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      Advances in Clinical and Basic Science of Coagulation: Illustrated abstracts of the 9th Chapel Hill Symposium on Hemostasis

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          Abstract

          This 9th Symposium on Hemostasis is an international scientific meeting held biannually in Chapel Hill, North Carolina. The meeting is in large measure the result of the close friendship between the late Dr. Harold R. Roberts of UNC Chapel Hill and Dr. Ulla Hedner of Novo Nordisk. When Novo Nordisk was developing the hemophilia therapy that would become NovoSeven, they sponsored a series of meetings to understand the basic biology and clinical applications of factor VIIa. The first meeting in Chapel Hill was held April 4‐6, 2002 with Dr. Roberts as the organizer. Over the years, the conference emphasis has expanded from discussions of factor VIIa and tissue factor to additional topics in hemostasis and thrombosis. This year's meeting includes presentations by internationally renowned speakers that discuss the state‐of‐the‐art on an array of important topics, including von Willebrand factor, engineering advances, coagulation and disease, tissue factor biology, therapeutic advances, and basic clotting factor biology. Included in this review article are illustrated abstracts provided by our speakers, which highlight the main conclusions of each invited talk. This will be the first meeting without Dr. Roberts in attendance, yet his commitment to excellent science and his focus on turning science to patient care are pervasively reflected in the presentations by our speakers.

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          Most cited references45

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          The lung is a site of platelet biogenesis and a reservoir for hematopoietic progenitors

          Platelets are critical for hemostasis, thrombosis, and inflammatory responses 1,2 , yet the events leading to mature platelet production remain incompletely understood 3 . The bone marrow (BM) is proposed to be a major site of platelet production although indirect evidence points towards a potential pulmonary contribution to platelet biogenesis 4-7 . By directly imaging the lung microcirculation in mice 8 , we discovered that a large number of megakaryocytes (MKs) circulate through the lungs where they dynamically release platelets. MKs releasing platelets in the lung are of extrapulmonary origin, such as the BM, where we observed large MKs migrating out of the BM space. The lung contribution to platelet biogenesis is substantial with approximately 50% of total platelet production or 10 million platelets per hour. Furthermore, we identified populations of mature and immature MKs along with hematopoietic progenitors that reside in the extravascular spaces of the lung. Under conditions of thrombocytopenia and relative stem cell deficiency in the BM 9 , these progenitors can migrate out of the lung, repopulate the BM, completely reconstitute blood platelet counts, and contribute to multiple hematopoietic lineages. These results position the lung as a primary site of terminal platelet production and an organ with considerable hematopoietic potential.
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            Thrombin signalling and protease-activated receptors.

            S Coughlin (2000)
            How does the coagulation protease thrombin regulate cellular behaviour? The protease-activated receptors (PARs) provide one answer. In concert with the coagulation cascade, these receptors provide an elegant mechanism linking mechanical information in the form of tissue injury or vascular leakage to cellular responses. Roles for PARs are beginning to emerge in haemostasis and thrombosis, inflammation, and perhaps even blood vessel development.
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              Paraneoplastic thrombocytosis in ovarian cancer.

              The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear. We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained. Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti-interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis. These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. (Funded by the National Cancer Institute and others.).
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                Author and article information

                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
                12 April 2018
                July 2018
                : 2
                : 3 ( doiID: 10.1002/rth2.2018.2.issue-3 )
                : 407-428
                Affiliations
                [ 1 ] Department of Biochemistry and Biophysics University of North Carolina Chapel Hill NC USA
                [ 2 ] Department of Pathology and Laboratory Medicine University of North Carolina Chapel Hill NC USA
                [ 3 ] UBC Centre for Blood Research Vancouver BC Canada
                [ 4 ] INSERM U1176 Le Kremlin‐Bicetre Cedex France
                [ 5 ] University of Pennsylvania Children's Hospital of Philadelphia Philadelphia PA USA
                [ 6 ] University Magdeburg Magdeburg Germany
                [ 7 ] Department of Medicine University of North Carolina Chapel Hill NC USA
                [ 8 ] Department of Pediatrics and the Wallace H. Coulter Department of Biomedical Engineering Emory University and Georgia Institute of Technology Atlanta GA USA
                [ 9 ] Queen's University Kingston Kingston ON Canada
                [ 10 ] Eshelman School of Pharmacy University of North Carolina Chapel Hill NC USA
                [ 11 ] University of California San Francisco San Francisco CA USA
                [ 12 ] School of Medicine Puget Sound Blood Center Research Institute University of Washington Seattle WA USA
                [ 13 ] Department of Clinical Chemistry and Haematology University Medical Center Utrecht Utrecht the Netherlands
                [ 14 ] University of IRCCS Maggiore Hospital Milan Italy
                [ 15 ] The Scripps Research Institute La Jolla CA USA
                [ 16 ] University of Texas MD Anderson Cancer Center Houston TX USA
                [ 17 ] Leiden University Leiden the Netherlands
                [ 18 ] Transfusion Medicine Hematology Bristol‐Meyers Squibb Pennington NJ USA
                [ 19 ] Gill Heart and Vascular Institute University of Kentucky Lexington KY USA
                [ 20 ] Blood Research Institute Blood Center of Wisconsin Milwaukee WI USA
                Author information
                http://orcid.org/0000-0002-1211-8861
                http://orcid.org/0000-0003-4593-0976
                http://orcid.org/0000-0002-6064-2166
                http://orcid.org/0000-0002-2845-2303
                Article
                RTH212095
                10.1002/rth2.12095
                6046595
                eff0207e-991c-42f9-8975-37b1986a7042
                © 2018 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
                Page count
                Figures: 0, Tables: 0, Pages: 20, Words: 764
                Categories
                Illustrated Review
                Illustrated Review Article
                Custom metadata
                2.0
                rth212095
                July 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.3 mode:remove_FC converted:16.07.2018

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