Glioblastoma patients are considered to be at high risk of venous thromboembolism (VTE) and major bleeding (MB), although reliable incidence estimates are lacking. Moreover, the risk of arterial thromboembolism (ATE) in these patients is largely unknown. Our aim was to assess the cumulative incidence, predictors, and prognostic impact of VTE, ATE, and MB on subsequent complications and mortality. Cohort study of 967 consecutive patients diagnosed with glioblastoma between 2004–2020 in two hospitals. Patients were followed from 6 months before date of histopathological glioblastoma diagnosis up to 2 years after, or until an outcome of interest (VTE, ATE, and MB) or death occurred, depending on the analysis. Cumulative incidences were estimated with death as competing risk. Cox regression was used to identify predictors and the prognostic impact. A total of 101 patients were diagnosed with VTE, 50 with ATE, and 126 with MB during a median follow‐up of 15 months (interquartile range 9.0–22). The adjusted 1‐year cumulative incidence of VTE was 7.5% (95% confidence interval [CI] 5.9–9.3), of ATE 4.1% (95% CI 3.0–5.6), and of MB 12% (95% CI 9.6–14). Older age, type of surgery, and performance status were predictors of VTE. Incident VTE during follow‐up was associated with MB (adjusted HR 4.7, 95% CI 2.5–9.0). MB and VTE were associated with mortality (adjusted HR 1.7, 95% CI 1.3–2.1 and 1.3, 95% CI 1.0–1.7, respectively). We found considerable incidences of VTE and MB in glioblastoma patients, with both complications associated with poorer prognosis. Our observations emphasize the need for prospective studies to determine optimal thromboprophylaxis and VTE treatment strategy in these patients.

Patients with glioblastoma are among the cancer patients with the highest risk of developing venous thromboembolism (VTE). Long-term thromboprophylaxis is not generally prescribed because of the increased susceptibility of glioblastoma patients to intracranial hemorrhage. This review provides an overview of the current clinical standard for glioblastoma patients, as well as the molecular and genetic background which underlies the high incidence of VTE. The two main procoagulant proteins involved in glioblastoma-related VTE, podoplanin and tissue factor, are described, in addition to the genetic aberrations that can be linked to a hypercoagulable state in glioblastoma. Furthermore, possible novel biomarkers and future treatment strategies are discussed, along with the potential of sequencing approaches toward personalized risk prediction for VTE. A glioblastoma-specific VTE risk stratification model may help identifying those patients in which the increased risk of bleeding due to extended anticoagulation is outweighed by the decreased risk of VTE. ^* These authors contributed equally to this study. Received: 11 April 2024 Accepted: 06 August 2024 Article published online: 21 August 2024 © 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Cancer enhances the risk of venous thromboembolism, but a hypercoagulant microenvironment also promotes cancer progression. Although anticoagulants have been suggested as a potential anticancer treatment, clinical studies on the effect of such modalities on cancer progression have not yet been successful for unknown reasons. In normal physiology, complex formation between the subendothelial-expressed tissue factor (TF) and the blood-borne liver-derived factor VII (FVII) results in induction of the extrinsic coagulation cascade and intracellular signaling via protease-activated receptors (PARs). In cancer, TF is overexpressed and linked to poor prognosis. Here, we report that increased levels of FVII are also observed in breast cancer specimens and are associated with tumor progression and metastasis to the liver. In breast cancer cell lines, tumor-expressed FVII drives changes reminiscent of epithelial-to-mesenchymal transition (EMT), tumor cell invasion, and expression of the prometastatic genes, SNAI2 and SOX9. In vivo, tumor-expressed FVII enhanced tumor growth and liver metastasis. Surprisingly, liver-derived FVII appeared to inhibit metastasis. Finally, tumor-expressed FVII-induced prometastatic gene expression independent of TF but required a functional endothelial protein C receptor, whereas recombinant activated FVII acting via the canonical TF:PAR2 pathway inhibited prometastatic gene expression. Here, we propose that tumor-expressed FVII and liver-derived FVII have opposing effects on EMT and metastasis.

Glioblastoma (GBM) patients have one of the highest risks of venous thromboembolism (VTE), which is even further increased upon treatment with chemotherapy. Tissue factor (TF) is the initiator of the extrinsic coagulation pathway and expressed by GBM cells. In this study, we aimed to examine the effect of routinely used chemotherapeutic agents Temozolomide (TMZ) and Lomustine (LOM) on TF procoagulant activity and expression in GBM cells in vitro. Three human GBM cell lines (U-251, U-87, U-118) were exposed to 100 µM TMZ or 30 µM LOM for 72 h. TF procoagulant activity was assessed via an FXa generation assay and TF gene and protein expression through qPCR and Western blotting. The externalization of phosphatidylserine (PS) was studied using Annexin V flow cytometry. Treatment with TMZ and LOM resulted in increased procoagulant activity in all cell lines. Furthermore, both agents induced procoagulant activity in the supernatant and tumor-cell-secreted extracellular vesicles. In line, TF gene and protein expression were increased upon TMZ and LOM treatment. Additionally, PS externalization and induction of inflammatory-associated genes were observed. Overall, the chemotherapeutic modalities TMZ and LOM induced procoagulant activity and increased TF gene and protein expression in all GBM cell lines tested, which may contribute to the increased VTE risk observed in GBM patients undergoing chemotherapy.