Elevated plasma levels of P‐selectin glycoprotein ligand‐1‐positive microvesicles in patients with unprovoked venous thromboembolism

Jamaly, Simin; Basavaraj, Manjunath Goolyam; Starikova, Irina; Olsen, Randi; Brækkan, Sigrid Kufaas; Hansen, John‐Bjarne

doi:10.1111/jth.14162

Cited by 19 publications

(18 citation statements)

References 40 publications

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“…Circumstantial evidence support the concept that complement activation, assessed by plasma TCC, may be a mediator of VTE risk through platelet and coagulation activation because it reflects the degree of membrane‐inserted C5b‐9. First, incorporation of the C5b‐9‐complex into the cell membrane activates platelets and results in (i) the exposure of negatively charged phosphatidylserine, which may assemble and amplify coagulation reactions; (ii) the formation of procoagulant microvesicles, which is associated with risk of VTE; and (iii) secretion of procoagulant granules from the cytoplasm of platelets . Second, the complement system has direct procoagulant activities, including the ability to cleave and activate coagulation factors and increase TF expression in various cell types.…”

Section: Discussionmentioning

confidence: 99%

Complement activation assessed by the plasma terminal complement complex and future risk of venous thromboembolism

Høiland

Liang

Brækkan

et al. 2019

Journal of Thrombosis and Haemostasis

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Background: It remains uncertain whether activation of the complement system, assessed by the soluble terminal C5b-9 complement complex (plasma TCC), is associated with future risk of incident venous thromboembolism (VTE). Objectives:To investigate the association between plasma levels of TCC and future risk of incident VTE in a nested case-control study, and to explore genetic variants associated with TCC using protein quantitative trait loci analysis of exome sequencing data. Methods:We sampled 415 VTE cases and 848 age-and sex-matched controls from a population-based cohort, the Tromsø study. Logistic regression models were used to calculate odds ratios with 95% confidence intervals for VTE across quartiles of plasma levels of TCC. Whole exome sequencing was conducted using the Agilent SureSelect 50 Mb capture kit.Results: The risk of VTE increased across increasing quartiles of plasma TCC, particularly for unprovoked VTE. Participants with TCC in the highest quartile (>1.40 complement arbitrary units/mL) had an odds ratio for unprovoked VTE of 1.74 (95% confidence interval: 1.10-2.78) compared with those with TCC in the lowest quartile (≤0.80 complement arbitrary units/mL) in analyses adjusted for age, sex, and body mass index. A substantially higher risk for VTE was observed in samples taken shortly before VTE event. We found no association between genome-wide or complementrelated gene variants and plasma levels of TCC. Conclusions:We found that high levels of plasma TCC were associated with VTE risk, and unprovoked events in particular. There was no genome-wide association between gene variants and plasma levels of TCC. K E Y W O R D S complement system, protein quantitative trait loci analysis, terminal complement complex, venous thromboembolism, whole exome sequencing | 935 HØILAND et AL. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Høiland II, Liang RA, Braekkan SK, Pettersen K, Ludviksen JK, Latysheva N, et al. Complement activation assessed by the plasma terminal complement complex and future risk of venous thromboembolism. J Thromb Haemost. 2019;17:934-943. https ://doi.

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Section: Discussionmentioning

confidence: 99%

Complement activation assessed by the plasma terminal complement complex and future risk of venous thromboembolism

Høiland

Liang

Brækkan

et al. 2019

Journal of Thrombosis and Haemostasis

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“…Circumstantial evidence supports an association between plasma PPL CT and the risk of future VTE. First, the PPL CT is inversely associated with annexin V‐positive EVs 15 , 27 and high plasma levels of EVs are associated with VTE risk in most, 16 , 17 , 18 , 19 but not all studies. 20 , 28 Second, in a cross‐sectional study including plasma samples from 100 healthy individuals and patients with obstructive sleep apnea, plasma PPL CT showed strong and inverse correlations to parameters of thrombin generation, such as ETP and peak thrombin concentration, using the CAT assay with the addition of minimal amounts of phospholipids and tissue factor (1 pM) to trigger thrombin generation.…”

Section: Discussionmentioning

confidence: 99%

“…Because most, 16 , 17 , 18 , 19 but not all 20 observational studies have reported elevated plasma levels of EVs in VTE, implying short plasma PPL CT , we hypothesized that prolonged PPL CT was associated with lowered risk of VTE. We therefore aimed to investigate the association between plasma PPL CT , measured by a modified factor Xa‐dependent clotting assay, and the risk of incident VTE in a nested case‐control study derived from the general population.…”

Section: Introductionmentioning

confidence: 99%

Plasma procoagulant phospholipid clotting time and venous thromboembolism risk

Ramberg

Wilsgård

Latysheva

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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Background Negatively charged procoagulant phospholipids, phosphatidylserine (PS) in particular, are vital to coagulation and expressed on the surface membrane of extracellular vesicles. No previous study has investigated the association between plasma procoagulant phospholipid clotting time (PPL CT ) and future risk of venous thromboembolism (VTE). Objectives To investigate the association between plasma PPL CT and the risk of incident VTE in a nested case‐control study. Methods We conducted a nested case‐control study in 296 VTE patients and 674 age‐ and sex‐matched controls derived from a general population cohort (The Tromsø Study 1994–2007). PPL CT was measured in platelet‐free plasma using a modified factor Xa‐dependent clotting assay. Logistic regression was used to estimate odds ratio (OR) with 95% confidence intervals (CI) for VTE with PPL CT modelled as a continuous variable across quartiles and in dichotomized analyses. Results There was a weak inverse association between plasma PPL CT and risk of VTE per 1 standard deviation increase of PPL CT (OR 0.93, 95% CI 0.80–1.07) and when comparing those with PPL CT in the highest quartile (OR 0.89, 95% CI 0.60–1.30) with those in the lowest quartile. Subjects with PPL CT >95th percentile had substantially lowered OR for VTE (OR 0.35, 95% CI 0.13–0.81). The inverse association was stronger when the analyses were restricted to samples taken shortly before the event. The risk estimates by categories of plasma PPL CT were similar for deep vein thrombosis and pulmonary embolism. Conclusion Our findings suggest that high plasma PPL CT is associated with reduced risk of VTE.

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“…Circulating total EV numbers were also higher in patients with VTE, and the VTE risk was found to increase progressively with increasing MP numbers, independent of other risk factors associated with a hypercoagulable state [201]. Elevated CD62P-positive platelet MPs were observed in patients with unprovoked DVT [202], and their numbers also were elevated in patients with acute PE, whereas endothelial MP levels did not differ [193,194]. Others report elevations in circulating endothelial MP numbers, also in conjunction with monocytes, in patients with acute venous thromboembolism (VTE) [203].…”

Section: Evs and Thrombosis In The Venous System: Findings In Human Studiesmentioning

confidence: 90%

Extracellular Vesicles and Thrombosis: Update on the Clinical and Experimental Evidence

Zifkos

Dubois

Schäfer

2021

IJMS

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Extracellular vesicles (EVs) compose a heterogenous group of membrane-derived particles, including exosomes, microvesicles and apoptotic bodies, which are released into the extracellular environment in response to proinflammatory or proapoptotic stimuli. From earlier studies suggesting that EV shedding constitutes a cellular clearance mechanism, it has become evident that EV formation, secretion and uptake represent important mechanisms of intercellular communication and exchange of a wide variety of molecules, with relevance in both physiological and pathological situations. The putative role of EVs in hemostasis and thrombosis is supported by clinical and experimental studies unraveling how these cell-derived structures affect clot formation (and resolution). From those studies, it has become clear that the prothrombotic effects of EVs are not restricted to the exposure of tissue factor (TF) and phosphatidylserines (PS), but also involve multiplication of procoagulant surfaces, cross-linking of different cellular players at the site of injury and transfer of activation signals to other cell types. Here, we summarize the existing and novel clinical and experimental evidence on the role and function of EVs during arterial and venous thrombus formation and how they may be used as biomarkers as well as therapeutic vectors.

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Elevated plasma levels of P‐selectin glycoprotein ligand‐1‐positive microvesicles in patients with unprovoked venous thromboembolism

Cited by 19 publications

References 40 publications

Complement activation assessed by the plasma terminal complement complex and future risk of venous thromboembolism

Complement activation assessed by the plasma terminal complement complex and future risk of venous thromboembolism

Plasma procoagulant phospholipid clotting time and venous thromboembolism risk

Extracellular Vesicles and Thrombosis: Update on the Clinical and Experimental Evidence

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