Konstantin Stark1, Irene Schubert2, Urjita Joshi2, Badr Kilani2, Parandis Hoseinpour2, Manovriti Thakur2, Petra Grünauer2, Susanne Pfeiler2, Tobias Schmidergall2, Sven Stockhausen2, Markus Bäumer2, Sue Chandraratne2, Marie-Luise von Brühl2, Michael Lorenz2, Raffaele Coletti2, Sven Reese2, Iina Laitinen2, Sonja Maria Wörmann2, Hana Algül2, Christiane J Bruns2, Jerry Ware2, Nigel Mackman2, Bernd Engelmann2, Steffen Massberg2. 1. From the Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität, Munich, Germany (K.S., I.S., B.K., P.H., T.S., S.S., S.C., M.-L.v.B., M.L., R.C., S.M.); German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Germany (K.S., S.M.); Institut für Laboratoriumsmedizin (U.J., M.T., P.G., S.P., M.B., B.E.) and Lehrstuhl für Anatomie, Histologie und Embryologie, Department of Veterinary Medicine (S.R.), Ludwig-Maximilians-Universität, Munich, Germany; Nuklearmedizinische Klinik und Poliklinik (I.L.) and II. Medizinische Klinik und Poliklinik (S.M.W., H.A.), Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Klinik und Poliklinik für Allgemein-, Viszeral- und Tumorchirurgie, Universitätsklinik Köln, Cologne, Germany (C.J.B.); Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock (J.W.); and Department of Medicine, University of North Carolina at Chapel Hill (N.M.). konstantin.stark@med.uni-muenchen.de. 2. From the Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität, Munich, Germany (K.S., I.S., B.K., P.H., T.S., S.S., S.C., M.-L.v.B., M.L., R.C., S.M.); German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Germany (K.S., S.M.); Institut für Laboratoriumsmedizin (U.J., M.T., P.G., S.P., M.B., B.E.) and Lehrstuhl für Anatomie, Histologie und Embryologie, Department of Veterinary Medicine (S.R.), Ludwig-Maximilians-Universität, Munich, Germany; Nuklearmedizinische Klinik und Poliklinik (I.L.) and II. Medizinische Klinik und Poliklinik (S.M.W., H.A.), Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Klinik und Poliklinik für Allgemein-, Viszeral- und Tumorchirurgie, Universitätsklinik Köln, Cologne, Germany (C.J.B.); Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock (J.W.); and Department of Medicine, University of North Carolina at Chapel Hill (N.M.).
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.
OBJECTIVE:Cancerpatients 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 phospholipidphosphatidylethanolamine 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.
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2019-12-23 Impact factor: 8.311