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History of rFVIIa therapy.

Hedner, Ulla LU (2010) In Thrombosis Research 125 Suppl 1. p.4-6
Abstract
Hemophilia patients with inhibitors against FVIII/FIX present with a major challenge in the clinical practice. In the 1970s such patients were treated in association with emergency situations and essential surgery using huge amounts of FVIII/FIX concentrates often preceded by extracorporal adsorption of antibodies against FVIII/FIX. However, moderate to mild bleedings were not effectively treated. A certain hemostatic effect of activated prothrombin complex concentrates (aPCC) not exceeding 65% was reported. Unfortunately, also thromboembolic events occurred, which made them less attractive to use in inhibitor patients. In a dog model the thrombogenic effects on the coagulation system was almost completely avoided by adding antithrombin... (More)
Hemophilia patients with inhibitors against FVIII/FIX present with a major challenge in the clinical practice. In the 1970s such patients were treated in association with emergency situations and essential surgery using huge amounts of FVIII/FIX concentrates often preceded by extracorporal adsorption of antibodies against FVIII/FIX. However, moderate to mild bleedings were not effectively treated. A certain hemostatic effect of activated prothrombin complex concentrates (aPCC) not exceeding 65% was reported. Unfortunately, also thromboembolic events occurred, which made them less attractive to use in inhibitor patients. In a dog model the thrombogenic effects on the coagulation system was almost completely avoided by adding antithrombin and heparin, suggesting factors like IXa, Xa or XIa to be responsible. On the other hand FVIIa is not readily inactivated by antithrombin in the circulation. Furthermore, a detailed literature review revealed very high levels of FVII in the aPCC used with some success in the treatment of hemophilia patients with inhibitors. The potential possibility to use FVIIa as a hemostatic agent was investigated by the administration of pure human FVIIa to two hemophilia patients with inhibitors. In both, a hemostatic effect was recorded. The development of recombinant FVIIa was initiated by Novo Nordisk A/S, Denmark, in June 1986 resulting in NovoSeven (rFVIIa) being licensed for use in patients with inhibitors against coagulation factors in EU in 1996. By then, a hemostatic effect of rFVIIa also in non-hemophilia patients such as patients with platelet dysfunctions or suffering from profuse, heavy bleedings initiated by extensive surgery or trauma had been demonstrated. In parallel the mechanism of action of pharmacological doses of rFVIIa was investigated resulting in a revision of the hemostatic process in stressing the compartmentalization of the process to TF-bearing cells and to thrombin activated platelets at the site of injury. The initial thrombin generation is generated by the formation of the TF-FVIIa-complex formed initially on the TF-bearing cells. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Thrombosis Research
volume
125 Suppl 1
pages
4 - 6
publisher
Elsevier Ltd
external identifiers
  • wos:000275787800002
  • pmid:20188400
  • scopus:77949273934
ISSN
1879-2472
DOI
10.1016/j.thromres.2010.01.021
language
English
LU publication?
yes
id
1088b420-3f46-4ffb-a133-55bb41d5a691 (old id 1582786)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20188400?dopt=Abstract
date added to LUP
2010-04-06 17:07:28
date last changed
2018-05-29 10:48:42
@article{1088b420-3f46-4ffb-a133-55bb41d5a691,
  abstract     = {Hemophilia patients with inhibitors against FVIII/FIX present with a major challenge in the clinical practice. In the 1970s such patients were treated in association with emergency situations and essential surgery using huge amounts of FVIII/FIX concentrates often preceded by extracorporal adsorption of antibodies against FVIII/FIX. However, moderate to mild bleedings were not effectively treated. A certain hemostatic effect of activated prothrombin complex concentrates (aPCC) not exceeding 65% was reported. Unfortunately, also thromboembolic events occurred, which made them less attractive to use in inhibitor patients. In a dog model the thrombogenic effects on the coagulation system was almost completely avoided by adding antithrombin and heparin, suggesting factors like IXa, Xa or XIa to be responsible. On the other hand FVIIa is not readily inactivated by antithrombin in the circulation. Furthermore, a detailed literature review revealed very high levels of FVII in the aPCC used with some success in the treatment of hemophilia patients with inhibitors. The potential possibility to use FVIIa as a hemostatic agent was investigated by the administration of pure human FVIIa to two hemophilia patients with inhibitors. In both, a hemostatic effect was recorded. The development of recombinant FVIIa was initiated by Novo Nordisk A/S, Denmark, in June 1986 resulting in NovoSeven (rFVIIa) being licensed for use in patients with inhibitors against coagulation factors in EU in 1996. By then, a hemostatic effect of rFVIIa also in non-hemophilia patients such as patients with platelet dysfunctions or suffering from profuse, heavy bleedings initiated by extensive surgery or trauma had been demonstrated. In parallel the mechanism of action of pharmacological doses of rFVIIa was investigated resulting in a revision of the hemostatic process in stressing the compartmentalization of the process to TF-bearing cells and to thrombin activated platelets at the site of injury. The initial thrombin generation is generated by the formation of the TF-FVIIa-complex formed initially on the TF-bearing cells.},
  author       = {Hedner, Ulla},
  issn         = {1879-2472},
  language     = {eng},
  pages        = {4--6},
  publisher    = {Elsevier Ltd},
  series       = {Thrombosis Research},
  title        = {History of rFVIIa therapy.},
  url          = {http://dx.doi.org/10.1016/j.thromres.2010.01.021},
  volume       = {125 Suppl 1},
  year         = {2010},
}