Determining venous thromboembolism risk in patients with adult-type diffuse glioma

Abstract

Venous thromboembolism (VTE) is a life-threating condition that is common in patients with adult-type diffuse gliomas, yet thromboprophylaxis is controversial because of possible intracerebral hemorrhage. Effective VTE prediction models exist for other cancers, but not glioma. Our objective was to develop a VTE prediction tool to improve glioma patient care, incorporating clinical, blood-based, histologic, and molecular markers. We analyzed preoperative arterial blood, tumor tissue, and clinical-pathologic data (including next-generation sequencing data) from 258 patients with newly diagnosed World Health Organization (WHO) grade 2 to 4 adult-type diffuse gliomas. Forty-six (17.8%) experienced VTE. Tumor expression of tissue factor (TF) and podoplanin (PDPN) each positively correlated with VTE, although only circulating TF and D-dimers, not circulating PDPN, correlated with VTE risk. Gliomas with mutations in isocitrate dehydrogenase 1 (IDH1) or IDH2 (IDHmut) caused fewer VTEs; multivariable analysis suggested that this is due to IDHmut suppression of TF, not PDPN. In a predictive time-to-event model, the following predicted increased VTE risk in newly diagnosed patients with glioma: (1) history of VTE; (2) hypertension; (3) asthma; (4) white blood cell count; (5) WHO tumor grade; (6) patient age; and (7) body mass index. Conversely, IDHmut, hypothyroidism, and MGMT promoter methylation predicted reduced VTE risk. These 10 variables were used to create a web-based VTE prediction tool that was validated in 2 separate cohorts of patients with adult-type diffuse glioma from other institutions. This study extends our understanding of the VTE landscape in these tumors and provides evidence-based guidance for clinicians to mitigate VTE risk in patients with glioma.

Graphical abstract

Figure 1.

TF expression and circulating TF-MV activity in NMH newly diagnosed adult-type diffuse glioma cases. (A) Cumulative VTE incidence according to glioma genotype. (B) Representative photomicrographs of TF IHC, on a semiquantitative scale from 0 (negative) to 4 (strongest). Scale bar = 50 μm. (C) TF IHC scores across the 3 subsets of adult-type diffuse gliomas. (D) Cumulative VTE incidence according to glioma TF IHC score. (E) Circulating TF-MV activity, at the time of initial surgery, across the 3 subsets of patients with adult-type diffuse glioma. (F) Cumulative VTE incidence according to circulating TF-MV activity at the time of initial surgery. Astro, IDH^mut grade 2 to 4 astrocytoma; GBM, IDH^wt glioblastoma; oligo, IDH^mut, 1p/19q-codeleted WHO grade 2 to 3 oligodendroglioma.

Figure 2.

PDPN expression and circulating PDPN in NMH newly diagnosed adult-type diffuse glioma cases. (A) Representative photomicrographs of PDPN IHC, on a semiquantitative scale from 0 (negative) to 4 (strongest). Scale bar = 50 μm. (B) PDPN IHC scores across the 3 subsets of adult-type diffuse gliomas. (C) Cumulative VTE incidence according to glioma PDPN IHC score. (D) Circulating PDPN, at the time of initial surgery, across the 3 subsets of patients with adult-type diffuse glioma. (E) Cumulative VTE incidence according to circulating PDPN at the time of initial surgery. (F) Linear regression plot of circulating TF-MV activity vs circulating PDPN at the time of initial surgery. Astro, IDH^mut grade 2 to 4 astrocytoma; GBM, IDH^wt glioblastoma; oligo, IDH^mut, 1p/19q-codeleted WHO grade 2 to 3 oligodendroglioma.

Figure 3.

Circulating D-dimers in NMH patients with newly diagnosed adult-type diffuse glioma. (A) Circulating D-dimers according to glioma molecular subtype. P value was calculated by Kruskal-Wallis test, with Dunn multiple comparisons test, ∗∗∗P<.001. (B) Cumulative VTE incidence according to circulating D-dimers at the time of initial surgery. (C) Linear regression plot of circulating TF-MV activity vs circulating D-dimers. (D) Linear regression plot of circulating PDPN vs circulating D-dimers. Astro, IDH^mut grade 2 to 4 astrocytoma; GBM, IDH^wt glioblastoma; oligo, IDH^mut, 1p/19q-codeleted WHO grade 2 to 3 oligodendroglioma.

Figure 4.

Predictors of interest and time to VTE in the NMH cohort of newly diagnosed adult-type diffuse glioma cases. Forest plot showing univariable and multivariable Cox models with resulting hazard ratio effect estimates and corresponding P values for each predictor. EGFR, epidermal growth factor receptor; MGMT, O-6-methylguanine–DNA methyltransferase.

Figure 5.

Receiver operating characteristic curves for the LASSO time-to-VTE prediction model across all 3 cohorts. (A) Kaplan-Meier curves of all 3 cohorts pooled together, stratified by low vs high risk, as defined by the prediction model. (B) NMH discovery cohort. (C) Duke validation cohort. (D) UCLA validation cohort. AUC, area under the curve; FP, false positive; TP, true positive.