent risk factors for venous thromboembolism, and an elevated factor VII level was a possible risk factor. Venous thromboembolism, unlike arterial disease, was not related to inflammatory markers.
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              Immunolocalization of von Willebrand protein in Weibel-Palade bodies of human endothelial cells

              Immunofluorescence staining of cultured human umbilical vein endothelial cells has shown the presence of von Willebrand protein in the perinuclear region, in small rodlike structures through the cytoplasm, and on filaments of the extracellular matrix. Nonendothelial cells showed no staining with anti-von Willebrand protein antiserum. At the light microscope level, immunoperoxidase treatment of endothelial cells revealed the same pattern and antibody specificity as the fluorescence staining. Thin sections of the peroxidase-stained cells showed decorated filaments close to the substratum and also specific deposits in the endoplasmic reticulum and Weibel-Palade bodies. Control antisera against other selected proteins in endothelial cells failed to stain the Weibel-Palade bodies. These data suggest that the Weibel- Palade bodies of endothelial cells are storage and/or processing organelles for von Willebrand protein.
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                Author and article information

                Contributors
                htps://twitter.com/EvensenL
                Sigrid.brakkan@uit.no , htps://twitter.com/TREC_UiT
                Journal
                Res Pract Thromb Haemost
                Res Pract Thromb Haemost
                10.1002/(ISSN)2475-0379
                RTH2
                Research and Practice in Thrombosis and Haemostasis
                John Wiley and Sons Inc. (Hoboken )
                2475-0379
                09 January 2020
                February 2020
                : 4
                : 2 ( doiID: 10.1002/rth2.v4.2 )
                : 255-262
                Affiliations
                [ 1 ] K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) Department of Clinical Medicine UiT‐The Arctic University of Norway Tromsø Norway
                [ 2 ] Division of Internal Medicine University Hospital of North Norway Tromsø Norway
                [ 3 ] General Practice Research Unit Department of Community Medicine UiT‐The Arctic University of Norway Tromsø Norway
                Author notes
                [*] [* ] Correspondence

                Sigrid K. Brækkan, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), Department of Clinical Medicine, UiT‐The Arctic University of Tromsø, N‐9037 Tromsø, Norway.

                Email: Sigrid.brakkan@ 123456uit.no

                Author information
                https://orcid.org/0000-0002-7169-9408
                Article
                RTH212299
                10.1002/rth2.12299
                7040548
                f5de5a6f-a9e7-40dc-b135-b94cd93dd039
                © 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 23 September 2019
                : 27 November 2019
                : 01 December 2019
                Page count
                Figures: 1, Tables: 3, Pages: 8, Words: 6114
                Funding
                Funded by: Stiftelsen Kristian Gerhard Jebsen , open-funder-registry 10.13039/100007793;
                Categories
                Original Article
                Original Articles: Thrombosis
                Custom metadata
                2.0
                February 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.6.1 mode:remove_FC converted:25.02.2020

                chronic obstructive pulmonary disease,oxygen saturation,respiratory symptoms,risk,venous thromboembolism

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