Background: Cerebral malaria is a major cause of mortality and morbidity in African children. Pathology is related to interactions between malaria-infected red blood cells (iRBC) and the endothelium but the aetiology of the neurological compromise remains unclear. Methods: This thesis involved direct and downstream investigation of the endothelium in Malawian children with cerebral malaria and controls in post-mortem samples, plasma and through developing a novel ex vivo method to examine endothelium in subcutaneous tissue. Results: In post-mortem samples of brain in fatal cerebral malaria, there was thrombosis and loss of endothelial protein C receptor (EPCR) associated with iRBC sequestration. iRBC associated loss of EPCR and thrombomodulin was also demonstrated in post- mortem samples of gut and subcutaneous tissue but this was less marked than in the brain and rarely associated with thrombosis. Subcutaneous biopsies taken on admission with cerebral malaria demonstrated reduced EPCR and thrombomodulin ex vivo, showing that loss of these receptors is present at the time of presentation and are not just agonal events. Examination of coagulation in blood demonstrated activation of coagulation, as indicated by raised thrombin-anti-thrombin complexes and reduced protein C and antithrombin levels. However this was compensated as there was normal prothrombin fragment (F1+2)-to-activated protein C ratios and only mildly altered clotting times. Examination of markers of endothelial activation (soluble Intracellular Adhesion 2 Molecule-1 [sICAM-1] and Angiopoetin-2 [Ang-2]) and inflammation (C-reactive protein [CRP]) revealed endothelial activation and inflammation at presentation and during recovery and demonstrated that in cerebral malaria and in uncomplicated malaria there is persistent endothelial activation after parasites are cleared, up to a month after presentation. Complexes of very low density lipoprotein (VLDL) and CRP were also raised in cerebral and uncomplicated malaria. Conclusions: In cerebral malaria in Malawian children there is localised microvascular loss of endothelial anticoagulant receptors at sites of iRBC sequestration. In the brain, where constitutive expression of EPCR and thrombomodulin is low, this is accompanied by thrombosis; outside the brain, where constitutive EPCR and thrombomodulin expression is high, coagulation is compensated. This activation of coagulation and of the endothelium in response to acute infection leaves a residual imprint as detected by markers of endothelial activation and inflammation even in uncomplicated malaria several weeks after parasites are cleared. Since children in sub-Saharan African frequently suffer repeated infections these endothelial alterations may have important consequences both for subsequent infections and for long-term health. These mechanisms highlight potential targets for therapy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:579301 |
| Date | January 2012 |
| Creators | Moxon, Chris |
| Contributors | Craig, Alister; Heyderman, Robert; Toh, C.; Wassmer, Samuel |
| Publisher | University of Liverpool |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://livrepository.liverpool.ac.uk/9673/ |
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