Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Tomas Lindahl, Linköping University, Sweden
- Second opponent: Professor Søren Risom Kristensen, Aalborg Universitetshospital / Aalborg University, Denmark
- Third member and chair of the evaluation committee: Professor Ingebjørg Seljeflot, Faculty of medicine, University of Oslo
Chair of the Defence
Associate Professor Anders Erik Astrup Dahm, Faculty of Medicine, University of Oslo
Principal Supervisor
Associate Professor Carola Elisabeth Henriksson, Faculty of Medicine, University of Oslo
Summary
Meningococcal disease may present either as meningitis or sepsis, and patients with massive bacterial growth in the circulation may develop disseminated intravascular coagulation (DIC). The lipopolysaccharides (LPS) in the outer membrane of the meningococci induce blood-borne monocytes to express tissue factor (TF), and also to shed small (<1 µm) TF-positive microvesicles (MVs). TF is the main initiator of coagulation, and monocyte- and MV-bound TF may therefore be circulating procoagulant entities that contribute to DIC.
In this thesis, Hellum et al show that patients with meningococcal septic shock have MVs with a much more procoagulant phenotype than MVs from patients with meningococcal meningitis. The MV-associated procoagulant activity was associated with the levels of bacterial LPS in plasma, which in turn were closely associated with the clinical outcome. Patients infected with a mutant meningococcus (lpxL1), which has an altered LPS structure, have less coagulopathy than patients infected with the wild type meningococcus. In line with this, Hellum et al show that the lpxL1 mutant has a significantly lower ability than the wild type bacteria to enhance TF-expression and the release of TF-bearing MVs from monocytes cultured ex vivo.
A thrombin generation assay (TGA) was used to measure procoagulant activity of circulating MVs throughout the thesis. The influence of different preanalytical and analytical variables in this method was studied, and the performance of the TGA was evaluated in samples from patients with different prothrombotic diseases (meningococcal disease, pancreatic cancer).
In conclusion, the work of this thesis extends the knowledge of circulating MVs in the pathophysiology of meningococcal disease. The thesis also encompasses methodological improvements of the TGA that may be valuable for future measurements of procoagulant MVs in a wide range of diseases with coagulation disturbances.
Additional information
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