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Endothelial cell protein C receptor-mediated redistribution and tissue-level accumulation of factor VIIa.

Clark, C A; Vatsyayan, R; Hedner, Ulla LU ; Esmon, C T; Pendurthi, U R and Rao, L V M (2012) In Journal of Thrombosis and Haemostasis 10(11). p.2383-2391
Abstract
Background: Recent studies show that FVIIa binds to endothelial cell protein C receptor (EPCR) on vascular endothelium; however, the importance of this interaction in hemostasis or pathophysiology is unknown. Objective, The aim of the present study is to investigate the role of FVIIa interaction with EPCR on the endothelium in mediating FVIIa transport from the circulation to extravascular tissues. Methods: Wild-type, EPCR-deficient or ECPR-over expressing mice were injected with human rFVIIa (120 μg/kg b.w.) via tail vein. At varying time intervals following rFVIIa administration, blood and various tissues were collected to measure FVIIa antigen and activity levels. Tissue sections were analyzed by immunohistochemistry for FVIIa and EPCR.... (More)
Background: Recent studies show that FVIIa binds to endothelial cell protein C receptor (EPCR) on vascular endothelium; however, the importance of this interaction in hemostasis or pathophysiology is unknown. Objective, The aim of the present study is to investigate the role of FVIIa interaction with EPCR on the endothelium in mediating FVIIa transport from the circulation to extravascular tissues. Methods: Wild-type, EPCR-deficient or ECPR-over expressing mice were injected with human rFVIIa (120 μg/kg b.w.) via tail vein. At varying time intervals following rFVIIa administration, blood and various tissues were collected to measure FVIIa antigen and activity levels. Tissue sections were analyzed by immunohistochemistry for FVIIa and EPCR. Results: The data reveal that, following intravenous injection, rFVIIa rapidly disappears from blood and associates with the endothelium in an EPCR-dependent manner. Immunohistochemical analyses revealed that association of FVIIa with the endothelium was maximal at 30 min and thereafter progressively declined. FVIIa association with the endothelium was undetectable at time points exceeding 24 h post FVIIa administration. The levels of rFVIIa accumulated in tissue correlates with expression levels of EPCR in mice and FVIIa associated with tissues remained functionally active for periods of at least 7 days. Conclusions: The observation that EPCR-dependent association of FVIIa with the endothelium is most pronounced soon after rFVIIa administration and subsequently declines temporally, combined with the retention of functionally-active FVIIa in tissue homogenates for extended periods, indicates that FVIIa binding to EPCR on the endothelium facilitates the transport of FVIIa from circulation to extravascular tissues where TF resides. © 2012 International Society on Thrombosis and Haemostasis. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Thrombosis and Haemostasis
volume
10
issue
11
pages
2383 - 2391
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000310548400022
  • pmid:22950420
  • scopus:84868159252
ISSN
1538-7933
DOI
10.1111/j.1538-7836.2012.04917.x
language
English
LU publication?
yes
id
35163941-e941-4e0e-907d-f60545a57b16 (old id 3124292)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22950420?dopt=Abstract
date added to LUP
2012-10-04 15:13:56
date last changed
2017-08-27 05:43:30
@article{35163941-e941-4e0e-907d-f60545a57b16,
  abstract     = {Background: Recent studies show that FVIIa binds to endothelial cell protein C receptor (EPCR) on vascular endothelium; however, the importance of this interaction in hemostasis or pathophysiology is unknown. Objective, The aim of the present study is to investigate the role of FVIIa interaction with EPCR on the endothelium in mediating FVIIa transport from the circulation to extravascular tissues. Methods: Wild-type, EPCR-deficient or ECPR-over expressing mice were injected with human rFVIIa (120 μg/kg b.w.) via tail vein. At varying time intervals following rFVIIa administration, blood and various tissues were collected to measure FVIIa antigen and activity levels. Tissue sections were analyzed by immunohistochemistry for FVIIa and EPCR. Results: The data reveal that, following intravenous injection, rFVIIa rapidly disappears from blood and associates with the endothelium in an EPCR-dependent manner. Immunohistochemical analyses revealed that association of FVIIa with the endothelium was maximal at 30 min and thereafter progressively declined. FVIIa association with the endothelium was undetectable at time points exceeding 24 h post FVIIa administration. The levels of rFVIIa accumulated in tissue correlates with expression levels of EPCR in mice and FVIIa associated with tissues remained functionally active for periods of at least 7 days. Conclusions: The observation that EPCR-dependent association of FVIIa with the endothelium is most pronounced soon after rFVIIa administration and subsequently declines temporally, combined with the retention of functionally-active FVIIa in tissue homogenates for extended periods, indicates that FVIIa binding to EPCR on the endothelium facilitates the transport of FVIIa from circulation to extravascular tissues where TF resides. © 2012 International Society on Thrombosis and Haemostasis.},
  author       = {Clark, C A and Vatsyayan, R and Hedner, Ulla and Esmon, C T and Pendurthi, U R and Rao, L V M},
  issn         = {1538-7933},
  language     = {eng},
  number       = {11},
  pages        = {2383--2391},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Journal of Thrombosis and Haemostasis},
  title        = {Endothelial cell protein C receptor-mediated redistribution and tissue-level accumulation of factor VIIa.},
  url          = {http://dx.doi.org/10.1111/j.1538-7836.2012.04917.x},
  volume       = {10},
  year         = {2012},
}