Plasmodium falciparum-infected erythrocytes induce tissue factor expression in endothelial cells and support the assembly of multimolecular coagulation complexes.
BACKGROUND
Plasmodium falciparum malaria infects 300-500 million people every year, causing 1-2 million deaths annually. Evidence of a coagulation disorder, activation of endothelial cells (EC) and increase in inflammatory cytokines are often present in malaria.


OBJECTIVE
We have asked whether interaction of parasitized red blood cells (pRBC) with EC induces tissue factor (TF) expression in vitro and in vivo. The role of phosphatidylserine-containing pRBC to support the assembly of blood coagulation complexes was also investigated.


RESULTS
We demonstrate that mature forms of pRBC induce functional expression of TF by EC in vitro with productive assembly of the extrinsic Xnase complex and initiation of the coagulation cascade. Late-stage pRBC also support the prothrombinase and intrinsic Xnase complex formation in vitro, and may function as activated platelets in the amplification phase of the blood coagulation. Notably, post-mortem brain sections obtained from P. falciparum-infected children who died from cerebral malaria and other causes display a consistent staining for TF in the EC.


CONCLUSIONS
These findings place TF expression by endothelium and the amplification of the coagulation cascade by pRBC and/or activated platelets as potentially critical steps in the pathogenesis of malaria. Furthermore, it may allow investigators to test other therapeutic alternatives targeting TF or modulators of EC function in the treatment of malaria and/or its complications.
Francischetti
I M B
IM
Vector Biology Section, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892-8132, USA. ifrancischetti@niaid.nih.gov
Seydel
K B
KB
Monteiro
R Q
RQ
Whitten
R O
RO
Erexson
C R
CR
Noronha
A L L
AL
Ostera
G R
GR
Kamiza
S B
SB
Molyneux
M E
ME
Ward
J M
JM
Taylor
T E
TE
D000293:Adolescent; D000818:Animals; D001777:Blood Coagulation; D001921:Brain / Q000098:blood supply / Q000469:parasitology / Q000473:pathology; D001923:Brain Chemistry; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D042783:Endothelial Cells / Q000737:chemistry / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism* / Q000469:parasitology*; D005165:Factor V / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D016779:Malaria, Cerebral / Q000097:blood* / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D008297:Male; D008833:Microcirculation / Q000166:cytology / Q000378:metabolism; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000302:isolation & purification*; D012720:Severity of Illness Index; D013925:Thromboplastin / Q000032:analysis / Q000378:metabolism*; D013997:Time Factors
C022475:prothrombinase complex; D005165:Factor V; D013925:Thromboplastin; D015951:Factor Xa