Bio-distribution of pharmacologically administered recombinant factor VIIa (rFVIIa)
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1547268
- author
- Gopalakrishnan, R. ; Hedner, Ulla LU ; Ghosh, S. ; Nayak, R. C. ; Allen, T. C. ; Pendurthi, U. R. and Rao, L. V. M.
- organization
- publishing date
- 2010
- 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
- Wiley-Blackwell
- external identifiers
-
- wos:000273687600014
- scopus:74749095228
- pmid:19943873
- ISSN
- 1538-7933
- DOI
- 10.1111/j.1538-7836.2009.03696.x
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Emergency medicine/Medicine/Surgery (013240200)
- id
- 271685f7-e186-4dd1-ad0a-3fff335a5197 (old id 1547268)
- date added to LUP
- 2016-04-01 10:41:57
- date last changed
- 2022-01-26 01:35:57
@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}},
keywords = {{prophylaxis; rFVIIa; tissue factor; hemophilia; bio-distribution; endothelial cell protein C receptor}},
language = {{eng}},
number = {{2}},
pages = {{301--310}},
publisher = {{Wiley-Blackwell}},
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}},
doi = {{10.1111/j.1538-7836.2009.03696.x}},
volume = {{8}},
year = {{2010}},
}