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      Different Potential of Extracellular Vesicles to Support Thrombin Generation: Contributions of Phosphatidylserine, Tissue Factor, and Cellular Origin

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          Abstract

          Cells release diverse types of vesicles constitutively or in response to proliferation, injury, inflammation, or stress. Extracellular vesicles (EVs) are crucial in intercellular communication, and there is emerging evidence for their roles in inflammation, cancer, and thrombosis. We investigated the thrombogenicity of platelet-derived EVs, which constitute the majority of circulating EVs in human blood, and assessed the contributions of phosphatidylserine and tissue factor exposure on thrombin generation. Addition of platelet EVs to vesicle-free human plasma induced thrombin generation in a dose-dependent manner, which was efficiently inhibited by annexin V, but not by anti-tissue factor antibodies, indicating that it was primarily due to the exposure of phosphatidylserine on platelet EVs. Platelet EVs exhibited higher thrombogenicity than EVs from unstimulated monocytic THP-1 cells, but blockade of contact activation significantly reduced thrombin generation by platelet EVs. Stimulation of monocytic cells with lipopolysaccharide enhanced their thrombogenicity both in the presence and in the absence of contact activation, and thrombin generation was efficiently blocked by anti-tissue factor antibodies. Our study provides evidence that irrespective of their cellular origin, EVs support the propagation of coagulation via the exposure of phosphatidylserine, while the expression of functional tissue factor on EVs appears to be limited to pathological conditions.

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          Most cited references 31

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          Microparticles in hemostasis and thrombosis.

          Blood contains microparticles (MPs) derived from a variety of cell types, including platelets, monocytes, and endothelial cells. In addition, tumors release MPs into the circulation. MPs are formed from membrane blebs that are released from the cell surface by proteolytic cleavage of the cytoskeleton. All MPs are procoagulant because they provide a membrane surface for the assembly of components of the coagulation protease cascade. Importantly, procoagulant activity is increased by the presence of anionic phospholipids, particularly phosphatidylserine (PS), and the procoagulant protein tissue factor (TF), which is the major cellular activator of the clotting cascade. High levels of platelet-derived PS(+) MPs are present in healthy individuals, whereas the number of TF(+), PS(+) MPs is undetectable or very low. However, levels of PS(+), TF(+) MPs are readily detected in a variety of diseases, and monocytes appear to be the primary cellular source. In cancer, PS(+), TF(+) MPs are derived from tumors and may serve as a useful biomarker to identify patients at risk for venous thrombosis. This review will summarize our current knowledge of the role of procoagulant MPs in hemostasis and thrombosis.
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            Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation.

            We determined the numbers, cellular origin and thrombin-generating properties of microparticles in healthy individuals (n = 15). Microparticles, isolated from fresh blood samples and identified by flow cytometry, originated from platelets [237 x 10(6)/L (median; range 116-565)], erythrocytes (28 x 10(6)/L; 13-46), granulocytes (46 x 10(6)/L; 16-94) and endothelial cells (64 x 10(6)/L; 16-136). They bound annexin V, indicating surface exposure of phosphatidylserine, and supported coagulation in vitro. Interestingly, coagulation occurred via tissue factor (TF)-independent pathways, because antibodies against TF or factor (F)VII were ineffective. In contrast, in our in vitro experiments coagulation was partially inhibited by antibodies against FXII (12%, p = 0.006), FXI (36%, p <0.001), FIX (28%, p <0.001) or FVIII (32%, p <0.001). Both the number of annexin V-positive microparticles present in plasma and the thrombin-generating capacity inversely correlated to the plasma concentrations of thrombin-antithrombin complex (r = -0.49, p = 0.072 and r = -0.77, p = 0.001, respectively), but did not correlate to prothrombin fragment F1+2 (r = -0.002, p = 0.99). The inverse correlations between the number of microparticles and their thrombin-forming capacity and the levels of thrombin-antithrombin complex in plasma may indicate that microparticles present in the circulation of healthy individuals have an anticoagulant function by promoting the generation of low amounts of thrombin that activate protein C. We conclude that microparticles in blood from healthy individuals support thrombin generation via TF- and FVII-independent pathways, and which may have an anticoagulant function.
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              Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients.

              Patients with cancer have an increased risk for venous thrombosis. Interestingly, different cancer types have different rates of thrombosis, with pancreatic cancer having one of the highest rates. However, the mechanisms responsible for the increase in venous thrombosis in patients with cancer are not understood. Tissue factor (TF) is a transmembrane receptor and primary initiator of blood coagulation. Tumor cells express TF and spontaneously release TF-positive microparticles (MPs) into the blood. MPs are small membrane vesicles that are highly procoagulant. It has been proposed that these circulating tumor-derived, TF-positive MPs may explain the increased rates of venous thrombosis seen in patients with cancer. In animal models, increased levels of tumor-derived, TF-positive MPs are associated with activation of coagulation. Moreover, these MPs bind to sites of vascular injury and enhance thrombosis. We and others have found that patients with cancer have elevated levels of circulating TF-positive MPs. These MPs are derived from tumors because they express tumor markers and are decreased by tumor resection. Importantly, several studies have shown that increased levels of TF-positive MPs correlate with venous thrombosis in patients with cancer. Taken together, these results suggest that TF-positive MPs may be a useful biomarker to identify patients with cancer who are at high risk for thrombosis.
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                Author and article information

                Contributors
                viktoria.weber@donau-uni.ac.at
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                26 July 2017
                26 July 2017
                2017
                : 7
                Affiliations
                [1 ]ISNI 0000 0001 2108 5830, GRID grid.15462.34, Christian Doppler Laboratory for Innovative Therapy Approaches in Sepsis, , Danube University Krems, Dr.-Karl-Dorrek-Strasse 30, ; 3500 Krems, Austria
                [2 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Core Facility Flow Cytometry & Surgical Research Laboratories, , Medical University of Vienna, Lazarettgasse 14, ; 1090 Vienna, Austria
                [3 ]GRID grid.419003.f, Electron Microscopy Facility, , Vienna Biocenter Core Facilities, Dr.-Bohr-Gasse 3, ; 1030 Vienna, Austria
                [4 ]ISNI 0000 0001 2108 5830, GRID grid.15462.34, Center for Biomedical Technology, , Department for Health Sciences and Biomedicine, Danube University Krems, Dr.-Karl-Dorrek-Strasse 30, ; 3500 Krems, Austria
                Article
                3262
                10.1038/s41598-017-03262-2
                5529579
                28747771
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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