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.

中文翻译：

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硫酸乙酰肝素链有助于恶性胸腔积液中的抗凝环境

背景 虽然恶性胸腔积液 (MPE) 是癌症患者发病的常见且重要的原因，但目前的治疗选择是有限的。参与血管生成和转移的人乙酰肝素酶切割细胞表面的硫酸乙酰肝素 (HS) 侧链。目的 探讨 MPE 和传染性胸腔积液 (IPE) 的凝血环境，重点关注乙酰肝素酶的参与。方法 使用乙酰肝素酶 ELISA、乙酰肝素酶促凝血活性测定、凝血酶和因子 Xa 显色测定以及血栓弹力图评估 30 名 MPE 患者和 44 名 IPE 患者的样本与 33 名漏出液胸腔积液患者的样本进行比较。进行细胞增殖测定。EMT-6 乳腺癌细胞被注射到小鼠的胸膜腔中。皮下施用抑制乙酰肝素酶活性的肽。结果渗出液中乙酰肝素酶、Xa因子和凝血酶的水平显着高于渗出液。血栓弹力图检测到全血中几乎没有血栓形成，主要是添加 MPE。这种作用被细菌肝素酶完全逆转。直接测量显示胸腔积液中有高水平的 HS 链。在与渗出液培养的肿瘤细胞系中观察到比与渗出液培养的肿瘤细胞系具有更高的增殖，并且当添加细菌肝素酶时增殖减少。与对照相比，用乙酰肝素酶抑制剂治疗的小鼠胸膜腔中的肿瘤大小明显更小（p=0.005）。结论 乙酰肝素酶释放的 HS 链在 MPE 中形成抗凝环境，防止局部血栓形成并促进肿瘤细胞增殖。抑制乙酰肝素酶可能为复发性 MPE 患者提供一种治疗选择。