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Recombinant human factor VIIa and a factor VIIa-analogue reduces heparin and low molecular weight heparin (LMWH)-induced bleeding in rats

Lauritzen, B; Hedner, Ulla LU ; Johansen, P B; Tranholm, M and Ezban, M (2008) In Journal of Thrombosis and Haemostasis 6(5). p.804-811
Abstract
Background: Heparin and low molecular weight heparin (LMWH) are widely used for prevention and treatment of thromboemobolic events, but may occasionally cause uncontrollable bleeding. Heparin can readily be antagonized with protamine, but this is less effective against LMWH. Objectives: To test the effects of rFVIIa or an analogue of rFVIIa, NN1731, on heparin- and LMWH-induced bleeding in rats. Methods: Initially the doses of heparin and tinzaparin (a LMWH) were determined by dose-titration. Following pretreatment with heparin or tinzaparin in rats, tail-transection was performed, and the effect of rFVIIa and NN1731 on the bleeding was observed. Results: rFVIIa (5, 10 and 20 mg kg(-1)) reduced bleeding time and blood loss caused by... (More)
Background: Heparin and low molecular weight heparin (LMWH) are widely used for prevention and treatment of thromboemobolic events, but may occasionally cause uncontrollable bleeding. Heparin can readily be antagonized with protamine, but this is less effective against LMWH. Objectives: To test the effects of rFVIIa or an analogue of rFVIIa, NN1731, on heparin- and LMWH-induced bleeding in rats. Methods: Initially the doses of heparin and tinzaparin (a LMWH) were determined by dose-titration. Following pretreatment with heparin or tinzaparin in rats, tail-transection was performed, and the effect of rFVIIa and NN1731 on the bleeding was observed. Results: rFVIIa (5, 10 and 20 mg kg(-1)) reduced bleeding time and blood loss caused by heparin- and tinzaparin-induced bleeding, using doses of 200 IU kg(-1) (n = 8) and 500 IU kg(-1) (n = 9), respectively. Similarly, 10 mg kg(-1) NN1731 significantly reduced both heparin- and tinzaparin-induced bleeding to the normal level. Following severe anticoagulation with 1800 IU kg(-1) tinzaparin, 10 mg kg(-1) NN1731 reduced and normalized the bleeding, while the effect of 20 mg kg(-1) rFVIIa failed to reach statistical significance. These data are consistent with the hypothesis that rFVIIa/NN1731 are capable of generating sufficient thrombin locally on the surface of activated platelets to induce hemostasis in the presence of heparin/LMWH. Conclusions: This study suggests that rFVIIa and NN1731 may have the potential to control bleedings caused by heparin or LMWH. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
NN1731, heparin, low molecular weight heparin, rats, rFVIIa
in
Journal of Thrombosis and Haemostasis
volume
6
issue
5
pages
804 - 811
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000254991400014
  • scopus:42149134772
ISSN
1538-7933
DOI
10.1111/j.1538-7836.2008.02933.x
language
English
LU publication?
yes
id
b5d90d69-8a07-492d-8ffb-6dbd74f8e478 (old id 1206279)
date added to LUP
2008-09-19 12:16:04
date last changed
2017-01-01 05:17:46
@article{b5d90d69-8a07-492d-8ffb-6dbd74f8e478,
  abstract     = {Background: Heparin and low molecular weight heparin (LMWH) are widely used for prevention and treatment of thromboemobolic events, but may occasionally cause uncontrollable bleeding. Heparin can readily be antagonized with protamine, but this is less effective against LMWH. Objectives: To test the effects of rFVIIa or an analogue of rFVIIa, NN1731, on heparin- and LMWH-induced bleeding in rats. Methods: Initially the doses of heparin and tinzaparin (a LMWH) were determined by dose-titration. Following pretreatment with heparin or tinzaparin in rats, tail-transection was performed, and the effect of rFVIIa and NN1731 on the bleeding was observed. Results: rFVIIa (5, 10 and 20 mg kg(-1)) reduced bleeding time and blood loss caused by heparin- and tinzaparin-induced bleeding, using doses of 200 IU kg(-1) (n = 8) and 500 IU kg(-1) (n = 9), respectively. Similarly, 10 mg kg(-1) NN1731 significantly reduced both heparin- and tinzaparin-induced bleeding to the normal level. Following severe anticoagulation with 1800 IU kg(-1) tinzaparin, 10 mg kg(-1) NN1731 reduced and normalized the bleeding, while the effect of 20 mg kg(-1) rFVIIa failed to reach statistical significance. These data are consistent with the hypothesis that rFVIIa/NN1731 are capable of generating sufficient thrombin locally on the surface of activated platelets to induce hemostasis in the presence of heparin/LMWH. Conclusions: This study suggests that rFVIIa and NN1731 may have the potential to control bleedings caused by heparin or LMWH.},
  author       = {Lauritzen, B and Hedner, Ulla and Johansen, P B and Tranholm, M and Ezban, M},
  issn         = {1538-7933},
  keyword      = {NN1731,heparin,low molecular weight heparin,rats,rFVIIa},
  language     = {eng},
  number       = {5},
  pages        = {804--811},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Journal of Thrombosis and Haemostasis},
  title        = {Recombinant human factor VIIa and a factor VIIa-analogue reduces heparin and low molecular weight heparin (LMWH)-induced bleeding in rats},
  url          = {http://dx.doi.org/10.1111/j.1538-7836.2008.02933.x},
  volume       = {6},
  year         = {2008},
}