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Original research
Heparan sulfate chains contribute to the anticoagulant milieu in malignant pleural effusion
  1. Emilia Hardak1,
  2. Eli Peled2,
  3. Yonatan Crispel3,
  4. Shourouk Ghanem3,
  5. Judith Attias4,
  6. Keren Asayag3,
  7. Inna Kogan3,
  8. Yona Nadir3
  1. 1 Pulmonology Institute, Rambam Health Care Campus, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
  2. 2 Division of Orthopedic, Rambam Health Care Campus, The Rappaport Faculty of Medicine, Technion, Haifa, Israel
  3. 3 Thrombosis and Hemostasis Unit, Rambam Health Care Campus, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
  4. 4 Stat Laboratory, Rambam Health Care Campus, The Bruce Rappaport Faculty of Medicine, The Technion, Haifa, Israel
  1. Correspondence to Professor ‪Yona Nadir‬‏, Thrombosis and Hemostasis Unit, Rambam Health Care Campus, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 3093015, Israel; nadir.yona{at}


Background While malignant pleural effusion (MPE) is a common and significant cause of morbidity in patients with cancer, current treatment options are limited. Human heparanase, involved in angiogenesis and metastasis, cleaves heparan sulfate (HS) side chains on the cell surface.

Aims To explore the coagulation milieu in MPE and infectious pleural effusion (IPE) focusing on the involvement of heparanase.

Methods Samples of 30 patients with MPE and 44 patients with IPE were evaluated in comparison to those of 33 patients with transudate pleural effusions, using heparanase ELISA, heparanase procoagulant activity assay, thrombin and factor Xa chromogenic assays and thromboelastography. A cell proliferation assay was performed. EMT-6 breast cancer cells were injected to the pleural cavity of mice. A peptide inhibiting heparanase activity was administered subcutaneously.

Results Levels of heparanase, factor Xa and thrombin were significantly higher in exudate than transudate. Thromboelastography detected almost no thrombus formation in the whole blood, mainly on MPE addition. This effect was completely reversed by bacterial heparinase. Direct measurement revealed high levels of HS chains in pleural effusions. Higher proliferation was observed in tumour cell lines incubated with exudate than with transudate and it was reduced when bacterial heparinase was added. The tumour size in the pleural cavity of mice treated with the heparanase inhibitor were significantly smaller compared with control (p=0.005).

Conclusions HS chains released by heparanase form an anticoagulant milieu in MPE, preventing local thrombosis and enabling tumour cell proliferation. Inhibition of heparanase might provide a therapeutic option for patients with recurrent MPE.

  • heparan sulfate
  • pleural effusion
  • tumor
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  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests European Patent Application No. IL201200027 filed on 18 January 2012 in the name of Nadir, Brenner, Vlodavsky. Entitled: Methods and kits for assessing heparanase procoagulant activity, compositions comprising heparanase and methods for the treatment of coagulation-related disorders.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Institutional Review Board of the Rambam Health Care Campus (Approval #0578–14-RMB). The study was approved by the Technion Ethics Committee for Animal Research, and the procedures were conducted in accordance with institutional guidelines.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request.

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