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First 20 years with recombinant FVIIa (NovoSeven).

Hedner, Ulla LU and Lee, C A (2011) In Haemophilia 17. p.172-182
Abstract
Summary. This review describes the background for the development of recombinant FVIIa (rFVIIa; NovoSeven) for use in haemophilic patients with inhibitors. The first proof of principle for using pharmacological doses of FVIIa as a haemostatic agent was obtained by producing small amounts of pure plasma-derived FVIIa, which showed encouraging effect in two patients with haemophilia A and inhibitors. To make pure FVIIa available for use in a larger number of patients, rFVIIa was produced that was approved for use in patients with inhibitors against coagulation factors (congenital haemophilia and acquired haemophilia) in 1996 (EU), 1999 (USA) and 2000 (Japan). The efficacy rate in severe bleedings and in major surgery including major... (More)
Summary. This review describes the background for the development of recombinant FVIIa (rFVIIa; NovoSeven) for use in haemophilic patients with inhibitors. The first proof of principle for using pharmacological doses of FVIIa as a haemostatic agent was obtained by producing small amounts of pure plasma-derived FVIIa, which showed encouraging effect in two patients with haemophilia A and inhibitors. To make pure FVIIa available for use in a larger number of patients, rFVIIa was produced that was approved for use in patients with inhibitors against coagulation factors (congenital haemophilia and acquired haemophilia) in 1996 (EU), 1999 (USA) and 2000 (Japan). The efficacy rate in severe bleedings and in major surgery including major orthopaedic surgery has been found to be around 90% in controlled studies, and no serious safety concerns have been demonstrated. The availability of rFVIIa has facilitated the performance of elective major surgery in haemophilia patients with inhibitors. Further steps along the vision of providing a treatment for inhibitor patients similar to non-inhibitor patients have been the efficacy of rFVIIa in home-treatment and recently the encouraging experience in prophylaxis. The concept of using pharmacological doses of rFVIIa as a haemostatic agent is a new one, which has caused difficulties in finding the correct dose. A step forward has been the demonstration that similar efficacy can be achieved after one single dose of 270 mug kg(-1) instead of three injections of a dose of 90 mug kg(-1). The higher clearance rate in children suggests that higher doses may be beneficial in children. The availability of rFVIIa has made advances in the understanding of coagulation processes possible. In a cell-based in vitro model, it has been shown that rFVIIa binds to preactivated platelets if present in concentrations of 30 nm or higher. By doing so, it activates FX into FXa and enhances the thrombin generation on the activated platelet surface in the absence of FVIII/FIX. Through the increased thrombin generation, a firm, well-structured fibrin haemostatic plug, which is resistant to premature lysis, is formed. By exploiting this mechanism of action, rFVIIa may also be effective in situations other than haemophilia, characterized by an impaired thrombin generation. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Haemophilia
volume
17
pages
172 - 182
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000285762900037
  • pmid:20609014
  • scopus:79951933686
ISSN
1351-8216
DOI
10.1111/j.1365-2516.2010.02352.x
language
English
LU publication?
yes
id
cc48c9f1-97aa-461f-975b-2715ef4ff3fb (old id 1645235)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20609014?dopt=Abstract
date added to LUP
2010-08-02 10:14:46
date last changed
2017-11-05 04:42:15
@article{cc48c9f1-97aa-461f-975b-2715ef4ff3fb,
  abstract     = {Summary. This review describes the background for the development of recombinant FVIIa (rFVIIa; NovoSeven) for use in haemophilic patients with inhibitors. The first proof of principle for using pharmacological doses of FVIIa as a haemostatic agent was obtained by producing small amounts of pure plasma-derived FVIIa, which showed encouraging effect in two patients with haemophilia A and inhibitors. To make pure FVIIa available for use in a larger number of patients, rFVIIa was produced that was approved for use in patients with inhibitors against coagulation factors (congenital haemophilia and acquired haemophilia) in 1996 (EU), 1999 (USA) and 2000 (Japan). The efficacy rate in severe bleedings and in major surgery including major orthopaedic surgery has been found to be around 90% in controlled studies, and no serious safety concerns have been demonstrated. The availability of rFVIIa has facilitated the performance of elective major surgery in haemophilia patients with inhibitors. Further steps along the vision of providing a treatment for inhibitor patients similar to non-inhibitor patients have been the efficacy of rFVIIa in home-treatment and recently the encouraging experience in prophylaxis. The concept of using pharmacological doses of rFVIIa as a haemostatic agent is a new one, which has caused difficulties in finding the correct dose. A step forward has been the demonstration that similar efficacy can be achieved after one single dose of 270 mug kg(-1) instead of three injections of a dose of 90 mug kg(-1). The higher clearance rate in children suggests that higher doses may be beneficial in children. The availability of rFVIIa has made advances in the understanding of coagulation processes possible. In a cell-based in vitro model, it has been shown that rFVIIa binds to preactivated platelets if present in concentrations of 30 nm or higher. By doing so, it activates FX into FXa and enhances the thrombin generation on the activated platelet surface in the absence of FVIII/FIX. Through the increased thrombin generation, a firm, well-structured fibrin haemostatic plug, which is resistant to premature lysis, is formed. By exploiting this mechanism of action, rFVIIa may also be effective in situations other than haemophilia, characterized by an impaired thrombin generation.},
  author       = {Hedner, Ulla and Lee, C A},
  issn         = {1351-8216},
  language     = {eng},
  pages        = {172--182},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Haemophilia},
  title        = {First 20 years with recombinant FVIIa (NovoSeven).},
  url          = {http://dx.doi.org/10.1111/j.1365-2516.2010.02352.x},
  volume       = {17},
  year         = {2011},
}