Heparan sulfate chains contribute to the anticoagulant milieu in malignant pleural effusion

Hardak, Emília; Peled, Einat; Crispel, Yonatan; Ghanem, Shourouk; Attias, Judith; Asayag, Keren; Kogan, Inna; Nadir, Yona

doi:10.1136/thoraxjnl-2018-212964

Cited by 5 publications

(7 citation statements)

References 43 publications

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“…This heparanase inhibitor not only reduced the heparanase level but also attenuated the levels of TF, TFPI, and TFPI-2 in the pleura and microcirculation adjacent to the pleural cavity. 19 Interestingly, in the tissues derived from mice treated with the JAK-2 inhibitor, the degree of coagulation protein staining was even lower compared with control findings. This result may imply that JAK-2 pathway activation affects the constitutional levels of these proteins in the perivascular/ intravascular space.…”

Section: Discussionmentioning

confidence: 90%

Heparanase Level and Procoagulant Activity Are Increased in Thalassemia and Attenuated by Janus Kinase 2 Inhibition

Ghoti

Ackerman

Rivella

et al. 2020

The American Journal of Pathology

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Patients with thalassemia exhibit an increased risk of thrombotic events that is augmented after splenectomy. Heparanase protein enhances cancer progression, angiogenesis, and inflammation; it also activates the coagulation system through direct interaction with tissue factor (TF). Additionally, erythropoietin, which is elevated in anemic patients, up-regulates heparanase expression via the Janus kinase 2 (JAK-2) pathway. This study aimed was to explore the heparanase profile in thalassemia. Coagulation factors were analyzed via immunostaining, enzyme-linked immunosorbent assay, and heparanase procoagulant activity assay. In spleen specimens of thalassemia major patients, a higher level of heparanase staining was observed compared with control spleens resected after trauma (P < 0.001). Higher heparanase levels, heparanase and TF procoagulant activity, and erythropoietin levels were found in the plasma of 67 thalassemia major patients compared with 29 control subjects. No difference was found in pediatric patients (23 of 67) compared with adults or splenectomized versus nonsplenectomized patients. Higher levels of heparanase, TF, TF pathway inhibitor, and TF pathway inhibitor-2 were observed in liver, spleen, heart, and kidney tissues of thalassemia intermedia mice (Hbb th3/þ ). These protein levels significantly reduced when mice were treated with the JAK-2 inhibitor ruxolitinib (P < 0.0001). In summary, heparanase levels are elevated in thalassemia, which may contribute to thrombotic phenomena in these patients. Inhibition of heparanase or the JAK-2 pathway may reduce thrombotic risk in thalassemia.

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Section: Discussionmentioning

confidence: 90%

Heparanase Level and Procoagulant Activity Are Increased in Thalassemia and Attenuated by Janus Kinase 2 Inhibition

Ghoti

Ackerman

Rivella

et al. 2020

The American Journal of Pathology

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“…Our recent study revealed that while the levels of coagulation system activation markers were elevated in pleural effusions of transudate, infectious pleural effusion, and malignant pleural effusion, the net effect of these effusions was anticoagulant. 58 In samples obtained from 30 patients with malignant pleural effusion, 44 with infectious pleural effusion, and 33 patients with transudate pleural effusions, levels of heparanase, factor Xa, and thrombin were significantly higher in the exudate than in the transudate. Thromboelastography showed hardly any thrombus formation in the whole blood, mainly upon the addition of malignant pleural effusion.…”

Section: Heparanase and Heparan Sulfate Chains In The Pleural Cavitymentioning

confidence: 92%

“…Accordingly, inhibition of heparanase might provide a therapeutic option for patients with recurrent malignant pleural effusion. 58…”

Section: Heparanase and Heparan Sulfate Chains In The Pleural Cavitymentioning

confidence: 99%

Effect of Heparanase and Heparan Sulfate Chains in Hemostasis

Nadir

2021

Semin Thromb Hemost

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Heparanase, the only mammalian enzyme known to degrade heparan sulfate chains, affects the hemostatic system through several mechanisms. Along with the degrading effect, heparanase engenders release of syndecan-1 from the cell surface and directly enhances the activity of the blood coagulation initiator, tissue factor, in the coagulation system. Upregulation of tissue factor and release of tissue factor pathway inhibitor from the cell surface contribute to the prothrombotic effect. Tissue factor pathway inhibitor and the strongest physiological anticoagulant antithrombin are attached to the endothelial cell surface by heparan sulfate. Hence, degradation of heparan sulfate induces further release of these two natural anticoagulants from endothelial cells. Elevated heparanase procoagulant activity and heparan sulfate chain levels in plasma, demonstrated in cancer, pregnancy, oral contraceptive use, and aging, could suggest a potential mechanism for increased risk of thrombosis in these clinical settings. In contrast to the blood circulation, accumulation of heparan sulfate chains in transudate and exudate pleural effusions induces a local anticoagulant milieu. The anticoagulant effect of heparan sulfate chains in other closed spaces such as peritoneal or subdural cavities should be further investigated.

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“…24 Hardak et al suggested that human heparinase could facilitate the anticoagulant microenvironment in MPE and cause the pleural fluid recurrence. 25 Nosti et al also clarified how Colony Stimulating Factor 1 (CSF1) augmented vascular permeability and destabilized tumour vessels to regenerate MPE. 26 In addition, Wang et al suggested a Forkhead Box P3 (FOXP3)+ natural killer T-like cell could suppress the immune microenvironment in recurrent MPE.…”

Section: Introductionmentioning

confidence: 99%

“…Hardak et al. suggested that human heparinase could facilitate the anticoagulant microenvironment in MPE and cause the pleural fluid recurrence 25 . Nosti et al.…”

Section: Introductionmentioning

confidence: 99%

Single‐cell transcriptomics reveal metastatic CLDN4+ cancer cells underlying the recurrence of malignant pleural effusion in patients with advanced non‐small‐cell lung cancer

Zhang,

Wang,

Wen

et al. 2024

Clinical & Translational Med

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BackgroundRecurrent malignant pleural effusion (MPE) resulting from non‐small‐cell lung cancer (NSCLC) is easily refractory to conventional therapeutics and lacks predictive markers. The cellular or genetic signatures of recurrent MPE still remain largely uncertain.Methods16 NSCLC patients with pleural effusions were recruited, followed by corresponding treatments based on primary tumours. Non‐recurrent or recurrent MPE was determined after 3–6 weeks of treatments. The status of MPE was verified by computer tomography (CT) and cytopathology, and the baseline pleural fluids were collected for single‐cell RNA sequencing (scRNA‐seq). Samples were then integrated and profiled. Cellular communications and trajectories were inferred by bioinformatic algorithms. Comparative analysis was conducted and the results were further validated by quantitative polymerase chain reaction (qPCR) in a larger MPE cohort from the authors' centre (n = 64).ResultsThe scRNA‐seq revealed that 33 590 cells were annotated as 7 major cell types and further characterized into 14 cell clusters precisely. The cell cluster C1, classified as Epithelial Cell Adhesion Molecule (EpCAM)+ metastatic cancer cell and correlated with activation of tight junction and adherence junction, was significantly enriched in the recurrent MPE group, in which Claudin‐4 (CLDN4) was identified. The subset cell cluster C3 of C1, which was enriched in recurrent MPE and demonstrated a phenotype of ameboidal‐type cell migration, also showed a markedly higher expression of CLDN4. Meanwhile, the expression of CLDN4 was positively correlated with E74 Like ETS Transcription Factor 3 (ELF3), EpCAM and Tumour Associated Calcium Signal Transducer 2 (TACSTD2), independent of driver‐gene status. CLDN4 was also found to be associated with the expression of Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A) and Vascular Endothelial Growth Factor A (VEGFA), and the cell cluster C1 was the major mediator in cellular communication of VEGFA signalling. In the extensive MPE cohort, a notably increased expression of CLDN4 in cells from pleural effusion among patients diagnosed with recurrent MPE was observed, compared with the non‐recurrent group, which was also associated with a trend towards worse overall survival (OS).ConclusionsCLDN4 could be considered as a predictive marker of recurrent MPE among patients with advanced NSCLC. Further validation for its clinical value in cohorts with larger sample size and in‐depth mechanism studies on its biological function are warranted.Trial registrationNot applicable.

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Heparan sulfate chains contribute to the anticoagulant milieu in malignant pleural effusion

Cited by 5 publications

References 43 publications

Heparanase Level and Procoagulant Activity Are Increased in Thalassemia and Attenuated by Janus Kinase 2 Inhibition

Heparanase Level and Procoagulant Activity Are Increased in Thalassemia and Attenuated by Janus Kinase 2 Inhibition

Effect of Heparanase and Heparan Sulfate Chains in Hemostasis

Single‐cell transcriptomics reveal metastatic CLDN4+ cancer cells underlying the recurrence of malignant pleural effusion in patients with advanced non‐small‐cell lung cancer

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