Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children

Moxon, Christopher A., Wassmer, S. C., Milner, D. A., Chisala, N. V., Taylor, T. E., Seydel, K. B., Molyneux, Malcolm E, Faragher, Brian, Esmon, C. T., Downey, C., Toh, C.-H., Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164 and Heyderman, R. S. (2013) 'Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children'. Blood, Vol 122, Issue 5, pp. 842-851.

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Abstract

Cerebral malaria (CM) is a major cause of mortality in African children and the mechanisms underlying its development, namely how malaria-infected erythrocytes (IEs) cause disease and why the brain is preferentially affected, remain unclear. Brain microhemorrhages in CM suggest a clotting disorder, but whether this phenomenon is important in pathogenesis is debated. We hypothesized that localized cerebral microvascular thrombosis in CM is caused by a decreased expression of the anticoagulant and protective receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR) and that low constitutive expression of these regulatory molecules in the brain make it particularly vulnerable. Autopsies from Malawian children with CM showed cerebral fibrin clots and loss of EPCR, colocalized with sequestered IEs. Using a novel assay to examine endothelial phenotype ex vivo using subcutaneous microvessels, we demonstrated that loss of EPCR and TM at sites of IE cytoadherence is detectible in nonfatal CM. In contrast, although clotting factor activation was seen in the blood of CM patients, this was compensated and did not disseminate. Because of the pleiotropic nature of EPCR and TM, these data implicate disruption of the endothelial protective properties at vulnerable sites and particularly in the brain, linking coagulation and inflammation with IE sequestration.

Item Type:	Article
Subjects:	QX Parasitology > Protozoa > QX 135 Plasmodia WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 150 Erythrocytes WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 322 Blood coagulation disorders (General)
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1182/blood-2013-03-490219
Depositing User:	Martin Chapman
Date Deposited:	12 Aug 2013 15:21
Last Modified:	17 Aug 2022 08:56
URI:	https://archive.lstmed.ac.uk/id/eprint/3409

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