https://www.um.edu.mt/library/oar/handle/123456789/69979 2026-04-23T14:10:31Z 2026-04-23T14:10:31Z https://www.um.edu.mt/library/oar/handle/123456789/73580 2026-04-14T07:33:35Z 2020-01-01T00:00:00Z

Title: Laboratory and psycho-social aspects of anticoagulation and venous thromboembolism Abstract: This thesis aimed to provide more evidence in the grey areas of the management of anticoagulation and venous thromboembolism (VTE), from both a laboratory and a clinical perspective. The following gaps were identified from the literature review and addressed in this thesis: 1) The point-of-care (POC) coagulometers represent a simpler and quicker alternative to the standard laboratory monitoring of the international normalised ratio (INR) in patients on vitamin K antagonist (VKA) treatment; however, their accuracy was questioned by several studies. By performing a comparison of the POC INR with several other assays, the accuracy of the POC devices was ascertained. 2) Despite the importance of a timely diagnosis of VTE, the current diagnostic algorithms still require a composite of clinical pre-test probability, laboratory D-dimer and imaging test. From the analysis of several potential biomarkers of acute VTE, the human soluble P-selectin was found to improve the diagnostic accuracy of the D-dimers. 3) Thromboelastography and thrombin generation are global coagulation assays, which can assess all the phases of coagulation; however, variable sensitivity of these assays has been reported to ongoing anticoagulant treatment. The thrombin generation assay appeared to be more sensitive to the presence of the direct oral anticoagulants (DOAC) than the routine coagulation assays and the specific tests. The thromboelastography appeared to be sensitive to the presence of edoxaban, rivaroxaban and dabigatran. 4) Different strategies have been proposed to reverse the effect of the anticoagulant drugs in patients with treatment-related bleeding complications; however, no clear superiority of one agent over the others has been demonstrated. Fresh frozen plasma, when used for VKA reversal, did not obtain a complete normalisation of the haemostatic balance ex vivo. For DOAC reversal in vitro, different concentrations of prothrombin complex concentrates or recombinant factor VIIa were needed to normalise the coagulation profile, based on the initial DOAC plasma concentrations. The neutralising effect of DOAC Stop® in vitro on basic coagulation assays was confirmed, but there might be the risk of reduction of the plasma levels of several coagulation factors. 5) There is a known correlation between patients’ satisfaction and adherence to chronic treatment, but there was no validated questionnaire available in the Maltese language specifically assessing the satisfaction of anticoagulated patients. Two psychometric questionnaires (the DASS and the PACT-Q) were translated into the Maltese language and validated, by assessing their reliability and validity. 6) The use of the POC coagulometers by healthcare professionals can simplify the management of VKA patients; however, it was not clear whether they were also associated with an improvement in the quality of life. Through a comparison of patients’ satisfaction associated with the POC INR vs. the laboratory INR, the POC devices were found to be associated with increased convenience and decreased hassles and burdens. 7) While the use of the POC coagulometers for self-testing has the potential of improving the time within the INR therapeutic range (TTR) and reduce the risk of thromboembolic events, contradictory findings were reported for the POC devices used by healthcare professionals. By analysing the TTR in different time frames, it emerged that the POC devices correlated better with anticoagulation control. Based on these results, recommendations for future research and clinical practice were proposed. Description: PH.D. PATHOLOGY

2020-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/73532 2021-04-14T08:08:14Z 2020-01-01T00:00:00Z

Title: High AURKA expression in triple negative breast cancer correlates with expression of CIP2A and PME-1 Abstract: Triple negative breast cancer (TNBC) is a heterogeneous breast cancer subtype which lacks expression of receptors usually targeted in breast cancer therapy. Thus, treatment options rely only on generalised chemotherapy, which carries cytotoxic consequences. Studies have shown that the tumour suppressor, protein phosphatase 2A (PP2A) was found to be deregulated in approximately 60% of TNBCs. The aims of the study are to evaluate protein expression of AURKA and KIF2C as biomarkers of interest in relation to PP2A activity in a cohort of TNBC patients, to identify biomarkers correlating with AURKA and KIF2C at RNA level, to confirm the selected biomarkers at protein level in the TNBC cohort, and in TNBC cell models following treatment with PP2A activator FTY720. Protein expression of AURKA and KIF2C was investigated in 160 TNBC cases and 23 normal breast epithelia by immunohistochemistry. Overexpression of these biomarkers was correlated with RNA profiles (40-gene panel, established in previous studies) assessed using a branched DNA assay to identify potential complimentary biomarkers related to AURKA and KIF2C expression. Protein expression of these biomarkers together with proliferation marker Ki67 was assessed on TNBC cell line models (N=6) treated with PP2A activator, FTY720 and on the TNBC patient cohort. 72% of TNBC patients overexpressed AURKA protein while 56% showed KIF2C protein expression. PP2A negative regulators CIP2A and PME-1 were found to be positively correlated with AURKA and KIF2C RNA and protein expression. No significant reduction was observed in TNBC cell lines following treatment FTY720. The AURKA, CIP2A and PME-1 biomarker signature identifies a potential therapeutic group within the TNBC cohort characterised by PP2A deregulation. Furthermore, inhibitors targeting these biomarkers should also be considered for evaluation in TNBC. Description: M.SC.PATHOLOGY

2020-01-01T00:00:00Z