O’Connell, N.M.; (2011) Factor XI Deficiency: a study of clinical, laboratory and molecular modifiers of bleeding phenotype. Doctoral thesis , UCL (University College London).

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Abstract

Factor XI (FXI) is a plasma glycoprotein that participates in the consolidation phase of blood coagulation and is important in the creation of a stable fibrin clot. Deficiency of FXI leads to an injury-related bleeding diathesis, which is notable for the variability in the bleeding tendency and the lack of a clear relationship between bleeding and FXI coagulant activity (FXI:C). A comprehensive understanding of the factors which influence the bleeding tendency in factor XI deficiency would enable a more structured evaluation of bleeding risk and would focus the treatment choices for individual patients. The purpose of this work is to comprehensively analyse physiological and genetic factors which modify the clinical phenotype of FXI deficiency. In this study, a comprehensive bleeding history was obtained from participating patients with known FXI deficiency (n=102) which was then independently scored. This clinical bleeding score was utilised to compare the following laboratory parameters between patients with and without a clinical bleeding tendency: aPTT, FXI:C, FXI:Ag, Blood group, von Willebrand factor levels, inherited thrombophilic traits, Thrombin generation (by subsampling and continuous methods) and TAFI levels (as evaluated by TAFI antigen and a clot lysis assay). The underlying genetic mutation causing the FXI deficiency was evaluated in all patients and where an existing Jewish mutation was not found, novel mutations were sought. Molecular modelling of mutations in the FXI gene was undertaken which required development of molecular models of the apple domains and serine protease domain of the FXI protein. In addition, genetic analysis of a polymorphism in a gene (ALG6) encoding a specific glucosyl transferase was undertaken due to the link between FXI deficiency and congenital disorders of glycosylation. Finally, the first clinical trial of the use of recombinant FVIIa in FXI deficiency was conducted as part of this study.

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