Venous Thromboembolism in Brain Tumors: Risk Factors, Molecular Mechanisms, and Clinical Challenges

Abstract

Venous thromboembolism (VTE) is a common complication in patients with primary brain tumors, with up to 20% of patients per year having a VTE event. Clinical risk factors for VTE include glioblastoma subtype, paresis, or surgery. Furthermore, specific factors playing a role in tumor biology were recently identified to predispose to prothrombotic risk. For instance, mutations in the isocitrate dehydrogenase 1 (IDH1) gene, which occurs in a subgroup of glioma, correlate with risk of VTE, with low incidence in patients with presence of an IDH1 mutation compared with those with IDH1 wild-type status. In addition, expression of the glycoprotein podoplanin on brain tumors was associated with both intratumoral thrombi and high risk of VTE. As podoplanin has the ability to activate platelets, a mechanistic role of podoplanin-mediated platelet activation in VTE development has been suggested. From a clinical point of view, the management of patients with primary brain tumors and VTE is challenging. Anticoagulation is required to treat patients; however, it is associated with increased risk of intracranial hemorrhage. This review focuses on describing the epidemiology, risk factors, and mechanisms of brain tumor-associated thrombosis and discusses clinical challenges in the prevention and treatment of VTE in patients with brain tumors.

Low Systemic Levels of Chemokine C-C Motif Ligand 3 (CCL3) are Associated with a High Risk of Venous Thromboembolism in Patients with Glioma

“…The inverse association of CCL3 with VTE in our study was independent of previously described VTE risk factors in brain tumors [19][20][21][22][23]. For example, a higher glioma grade as well as distinct local tumor characteristics, such as the upregulation of podoplanin expression on tumor cells, are associated with a higher VTE risk [19].…”

“…Primary brain tumors belong to those tumor entities with a particularly high VTE risk, and 10% to 20% of the patients develop VTE during the course of the disease [18]. Previously, several risk factors have been described [19][20][21][22][23]. However, the impact of anti-and pro-inflammatory cytokines on thromboembolic events in patients with glioma has not been evaluated in detail.…”

Successful Free Tissue Transfer in the Profoundly Hypercoagulable Glioblastoma Multiforme Patient: Surgical Experience and Anticoagulation Protocol

“…4,8,9 Additionally, GBM patients are at a significantly increased risk for developing DVT and other thromboembolic events. 6,10,11 Postoperative immobility often confounded by hemiparesis and hemiplegia is felt to play a causal role in DVT formation. 12 A hallmark feature of GBM on magnetic resonance imaging (MRI) is the presence of two contrasting regions composed of a central necrotic zone encompassed by a leading edge of mobile, rapidly proliferating tumor cells.…”

“…Recent studies have observed that tumor cell expression of the transmembrane glycoprotein podoplanin (PDPN) correlates with susceptibility to VTE and overall mortality. 11 Patients with tumors exhibiting high levels of PDPN are at significantly increased risk for developing VTE (25%) as compared with those without expression (5%). PDPN is known to produce platelet aggregation; however, the exact mechanism creating hypercoagulability is complex and incompletely understood.…”

Emerging Paradigms of Thrombosis and Cancer (Part I): The yin yang Relationship between Thrombosis and Cancer

“…3 Within the wide spectrum of cancers, perhaps glioma is one of the most thrombogenic cancer types, as next discussed by Czap et al 4 Risk factor for thrombosis in brain tumors is discussed next by Riedl and Ay, with interesting recent findings that podoplanin plays a key role. 5 More severe thrombotic manifestations are frequently presented as disseminated intravascular coagulation, the many forms of which are therefore discussed by Levi. 6 Another significant manifestation of the coagulopathy seen in cancer is "cancerassociated thrombotic microangiopathy" as discussed by Weitz.…”