Lymph node status and coagulation biomarkers as predictors of venous thromboembolism in gynaecological cancer patients post surgery

Abstract

Venous thromboembolism (VTE) is a major complication of cancer ranging from 4- 20% depending on tumour type and stage. VTE risk increases post-surgical treatment especially in the first 90 days post-surgery. The precise mechanisms are unknown but are likely due to cancer hypercoagulability and the effects of surgery. This study aimed to assess the relationship between two of these factors and the risk of VTE. Surgical complexity significantly affects risk; Lymph node dissection (LND) is commonly used as part of cancer staging and treatment. Although emerging evidence links LND to VTE in different cancer types there is limited data in gynaecological cancer patients (1, 2). Thrombin is a key element in the formation of a thrombus; previous work by our group has shown that certain key coagulation factors and inhibitors were noted to contribute to thrombin generation in the gynaecological cancer population and hence increase the risk of VTE. These biomarkers were Factor V, Proteins S and Factor VIII. The ability of these biomarkers, measured preoperatively, to predict VTE post surgery was investigated in this study. The study was a retrospective cohort study performed using data and samples from the TCD gynaecological cancer bioresource collected between 2006 and 2019. The results of this study showed that paraaortic LND significantly increased VTE risk three-fold following adjustment for confounding factors. Paraaortic LND is a complex procedure in gynae oncology, this finding could be related to increased blood loss, blood stasis due to prolonged surgery time and endothelial vascular injury during surgery. Lymph node (LN) metastasis was another major factor in lymph node assessment contributing to VTE risk. Patients who had paraaortic lymph node metastasis had a significantly higher risk of VTE compared with those who were negative for metastasis. This could be explained by the pressure effect of the enlarged metastatic lymph node, but most likely is due to hypercoagulable status caused by advanced cancer stage. VTE in the first 90 days post operatively has a major adverse effect on overall survival of patients. In the biomarker study, coagulation factors VIIIc and V and the coagulation inhibitor Protein S (PS) was measured pre-operatively in 52 patients who developed VTE following surgery matched with 156 control patients who remained thrombosis free. The results showed that Factor VIIIc (FVIIIc) levels were increased in the VTE group; no difference in Factor V and protein S levels were observed. Higher FVIIIc levels were also associated with reduced overall survival. When the population was divided into quartiles of FVIIIc, the upper quartile of FVIIIc (> 174.05%) was associated with a 2.87 fold increased VTE risk after adjustment for age, stage and chemotherapy treatment. Similarly cumulative incidence of VTE in patients with levels above the median FVIIIc cut-off was significantly higher than cumulative incidence of for patients below the cut-off. In the final part of the study, the role of long term aspirin use in reducing the risk of VTE was investigated. A small cohort of patients from the study group were on long term aspirin (87 patients) of which 5 patients (5.7%) developed VTE during follow up. Long term aspirin use was not significantly associated with VTE risk in this cohort. Long term aspirin use did not significantly affect overall survival. This study has shown that paraaortic LND and the coagulation biomarker Fr VIIIc are potential predictors of VTE in gynaecological cancer patients’ post-surgery. The small number of patients in the aspirin group does not allow definite conclusions regarding its use for prophylaxis in this patient group.