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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children
Blood, Volume 122, No. 5, Year 2013
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Description
Cerebral malaria(CM)isamajor 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 microhem or rhages 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. © 2013 by The American Society of Hematology.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3731936/bin/supp_122_5_842__index.html
https://efashare.b-cdn.net/share/pmc/articles/PMC3731936/bin/supp_blood-2013-03-490219_blood-2013-03-490219-1.pdf
Authors & Co-Authors
Moxon, Christopher Alan
Malawi, Zomba
University of Malawi
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
United Kingdom, Liverpool
University of Liverpool
Wassmer, Samuel Crocodile
United States, New York
Nyu Grossman School of Medicine
Milner, Danny Arnold
United States, Boston
Brigham and Women's Hospital
Chisala, N. V.
Malawi, Zomba
University of Malawi
Taylor, Terrie Ellen
United States, East Lansing
Msu College of Osteopathic Medicine
Malawi, Zomba
University of Malawi
Seydel, Karl B.
United States, East Lansing
Msu College of Osteopathic Medicine
Malawi, Zomba
University of Malawi
Molyneux, Malcolm Edward
Malawi, Zomba
University of Malawi
Faragher, Brian E.
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Esmon, Charles T.
United States, Oklahoma City
Oklahoma Medical Research Foundation
United States, Chevy Chase
Howard Hughes Medical Institute
Downey, Colin
United Kingdom, Liverpool
University of Liverpool
Toh, Cheng Hock
United Kingdom, Liverpool
University of Liverpool
Craig, Alister Gordon
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Heyderman, Robert Simon
Malawi, Zomba
University of Malawi
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Statistics
Citations: 203
Authors: 13
Affiliations: 8
Identifiers
Doi:
10.1182/blood-2013-03-490219
ISSN:
00064971
Research Areas
Infectious Diseases
Maternal And Child Health