European Center for Cancer and Cell Therapy (ECCT), Nicosia, Cyprus.
Thrombosis and Hemostasis Unit, Rambam Health Care Campus, Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Am J Pathol. 2020 Oct;190(10):2146-2154. doi: 10.1016/j.ajpath.2020.07.011. Epub 2020 Aug 1.
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). 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.
患有地中海贫血症的患者发生血栓事件的风险增加，这种风险在脾切除术后会进一步增加。肝素酶蛋白可促进癌症进展、血管生成和炎症；它还可以通过与组织因子 (TF) 的直接相互作用激活凝血系统。此外，贫血患者中升高的促红细胞生成素通过 Janus 激酶 2 (JAK-2) 途径上调肝素酶的表达。本研究旨在探讨地中海贫血症中的肝素酶谱。通过免疫染色、酶联免疫吸附试验和肝素酶促凝血活性测定分析凝血因子。与外伤性切除的对照组脾脏相比，在重型地中海贫血症患者的脾脏标本中观察到更高水平的肝素酶染色（P < 0.001）。与 29 名对照组相比，在 67 名重型地中海贫血症患者的血浆中发现了更高水平的肝素酶、TF 促凝血活性和促红细胞生成素水平。在儿科患者（23/67）与成年患者或脾切除与非脾切除患者之间未发现差异。在中间型地中海贫血症小鼠（Hbb）的肝、脾、心脏和肾脏组织中观察到更高水平的肝素酶、TF、TF 途径抑制剂和 TF 途径抑制剂-2。当用 JAK-2 抑制剂芦可替尼治疗时，这些蛋白水平显著降低（P < 0.0001）。总之，肝素酶水平在地中海贫血症中升高，这可能导致这些患者发生血栓现象。抑制肝素酶或 JAK-2 途径可能会降低地中海贫血症的血栓形成风险。
