Coagulation and the endothelium in malawian children with cerebral malaria

Moxon, Chris Coagulation and the endothelium in malawian children with cerebral malaria. Doctor of Philosophy thesis, University of Liverpool.

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Abstract

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.

Item Type:	Thesis (Doctor of Philosophy)
Additional Information:	Date: 2012-08 (completed)
Uncontrolled Keywords:	Malaria, Cerebral, endothelium, protein c, coagulation
Subjects:	?? R1 ??
Divisions:	Faculty of Health and Life Sciences
Depositing User:	Symplectic Admin
Date Deposited:	05 Sep 2013 10:24
Last Modified:	16 Dec 2022 04:38
DOI:	10.17638/00009673
Supervisors:	Craig, Alister Heyderman, Robert Toh, C Wassmer, Samuel
URI:	https://livrepository.liverpool.ac.uk/id/eprint/9673