The clinical management of Factor XI (FXI) deficiency is problematic due to the marked phenotypic heterogeneity between individuals with this disorder and the lack of a reliable test to predict bleeding risk. FXI-deficient individuals are currently at risk of being over- or under treated, with associated risks of transfusion-related complications or haemorrhage respectively. The improvement of care of FXI-deficient patients requires the development of measures that can predict bleeding phenotype and enable the identification of individuals who need treatment at times of haemostatic challenge. In addition, for those requiring treatment, there is a need for development of tests which can determine the optimal type and dose of FXI replacement on an individually tailored basis, as well as assays which can accurately monitor the effect of treatment and guide clinicians in the requirement for further perioperative treatment. This thesis addresses these objectives by studying global haemostasis assays and bleeding scores as tools to predict bleeding tendency and by studying the utility of global haemostasis assays as potential tests by which FXI replacement treatment can be determined and monitored. For prediction of bleeding tendency, this research demonstrated that the thrombin generation assay (TGA) was able to differentiate bleeding tendency provided the sample conditions used in the assay were optimised to assess FXI involved coagulation pathways thought to be of relevance in vivo: using platelet rich plasma with inhibition of in vitro contact activation and a low tissue factor trigger. Thromboelastometry measured using the same sample type was similarly able to distinguish bleeding phenotype. However, when the potential clinical utility of the assays was compared using receiver operating characteristic curve analysis, thromboelastometry was inferior to TGA as an identifier of bleeding tendency. When the thromboelastometry sample type used was whole blood, or where assays were performed in the presence of tissue plasminogen activator the assays did not differentiate bleeding phenotype. For purposes of treatment planning, the potential of the TGA to determine the optimal dose of FXI replacement was assessed by in vitro spiking experiments using two commercially available FXI concentrates and samples from individuals with major FXI deficiency. Each concentrate improved thrombin generation, but dose response curves were found to differ, suggesting different properties for the two products. The clinical utility of the approach was then demonstrated with comparable TGA results obtained in ex vivo samples from patients treated with FXI concentrate and baseline samples spiked in vitro with equivalent amounts of the same FXI concentrate. The utility of global haemostasis assays to monitor the effect of FXI replacement in FXI-deficient individuals undergoing surgery was also tested. Improvement in assay parameters after treatment with solvent-detergent fresh frozen plasma or FXI concentrate was demonstrated suggesting assay value in FXI replacement monitoring. Finally the use of recently developed bleeding assessment tools and bleeding scores as descriptive, diagnostic or predictive measures was tested along with correlation with FXI:C levels and TGA parameters. This analysis confirmed that bleeding scores have a limited value in the clinical assessment of FXI deficiency.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:764474 |
| Date | January 2016 |
| Creators | Pike, Gillian |
| Contributors | Burthem, John |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/investigation-of-the-role-of-global-haemostasis-assays-and-bleeding-scores-in-the-assessment-and-management-of-patients-with-factor-xi-deficiency(0ff0defc-ba60-4f91-b283-86cb3fe0c9c5).html |
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