Stark, Konstantin ORCID: 0000-0002-5369-8399, Schubert, Irene ORCID: 0000-0003-3344-5324, Joshi, Urjita, Kilani, Badr, Hoseinpour, Parandis, Thakur, Manovriti, Gruenauer, Petra, Pfeiler, Susanne ORCID: 0000-0002-8591-6186, Schmidergall, Tobias, Stockhausen, Sven, Baeumer, Markus, Chandraratne, Sue, von Bruehl, Marie-Luise, Lorenz, Michael, Coletti, Raffaele, Reese, Sven ORCID: 0000-0002-4605-9791, Laitinen, Iina, Woermann, Sonja Maria, Alguel, Hana, Bruns, Christiane J., Ware, Jerry, Mackman, Nigel, Engelmann, Bernd and Massberg, Steffen (2018). Distinct Pathogenesis of Pancreatic Cancer Microvesicle-Associated Venous Thrombosis Identifies New Antithrombotic Targets In Vivo. Arterioscler. Thromb. Vasc. Biol., 38 (4). S. 772 - 787. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4636

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Abstract

Objective Cancer patients are at high risk of developing deep venous thrombosis (DVT) and venous thromboembolism, a leading cause of mortality in this population. However, it is largely unclear how malignant tumors drive the prothrombotic cascade culminating in DVT. Approach and Results Here, we addressed the pathophysiology of malignant DVT compared with nonmalignant DVT and focused on the role of tumor microvesicles as potential targets to prevent cancer-associated DVT. We show that microvesicles released by pancreatic adenocarcinoma cells (pancreatic tumor-derived microvesicles [pcMV]) boost thrombus formation in a model of flow restriction of the mouse vena cava. This depends on the synergistic activation of coagulation by pcMV and host tissue factor. Unlike nonmalignant DVT, which is initiated and propagated by innate immune cells, thrombosis triggered by pcMV was largely independent of myeloid leukocytes or platelets. Instead, we identified externalization of the phospholipid phosphatidylethanolamine as a major mechanism controlling the prothrombotic activity of pcMV. Disrupting phosphatidylethanolamine-dependent activation of factor X suppressed pcMV-induced DVT without causing changes in hemostasis. Conclusions Together, we show here that the pathophysiology of pcMV-associated experimental DVT differs markedly from innate immune cell-promoted nonmalignant DVT and is therefore amenable to distinct antithrombotic strategies. Targeting phosphatidylethanolamine on tumor microvesicles could be a new strategy for prevention of cancer-associated DVT without causing bleeding complications.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Stark, KonstantinUNSPECIFIEDorcid.org/0000-0002-5369-8399UNSPECIFIED
Schubert, IreneUNSPECIFIEDorcid.org/0000-0003-3344-5324UNSPECIFIED
Joshi, UrjitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kilani, BadrUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoseinpour, ParandisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thakur, ManovritiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruenauer, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfeiler, SusanneUNSPECIFIEDorcid.org/0000-0002-8591-6186UNSPECIFIED
Schmidergall, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stockhausen, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baeumer, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chandraratne, SueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Bruehl, Marie-LuiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coletti, RaffaeleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reese, SvenUNSPECIFIEDorcid.org/0000-0002-4605-9791UNSPECIFIED
Laitinen, IinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Woermann, Sonja MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alguel, HanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruns, Christiane J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ware, JerryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mackman, NigelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engelmann, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Massberg, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-190732
DOI: 10.1161/ATVBAHA.117.310262
Journal or Publication Title: Arterioscler. Thromb. Vasc. Biol.
Volume: 38
Number: 4
Page Range: S. 772 - 787
Date: 2018
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 1524-4636
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DEEP-VEIN THROMBOSIS; MICROPARTICLE TISSUE FACTOR; GLYCOPROTEIN-IB-ALPHA; VON-WILLEBRAND-FACTOR; THROMBOEMBOLIC EVENTS; INNATE IMMUNITY; P-SELECTIN; ARTERIAL THROMBOSIS; HEMOSTATIC FACTORS; ENDOTHELIAL-CELLSMultiple languages
Hematology; Peripheral Vascular DiseaseMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19073

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