Background: Multiple mechanisms might lead to cancer-related hypercoagulability. In brain tumors, podoplanin, via its ability to activate platelets, seems to play a crucial role in developing venous thromboembolism (VTE). Different stimuli (including activated platelets) can trigger the release of prothrombotic neutrophil extracellular traps (NETs) by neutrophils. It remains to be elucidated whether podoplanin-induced platelet aggregates might also impact NET formation and subsequent hypercoagulability and thrombosis.Methods: Patients with glioma were enrolled in this prospective observational cohort study. The primary endpoint was VTE. Immunohistochemical staining of NETs (via citrullinated histone H3 [H3Cit]) and neutrophils (via myeloperoxidase [MPO]) was conducted in glioma specimens and correlated with intravascular platelet clusters (via CD61) and podoplanin.Results: In total, 154 patients were included. H3Cit+ tumor vessels were found in 45/154 cases. H3Cit were significantly associated with increased intravascular platelet clusters (CD61− vs. CD61+ vs. CD61++ vs. CD61+++: 3.7% (1/27) vs. 18.6% (11/59) vs. 39.4% (13/33) vs. 57.1% (20/35),p< 0.001) and podoplanin expression (PDPN− vs. PDPN+: 14.3% (7/49) vs. 36.2% (38/105),p= 0.007) in the tumor tissue. Furthermore, H3Cit+ tumor vessels were significantly associated with tumor-infiltrating MPO+ neutrophils (H3Cit− vs. H3Cit+, median [Q1-Q3]: 6.0 [3.3–12.3] vs. 12.5 [5.9–22.0] cells/mm2,p< 0.001) and with D-dimer levels (H3Cit− vs. H3Cit+: 0.53 [0.32–1.10] vs. 0.84 [0.46–2.75] µg/mL,p= 0.034). The VTE risk was not linked to H3Cit+ tumor vessels (p= 0.613, log-rank).Conclusions: H3Cit in tumor vessels was not associated with VTE. However, H3Cit was linked to a local procoagulant phenotype in glioma, thereby potentially contributing to a systemic hypercoagulable state and thrombus formation.
背景：多种机制可能导致癌症相关的高凝状态。在脑肿瘤中，平足蛋白通过其激活血小板的能力，似乎在静脉血栓栓塞（VTE）的发生中起着关键作用。不同刺激（包括活化血小板）可触发中性粒细胞释放促血栓形成的中性粒细胞胞外诱捕网（NETs）。平足蛋白诱导的血小板聚集是否也会影响NET形成及后续的高凝状态和血栓形成，仍有待阐明。 方法：本研究为前瞻性观察性队列研究，纳入胶质瘤患者。主要终点为VTE。对胶质瘤标本进行NETs（通过瓜氨酸化组蛋白H3 [H3Cit]）和中性粒细胞（通过髓过氧化物酶[MPO]）的免疫组化染色，并与血管内血小板簇（通过CD61）及平足蛋白表达进行相关性分析。 结果：共纳入154例患者。45/154例患者肿瘤血管中检测到H3Cit阳性。H3Cit与肿瘤组织中血管内血小板簇增多（CD61− vs. CD61+ vs. CD61++ vs. CD61+++: 3.7% (1/27) vs. 18.6% (11/59) vs. 39.4% (13/33) vs. 57.1% (20/35), p < 0.001）及平足蛋白表达（PDPN− vs. PDPN+: 14.3% (7/49) vs. 36.2% (38/105), p = 0.007）显著相关。此外，H3Cit阳性肿瘤血管与肿瘤浸润的MPO阳性中性粒细胞（H3Cit− vs. H3Cit+, 中位数[Q1-Q3]: 6.0 [3.3–12.3] vs. 12.5 [5.9–22.0] 个细胞/mm², p < 0.001）及D-二聚体水平（H3Cit− vs. H3Cit+: 0.53 [0.32–1.10] vs. 0.84 [0.46–2.75] µg/mL, p = 0.034）显著相关。VTE风险与H3Cit阳性肿瘤血管无关联（p = 0.613，对数秩检验）。 结论：肿瘤血管中的H3Cit与VTE无关。然而，H3Cit与胶质瘤局部促凝血表型相关，从而可能促进全身性高凝状态和血栓形成。
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