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Bio-distribution of pharmacologically administered recombinant factor VIIa (rFVIIa)

Gopalakrishnan, R.; Hedner, Ulla LU ; Ghosh, S.; Nayak, R. C.; Allen, T. C.; Pendurthi, U. R. and Rao, L. V. M. (2010) In Journal of Thrombosis and Haemostasis 8(2). p.301-310
Abstract
Background: Recent clinical studies suggest that the prophylactic use of recombinant factor VIIa (rFVIIa) markedly reduces the number of bleeding episodes in hemophilic patients with inhibitors. Given the short biological half-life of rFVIIa, it is unclear how rFVIIa could be effective in prophylactic treatment. Objectives: To examine the extravascular distribution of pharmacologically administered rFVIIa to obtain clues on how rFVIIa could work in prophylaxis. Methods: Recombinant mouse FVIIa tagged with AF488 fluorophore (AF488-FVIIa) was administered into mice via the tail vein. At different time intervals following the administration, mice were exsanguinated and various tissues were collected. The tissue sections were processed for... (More)
Background: Recent clinical studies suggest that the prophylactic use of recombinant factor VIIa (rFVIIa) markedly reduces the number of bleeding episodes in hemophilic patients with inhibitors. Given the short biological half-life of rFVIIa, it is unclear how rFVIIa could be effective in prophylactic treatment. Objectives: To examine the extravascular distribution of pharmacologically administered rFVIIa to obtain clues on how rFVIIa could work in prophylaxis. Methods: Recombinant mouse FVIIa tagged with AF488 fluorophore (AF488-FVIIa) was administered into mice via the tail vein. At different time intervals following the administration, mice were exsanguinated and various tissues were collected. The tissue sections were processed for immunohistochemistry to evaluate distribution of rFVIIa. Results: rFVIIa, immediately following the administration, associated with the endothelium lining of large blood vessels. Within 1 h, rFVIIa bound to endothelial cells was transferred to the perivascular tissue surrounding the blood vessels and thereafter diffused throughout the tissue. In the liver, rFVIIa was localized to sinusoidal capillaries and accumulated in hepatocytes. In bone, rFVIIa was accumulated in the zone of calcified cartilage and some of it was retained there for a week. The common finding of the present study is that rFVIIa in extravascular spaces was mostly localized to regions that contain TF expressing cells. Conclusions: The present study demonstrates that pharmacologically administered rFVIIa readily associates with the vascular endothelium and subsequently enters into extravascular spaces where it is likely to bind to TF and is retained for extended time periods. This may explain the prolonged pharmacological effect of rFVIIa. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
prophylaxis, rFVIIa, tissue factor, hemophilia, bio-distribution, endothelial cell protein C receptor
in
Journal of Thrombosis and Haemostasis
volume
8
issue
2
pages
301 - 310
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000273687600014
  • scopus:74749095228
ISSN
1538-7933
DOI
10.1111/j.1538-7836.2009.03696.x
language
English
LU publication?
yes
id
271685f7-e186-4dd1-ad0a-3fff335a5197 (old id 1547268)
date added to LUP
2010-02-24 11:00:33
date last changed
2018-05-29 12:04:45
@article{271685f7-e186-4dd1-ad0a-3fff335a5197,
  abstract     = {Background: Recent clinical studies suggest that the prophylactic use of recombinant factor VIIa (rFVIIa) markedly reduces the number of bleeding episodes in hemophilic patients with inhibitors. Given the short biological half-life of rFVIIa, it is unclear how rFVIIa could be effective in prophylactic treatment. Objectives: To examine the extravascular distribution of pharmacologically administered rFVIIa to obtain clues on how rFVIIa could work in prophylaxis. Methods: Recombinant mouse FVIIa tagged with AF488 fluorophore (AF488-FVIIa) was administered into mice via the tail vein. At different time intervals following the administration, mice were exsanguinated and various tissues were collected. The tissue sections were processed for immunohistochemistry to evaluate distribution of rFVIIa. Results: rFVIIa, immediately following the administration, associated with the endothelium lining of large blood vessels. Within 1 h, rFVIIa bound to endothelial cells was transferred to the perivascular tissue surrounding the blood vessels and thereafter diffused throughout the tissue. In the liver, rFVIIa was localized to sinusoidal capillaries and accumulated in hepatocytes. In bone, rFVIIa was accumulated in the zone of calcified cartilage and some of it was retained there for a week. The common finding of the present study is that rFVIIa in extravascular spaces was mostly localized to regions that contain TF expressing cells. Conclusions: The present study demonstrates that pharmacologically administered rFVIIa readily associates with the vascular endothelium and subsequently enters into extravascular spaces where it is likely to bind to TF and is retained for extended time periods. This may explain the prolonged pharmacological effect of rFVIIa.},
  author       = {Gopalakrishnan, R. and Hedner, Ulla and Ghosh, S. and Nayak, R. C. and Allen, T. C. and Pendurthi, U. R. and Rao, L. V. M.},
  issn         = {1538-7933},
  keyword      = {prophylaxis,rFVIIa,tissue factor,hemophilia,bio-distribution,endothelial cell protein C receptor},
  language     = {eng},
  number       = {2},
  pages        = {301--310},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Journal of Thrombosis and Haemostasis},
  title        = {Bio-distribution of pharmacologically administered recombinant factor VIIa (rFVIIa)},
  url          = {http://dx.doi.org/10.1111/j.1538-7836.2009.03696.x},
  volume       = {8},
  year         = {2010},
}