Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism

Julia Riedl, Matthias Preusser, Pegah Mir Seyed Nazari, Florian Posch, Simon Panzer, Christine Marosi, Peter Birner, Johannes Thaler, Christine Brostjan, Daniela Lötsch, Walter Berger, Johannes A. Hainfellner, Ingrid Pabinger and Cihan Ay

Key points

  • Brain tumor patients have a very high risk of venous thromboembolism (VTE).

  • Podoplanin expression by primary brain tumors induces platelet aggregation and is associated with hypercoagulability and a high risk of VTE.


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 (CATS), 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 and 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<0.001) and higher D-dimer levels (p<0.001). Podoplanin staining intensity was associated with increasing levels of intravascular platelet aggregates in tumor specimens (p<0.001). High podoplanin expression was associated with an increased risk of VTE (hazard ratio for high vs. no podoplanin expression: 5.71, 95%CI: 1.52-21.26; p=0.010), independently of age, sex and tumor type. Podoplanin positive primary glioblastoma cells induced aggregation of human platelets in vitro, which could be abrogated by an anti-podoplanin 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.

  • Submitted June 6, 2016.
  • Accepted January 4, 2017.