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Human activated protein C variants in a rat model of arterial thrombosis

Malm, Karl LU ; Arnljots, Björn LU and Dahlbäck, Björn LU (2008) In Thrombosis Journal 6.
Abstract

BACKGROUND: Activated protein C (APC) inhibits coagulation by degrading activated factor V (FVa) and factor VIII (FVIIIa), protein S (PS) functioning as a cofactor to APC.

METHODS: By mutagenesis of the vitamin K-dependent Gla domain of APC, we have recently created an APC variant having enhanced anticoagulant activity due to increased affinity for negatively charged phospholipid membranes. In the present study, the potential antithrombotic effects of this APC variant, and of a variant APC that is additionally mutated in the serine protease domain, have been evaluated in a blind randomized study in a rat model of arterial thrombosis. In this model, we have previously found the combination of bovine APC and PS to be highly... (More)

BACKGROUND: Activated protein C (APC) inhibits coagulation by degrading activated factor V (FVa) and factor VIII (FVIIIa), protein S (PS) functioning as a cofactor to APC.

METHODS: By mutagenesis of the vitamin K-dependent Gla domain of APC, we have recently created an APC variant having enhanced anticoagulant activity due to increased affinity for negatively charged phospholipid membranes. In the present study, the potential antithrombotic effects of this APC variant, and of a variant APC that is additionally mutated in the serine protease domain, have been evaluated in a blind randomized study in a rat model of arterial thrombosis. In this model, we have previously found the combination of bovine APC and PS to be highly antithrombotic. Four treatment groups each containing 10 rats were, in a blind random fashion, given intravenous bolus injections of wild-type or mutant variants of APC (0.8 mg/kg) together with human PS (0.6 mg/kg) or human PS (0.6 mg/kg) alone. A control group with 20 animals where given vehicle only.

RESULTS: A trend to increased patency rates was noted in a group receiving one of the APC variants, but it did not reach statistical significance.

CONCLUSION: In conclusion, administration of human APC variants having enhanced anticoagulant efficacy together with human PS in a rat model of arterial thrombosis did not give an efficient antithrombotic effect. The lack of effect may be due to species-specific differences between the human protein C system and the rat hemostatic system.

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author
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published
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keywords
Journal Article
in
Thrombosis Journal
volume
6
publisher
BioMed Central
external identifiers
  • scopus:56649124873
ISSN
1477-9560
DOI
10.1186/1477-9560-6-16
language
English
LU publication?
yes
id
47c2ba35-04dd-465a-832b-ad6e0f40e6d0
date added to LUP
2017-02-27 10:36:15
date last changed
2017-03-05 04:41:19
@article{47c2ba35-04dd-465a-832b-ad6e0f40e6d0,
  abstract     = {<p>BACKGROUND: Activated protein C (APC) inhibits coagulation by degrading activated factor V (FVa) and factor VIII (FVIIIa), protein S (PS) functioning as a cofactor to APC.</p><p>METHODS: By mutagenesis of the vitamin K-dependent Gla domain of APC, we have recently created an APC variant having enhanced anticoagulant activity due to increased affinity for negatively charged phospholipid membranes. In the present study, the potential antithrombotic effects of this APC variant, and of a variant APC that is additionally mutated in the serine protease domain, have been evaluated in a blind randomized study in a rat model of arterial thrombosis. In this model, we have previously found the combination of bovine APC and PS to be highly antithrombotic. Four treatment groups each containing 10 rats were, in a blind random fashion, given intravenous bolus injections of wild-type or mutant variants of APC (0.8 mg/kg) together with human PS (0.6 mg/kg) or human PS (0.6 mg/kg) alone. A control group with 20 animals where given vehicle only.</p><p>RESULTS: A trend to increased patency rates was noted in a group receiving one of the APC variants, but it did not reach statistical significance.</p><p>CONCLUSION: In conclusion, administration of human APC variants having enhanced anticoagulant efficacy together with human PS in a rat model of arterial thrombosis did not give an efficient antithrombotic effect. The lack of effect may be due to species-specific differences between the human protein C system and the rat hemostatic system.</p>},
  articleno    = {16},
  author       = {Malm, Karl and Arnljots, Björn and Dahlbäck, Björn},
  issn         = {1477-9560},
  keyword      = {Journal Article},
  language     = {eng},
  month        = {10},
  publisher    = {BioMed Central},
  series       = {Thrombosis Journal},
  title        = {Human activated protein C variants in a rat model of arterial thrombosis},
  url          = {http://dx.doi.org/10.1186/1477-9560-6-16},
  volume       = {6},
  year         = {2008},
}