Haemostatic Gene Expression in Cancer-Related Immunothrombosis: Contribution for Venous Thromboembolism and Ovarian Tumour Behaviour

Abstract

Ovarian cancer (OC) is the deadliest gynaecological malignancy. Identifying new prognostic biomarkers is an important research field. Haemostatic components together with leukocytes can drive cancer progression while increasing the susceptibility to venous thromboembolism (VTE) through immunothrombosis. Unravelling the underlying complex interactions offers the prospect of uncovering relevant OC prognostic biomarkers, predictors of cancer-associated thrombosis (CAT), and even potential targets for cancer therapy. Thus, this study evaluated the expression of F3, F5, F8, F13A1, TFPI1, and THBD in peripheral blood cells (PBCs) of 52 OC patients. Those with VTE after tumour diagnosis had a worse overall survival (OS) compared to their counterparts (mean OS of 13.8 ± 4.1 months and 47.9 ± 5.7 months, respectively; log-rank test, p = 0.001). Low pre-chemotherapy F3 and F8 expression levels were associated with a higher susceptibility for OC-related VTE after tumour diagnosis (χ², p < 0.05). Regardless of thrombogenesis, patients with low baseline F8 expression had a shorter progression-free survival (PFS) than their counterparts (adjusted hazard ratio (aHR) = 2.54; p = 0.021). Among those who were not under platelet anti-aggregation therapy, low F8 levels were also associated with a shorter OS (aHR = 6.16; p = 0.006). Moving forward, efforts should focus on external validation in larger cohorts.

Keywords: genes; inflammation; liquid biopsy; ovarian neoplasms; prognosis; thrombosis.

Figure 1

Progression-free survival (PFS) (a,c) and overall survival (OS) (b,d) by Kaplan–Meier and log-rank test for ovarian cancer (OC) patients according to venous thromboembolism (VTE) status. (a) No association between PFS and VTE (log-rank test, p = 0.239) was observed in the overall cohort (N = 35). (c) When patients with VTE before OC diagnosis were dismissed, a marginally significant impact was detected (long-rank test, p = 0.055). Specifically, those with OC-related VTE had a faster disease progression compared to their counterparts (mean PFS of 10.2 ± 3.2 months and 21.6 ± 3.8 months, respectively). (b) Considering the entire cohort (N = 35), a significant association between OS and VTE was observed (log-rank test, p = 0.022). Those with the condition had a lower survival time than their counterparts (mean OS of 22.2 ± 6.2 months and 47.9 ± 5.7 months, respectively). (d) The same was observed excluding those with VTE before OC diagnosis (log-rank test, p = 0.001). Specifically, patients with OC-related VTE and those without had a mean OS of 13.8 ± 4.1 months and 47.9 ± 5.7 months, respectively.

Figure 2

Correlation between baseline haemostatic genes’ expression in peripheral blood cells (PBCs) in a cohort of ovarian cancer (OC) patients (N = 52) by Pearson’s correlation coefficient (P) test.

Figure 3

Normalised relative expression levels of the evaluated genes (−ΔCq) in peripheral blood cells (PBCs) in a cohort of ovarian cancer (OC) patients before and after first-line chemotherapy: (a) F3 expression; (b) F5 expression; (c) F8 expression; (d) F13A1 expression; (e) TFPI1 expression; and (f) THBD expression; paired t-test, ** p < 0.01, *** p < 0.001; ns, non-significant.

Figure 4

Normalised relative expression levels of the evaluated genes (−ΔCq) in peripheral blood cells (PBCs) in a cohort of ovarian cancer (OC) patients before first-line chemotherapy and in the context of venous thromboembolism (VTE): (a) F3 expression; (b) F5 expression; (c) F8 expression; (d) F13A1 expression; (e) TFPI1 expression; and (f) THBD expression; one-way ANOVA followed by Dunnett’s test for multiple comparisons, ** p < 0.01; ns, non-significant.

Figure 5

Progression-free survival (PFS) (a) and overall survival (OS) (b) by Kaplan–Meier and log-rank test for ovarian cancer (OC) patients according to F8 baseline expression in peripheral blood cells (PBCs). (a) Patients with low expression levels had a lower PFS than their counterparts (profile 4; mean PFS of 12.8 ± 1.6 months and 23.7 ± 3.5 months, respectively; log-rank test, p = 0.005). (b) Dismissing patients under platelet anti-aggregation therapy at OC diagnosis, those with low expression had an inferior OS compared to their counterparts (profile 4; mean OS of 27.5 ± 4.5 months and 53.7 ± 5.9 months, respectively; log-rank test, p = 0.008).