Date of Award
Masters of Science (Research)
Department of Biological Sciences
Dr. Séamus Fanning
Thrombophilia describes the familial or acquired disorders of the haemostatic mechanism that are likely to predispose to thrombosis. Venous thrombosis and its associated complications account for a significant number of hospital admissions and deaths annually having a significant health-economic impact on the heath-care industry globally. Mutations in genes that code for proteins involved directly (or indirectly) in blood coagulation have been associated with prothrombotic states. The majority of inherited genetic defects were attributed to polymorphisms in Antithrombin III, Protein C, and Protein S genes until 1994. Together these accounted for only 5-10% of individuals with thrombosis. Subsequently the Factor V Leiden allele (that results in activated protein C resistance) and the Prothrombin G20210A allele (that leads to increased levels of prothrombin in blood) have been shown to be prevalent in 45% and 18% of patients, respectively, with a history of venous thrombosis. More recently, a G->T transversion in the blood coagulation Factor XIII A-subunit (FXIII VaI34Leu), that interferes with fibrin cross-linking, and a C -> T transition in the Methylenetetrahydrofolate Reductase gene (MTHFR C677T) have been implicated as risk factors for thrombosis. The potential for thrombosis is greatly enhanced in individuals with acquired risk factors such as increased age, malignancy, prolonged immobility and surgical trauma.
A Test group comprised of 68 subjects suspected with cancer and a randomised age- and sex-matched Control group of 68 subjects (attending the same hospital) with no history of thrombotic or cancer-related disease were assessed in this study. Polymerase chain reaction (PCR), site-directed mutagenesis (SDM)-PCR, and Restriction Fragment Length Polymorphism (RFLP) analysis were used to determine Factor V Leiden, Protein C, Antithrombin III, and MTHFR C677T genotypes. Single Stranded Conformational Polymorphism (SSCP) analysis and DNA sequencing detected and confirmed the presence of the Factor XIII VaI34Leu allele. Genotypes for subjects in the Test group were compared with the ‘real-time’ coagulation characteristics of their respective blood samples as determined using Thromboelastography (TEG).
O'Sullivan, Pádraig, "Assessment of Prothrombotic Tendency in Humans using Functional and Genomic Determinants" (2000). Theses [online].
Available at: https://sword.cit.ie/allthe/369