title: Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism.
abstract: Venous thromboembolism (VTE) is common in patients with brain tumors, and underlying mechanisms are unclear. We hypothesized that podoplanin, a sialomucin-like glycoprotein, increases the risk of VTE in primary brain tumors via its ability to induce platelet aggregation. Immunohistochemical staining against podoplanin and intratumoral platelet aggregates was performed in brain tumor specimens of 213 patients (mostly high-grade gliomas [89%]) included in the Vienna Cancer and Thrombosis Study, a prospective observational cohort study of patients with newly diagnosed cancer or progressive disease aimed at identifying patients at risk of VTE. Platelet aggregation in response to primary human glioblastoma cells was investigated in vitro. During 2-year follow-up, 29 (13.6%) patients developed VTE. One-hundred fifty-one tumor specimens stained positive for podoplanin (33 high expression, 47 medium expression, 71 low expression). Patients with podoplanin-positive tumors had lower peripheral blood platelet counts (P< .001) and higher D-dimer levels (P< .001). Podoplanin staining intensity was associated with increasing levels of intravascular platelet aggregates in tumor specimens (P< .001). High podoplanin expression was associated with an increased risk of VTE (hazard ratio for high vs no podoplanin expression: 5.71; 95% confidence interval, 1.52-21.26;P =010), independent of age, sex, and tumor type. Podoplanin-positive primary glioblastoma cells induced aggregation of human platelets in vitro, which could be abrogated by an antipodoplanin antibody. In conclusion, high podoplanin expression in primary brain tumors induces platelet aggregation, correlates with hypercoagulability, and is associated with increased risk of VTE. Our data indicate novel insights into the pathogenesis of VTE in primary brain tumors.
authors.affiliation: Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center Vienna, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Riedl
authors.affiliation: Comprehensive Cancer Center Vienna, Vienna, Austria.|Clinical Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
authors.affiliation: Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center Vienna, Vienna, Austria.
authors.forename: Pegah Mir Seyed
authors.initials: PM
authors.lastname: Nazari
authors.affiliation: Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center Vienna, Vienna, Austria.|Clinical Division of Oncology, Department of Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Posch
authors.affiliation: Department of Blood Group Serology and Transfusion Medicine.
authors.forename: Simon
authors.initials: S
authors.lastname: Panzer
authors.affiliation: Comprehensive Cancer Center Vienna, Vienna, Austria.|Clinical Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Marosi
authors.affiliation: Clinical Institute of Pathology.
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
authors.affiliation: Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center Vienna, Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Thaler
authors.affiliation: Department of Surgery.
authors.forename: Christine
authors.initials: C
authors.lastname: Brostjan
authors.affiliation: Comprehensive Cancer Center Vienna, Vienna, Austria.|Institute of Cancer Research, Department of Medicine I, and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Lötsch
authors.affiliation: Comprehensive Cancer Center Vienna, Vienna, Austria.|Institute of Cancer Research, Department of Medicine I, and.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria; and.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Hainfellner
authors.affiliation: Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center Vienna, Vienna, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pabinger
authors.affiliation: Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center Vienna, Vienna, Austria.|Thrombosis and Hemostasis Program, McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Cihan
authors.initials: C
authors.lastname: Ay
mesh_terms: D001932:Brain Neoplasms / Q000097:blood / Q000150:complications* / Q000378:metabolism*; D015331:Cohort Studies; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D010974:Platelet Aggregation; D011446:Prospective Studies; D019851:Thrombophilia / Q000209:etiology; D054556:Venous Thromboembolism / Q000209:etiology*; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; C117468:PDPN protein, human; D000098853:Podoplanin