Mechanisms Underlying Coagulation Abnormalities in Ebola Hemorrhagic Fever

[Emily]

http://jid.oxfordjournals.org/content/188/11/1618.short

Mechanisms Underlying Coagulation Abnormalities in Ebola Hemorrhagic Fever: Overexpression of Tissue Factor in Primate Monocytes/Macrophages Is a Key Event J Infect Dis. (2003) 188 (11): 1618-1629 doi:10.1086/379724


Thomas W. Geisbert1,
Howard A. Young3,
Peter B. Jahrling2,
Kelly J. Davis2,
Elliott Kagan4 and
Lisa E. Hensley1

+ Author Affiliations

1Virology Division and
2Headquarters, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick,
3Cellular and Molecular Immunology Section, Laboratory of Experimental Immunology, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, and
4Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland
Abstract

Disseminated intravascular coagulation is a prominent manifestation of Ebola virus (EBOV) infection. Here, we report that tissue factor (TF) plays an important role in triggering the hemorrhagic complications that characterize EBOV infections. Analysis of samples obtained from 25 macaques showed increased levels of TF associated with lymphoid macrophages, whereas analysis of peripheral blood?cell RNA showed increased levels of TF transcripts by day 3. Plasma from macaques contained increased numbers of TF-expressing membrane microparticles. Dysregulation of the fibrinolytic system developed during the course of infection, including a rapid decrease in plasma levels of protein C. Infection of primary human monocytes/macrophages (PHMs) was used to further evaluate the role of TF in EBOV infections. Analysis of PHM RNA at 1?48 h showed increased TF transcripts, whereas levels of TF protein were dramatically increased by day 2. Thus, chemotherapeutic strategies aimed at controlling overexpression of TF may ameliorate the effects of EBOV hemorrhagic fever
Footnotes


Presented in part: XII International Congress of Virology, Paris, 27 July?1 August 2002 (symposium V-293)

The views, opinions, and findings contained herein are those of the authors and should not be construed as an official Department of the Army position, policy, or decision unless so designated by other documentation

Received February 12, 2003.
Accepted June 9, 2003.

Full text at link. :tiphat:

 

[Vibrant62]

Re: Mechanisms Underlying Coagulation Abnormalities in Ebola Hemorrhagic Fever

Interesting... Full exploration of TF pathway in this book. Must be some clues in here... but will take some digesting!

Full paper at http://www.ncbi.nlm.nih.gov/books/NBK6620/

Regulation of Tissue Factor Expression

Wolfram Ruf and Matthias Riewald.
Go to:
Summary

The cellular initiation of the coagulation protease cascade by tissue factor (TF) is the central pathway that initiates disseminated intravascular coagulation and contributes to lethality associated with septicemia. TF is induced by inflammatory mediators in monocytes and endothelial cells by predominantly transcriptional mechanisms involving a cooperation of transcription factors from the Jun/Fos, NF-κB, NFAT, and Egr families. Following TF expression within the vasculature, inflammatory responses can exaggerate the procoagulant effects by altering cell membrane properties and by destroying the inhibitory control of the TF-pathway. One consequence of the uncontrolled TF-initiated upstream protease cascade is autocrine cell signaling through protease activated receptors, capable of supporting a self-perpetuating inflammatory response. Anticoagulant strategies that target both the prothrombotic as well as the proinflammatory signaling effects of the coagulation protease cascade may result in effective attenuation of morbidity and mortality of sepsis.

 

[Vibrant62]

Re: Mechanisms Underlying Coagulation Abnormalities in Ebola Hemorrhagic Fever

http://circ.ahajournals.org/content/92/2/238.full

Copper-Induced Tissue Factor Expression in Human Monocytic THP-1 Cells and Its Inhibition by Antioxidants

Abstract

Background Transition metals such as copper are known to initiate free radical formation and lipid peroxidation. Recent reports suggest that intracellular reactive oxygen intermediates can induce the transcription of a number of important genes. The present study examines the effects of copper and iron on the ability of monocytic cells to synthesize and express tissue factor, the potent procoagulant factor.

Methods and Results Exposure of human monocytic THP-1 cells to 5 to 10 μmol/L Cu2+ led to cell damage and the expression of tissue factor activity to levels up to 70 times higher than control, as measured by a single-stage plasma coagulation assay. These effects were seen only in the presence of a lipophilic chelating agent, 8-hydroxyquinoline, suggesting that intracellular transport of Cu2+ was required. The effects of Cu2+ were mimicked by ceruloplasmin but not by Fe3+ or hemin. The induction of tissue factor activity by Cu2+ was slow in onset (6 hours) but sustained (24 hours) and was accompanied by increased tissue factor mRNA levels, measured by reverse transcription/polymerase chain reaction after annealing with oligomer primers. Increases in tissue factor protein, measured by a specific immunoassay, also occurred but were smaller than those in activity. Cu2+, therefore, appears to act at both the transcriptional and posttranslational levels. The effects of Cu2+ were inhibited by a number of lipophilic antioxidants, including probucol, vitamin E, butylated hydroxytoluene, and a 21-aminosteroid, U74389G.

Conclusions Exposure of monocytes to oxidizing conditions may lead to the expression of high levels of tissue factor activity, with accompanying risk for disseminated intravascular coagulation, and this may be inhibited by lipophilic antioxidants.

 

[Emily]

Re: Mechanisms Underlying Coagulation Abnormalities in Ebola Hemorrhagic Fever

Very interesting, Vibrant!