Coagulation Factor XIIIA: Clinical and Biological Significance in Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) is a heterogeneous group of malignant neoplasms that are usually detected at metastatic advance stages, leading to difficulty in its management. Abnormal hemostasis including hyper coagulation and increased fibrinolysis, as well as their clinical complications, are common in epithelial ovarian cancer. High levels of cross-linked fibrin degradation products (FDPs) have been found in epithelial ovarian cancer ascites. Coagulation factor XIIIA gene variants affect enzyme activity and properties of the cross-linked substrate structure. In this PhD study, plasma FXIII activity, plasma levels of its A-subunit, selected F13A1 genotypes, FXIIIA protein expression in tumour tissues, and plasma levels of stable FDP as determined by D-Dimer levels were concurrently explored for the first time in EOC (patients entered into the translational cohort of the ICON7 trial, n=91). The associations between these variables and EOC prognostic factors, survival outcome and the effect of treatment received were evaluated. High plasma FXIII activity was associated with EOC progression. Plasma FXIIIA levels was associated with serous high-grade disease. The haplotype 1951A_1954C, was significantly associated with low plasma FXIII activity. FXIIIA expression in tumour tissues was associated with the grade of disease. The functional capability of FXIIIA protein variants was assessed on substrates important in EOC fibrinogen, fibronectin, vitronectin and collagen. The data showed that the FXIIIA V34L variant produced an increased level of FXIIIA specific activity on fibronectin, fibrinogen, and vitronectin compared to the wildtype. These substrates were then examined for their cross-linking ability by a range of FXIIIA variants. The highest level of FXIIIA substrate cross-linking was seen in fibronectin, followed by fibrinogen, vitronectin and the lowest cross-links were observed on collagen. As FXIIIA cross-links substrates involved in cell adhesion, FXIIIA-mediated cross-linking of fibrinogen, fibronectin, and vitronectin was explored and found to result in an increased EOC cell adhesion. The activated FXIIIA variants have significantly inhibited EOC cell migration in cross-linked matrices and in the growth medium. In conclusion, the data presented in this thesis suggest that FXIIIA may aid EOC development and dissemination.