Can Podoplanin Explain the Connection Between Brain Tumors and Venous Thromboembolism?

Podoplanin, a sialomucin-like glycoprotein that can induce blood platelet activation, is frequently expressed by primary brain tumors. Its overexpression can contribute to a greater risk of venous thromboembolism (VTE) among patients with brain tumors, according to a report published in Blood.

“The risk of developing VTE was approximately six times higher in patients with high-podoplanin-expressing tumors compared to patients with podoplanin-negative tumors,” reported Julia Riedl, MD, from the Clinical Division of Hematology and Hemostaseology at the Medical University of Vienna in Austria, and co-authors.

In this prospective, single-center, observational cohort study, Dr. Riedl and researchers explored the association between podoplanin expression with hypercoagulability and risk of VTE and mortality in 213 patients (median age = 55 years; range = 44-66 years) from the Vienna Cancer and Thrombosis Study (CATS) who had a newly diagnosed malignancy (n=185, 86.9%) or progression of disease after remission (n=28, 13.1%). The authors also studied platelet response to glioblastoma cells in vitro to confirm the role of brain tumor-inducible platelet activation in VTE risk.

Patients were excluded if they received chemotherapy within the previous three months, received radiotherapy or surgery within the previous two weeks, had a diagnosis of VTE in the previous three months, and/or received continuous oral anticoagulation or low-molecular-weight heparin.

Patients were enrolled in the study at a median of 17 days after tumor biopsy or surgery, and they were followed for a median of 731 days (range = 3-731 days). Seventy-five patients had complete tumor resection, 77 had incomplete tumor resection, and 61 had tumor biopsy prior to the study.

Most patients (n=151, 70.9%) were positive for podoplanin (measured by immunohistochemical staining of tissue samples):

  • 71 had low expression (defined as isolated, small, CD61-positive thrombotic vessels)
  • 47 had medium expression (defined as multiple positive thrombotic vessels)
  • 33 had high expression (defined as very large and/or plenty of CD61-positive thrombotic vessels)

During a two-year follow-up period, 29 patients (13.6%) developed VTE (including 15 deep vein thromboses [DVTs] of the lower extremity, 13 pulmonary embolisms, and one DVT of the upper extremity); 113 patients (53.1%) died.

Podoplanin expression was positively correlated to grade of intravascular platelet aggregates in tumor specimens, decreased blood platelet counts, and increased plasma levels of D-dimer, suggesting “a functional role of podoplanin-induced platelet activation in hypercoagulability in brain tumor patients,” the authors reported.

In the entire population, the 6-, 12-, and 24-month risks of VTE were 10.1 percent, 13.3 percent, and 14.8 percent, respectively, whereas the probabilities of survival were 84.3 percent, 65.1 percent, and 40.6 percent.

Both the risks of VTE and mortality were significantly higher for patients with podoplanin-expressing tumors compared with patients with podoplanin-negative tumors, and both increased as expression levels increased (TABLE).

Patients with high podoplanin expression also experienced the lowest probability of survival at 6, 12, and 24 months:

  • 98.4%, 88.2%, and 68% for podoplanin-negative tumors
  • 81.5%, 61.4%, and 39% for low podoplanin expression
  • 78%, 50.8%, and 12.2% for moderate podoplanin expression
  • 72.2%, 49.3%, and 21.9% for high podoplanin expression

“Identifying patients at risk of VTE is a challenge, because the risk factors in this patient population are not well understood,” co-author Cihan Ay, MD, told ASH Clinical News. “As podoplanin expression correlated with intravascular platelet aggregates in brain tumor specimens and low platelet count in the circulation (as a result of its ability to induce platelet aggregation via the platelet receptor CLEC-2) our study supports the hypothesis that podoplanin might play an important role in the pathogenesis of VTE.”

Although the results “support the concept that podoplanin expression represents the missing pathobiologic link between cancer and thrombotic risk in patients with primary brain tumors,” the study was not able to provide “experimental in vivo evidence for a mechanistic relationship between podoplanin expression and development of VTE,” which the authors noted as a limitation of the study.

Future in vivo studies using animal models of glioblastoma and thrombosis are needed to confirm the current study’s findings, and other research should evaluate “the efficacy and safety of primary thromboprophylaxis in brain tumor patients with high risk of VTE, based on podoplanin expression levels in tumor tissue.”



Reference

Riedl J, Preusser M, Nazari PMS, et al. Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism. Blood. 2017 January 10. [Epub ahead of print]

TABLE. Association of Podoplanin Expression With Risk of Future VTE
Podoplanin Expression Univariable HR P Value Multivariable HR P Value
Risk for Future VTE
Negative Reference Reference Reference Reference
Low 2.48

(95% CI 0.76-8.09)

0.131 2.44

(95% CI 0.73-8.17)

0.148
Medium 3.64

(95% CI 1.09-12.17)

0.036 3.28

(95% CI 0.91-11.75)

0.068
High 5.75

(95% CI 1.71-19.27)

0.005 5.71

(95% CI 1.52-21.36)

0.010
Mortality Risk
Negative Reference Reference Reference Reference
Low 2.78
(95% CI 1.59-4.87)
<0.001 2.14

(95% CI 1.18-3.89)

0.012
Medium 4.70

(95% CI 2.63-8.40)

<0.001 3.03

(95% CI 1.62-5.68)

0.001
High 4.44

(95% CI 2.37-8.31)

<0.001 2.58

(95% CI 1.29-5.15)

0.007
VTE = venous thromboembolism; HR = hazard ratio
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