Mechanistic insights into cancer-associated thrombosis in brain cancer

Cancer-associated thrombosis (CAT) is an umbrella term describing multiple forms of deregulated hemostasis and clotting related to cancer progression or therapy. Venous thromboembolism (VTE) is the most prevalent and widely studied systemic manifestation of CAT associated with considerable morbidity and risk of life-threatening pulmonary embolism (PE). While some aspects of CAT may be unspecific or iatrogenic, the biology of cancer cells contributes to this condition through the expression of the procoagulant phenotype, often attributable to upstream oncogenic mutations, the state of the epigenome, and influences of the tumor microenvironment (TME). High-grade astrocytic brain tumors (HGGs) are among the most procoagulant neoplastic disease states. Podoplanin (PDPN) and tissue factor (TF) have been implicated in HGG-associated VTE risk, while isocitrate dehydrogenase (IDH) mutations protect from thrombosis in HGG. Highly procoagulant, IDH-wild-type HGGs, such as glioblastoma (GBM), represent a cluster of disease states, each comprising cellular populations endowed with different repertoires of TF and PDPN expression. GBM cells project their influence systemically, at least in part, through the release of extracellular vesicles (EVs) carrying TF, PDPN, and other factors. The specific roles of these mechanisms in GBM-associated VTE are under investigation. Given the intense interest in developing new treatment strategies in GBM, the interplay between these interventions and the activity of the hemostatic system is of paramount importance. Indeed, a better understanding of mechanisms driving CAT in molecular and therapeutic contexts of specific brain tumor subtypes could inform more individualized approaches to management of thrombosis in patients.