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. 2014 Aug;34(8):1668-73.
doi: 10.1161/ATVBAHA.114.303209. Epub 2014 Jun 19.

Factor XI regulates pathological thrombus formation on acutely ruptured atherosclerotic plaques

Maurits L van Montfoort  1 , Marijke J E Kuijpers  1 , Véronique L Knaup  1 , Sanjay Bhanot  1 , Brett P Monia  1 , Joris J T H Roelofs  1 , Johan W M Heemskerk  1 , Joost C M Meijers  2
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Factor XI regulates pathological thrombus formation on acutely ruptured atherosclerotic plaques

Maurits L van Montfoort et al. Arterioscler Thromb Vasc Biol. 2014 Aug.

Abstract

Objective: Coagulation factor XI is proposed as therapeutic target for anticoagulation. However, it is still unclear whether the antithrombotic properties of factor XI inhibitors influence atherosclerotic disease and atherothrombosis. Our aim is to investigate whether factor XI antisense oligonucleotides could prevent thrombus formation on acutely ruptured atherosclerotic plaques.

Approach and results: Atherosclerotic plaques in the carotid arteries of Apoe(-/-) mice were acutely ruptured using ultrasound. The subsequent thrombus formation was visualized and quantified by intravital microscopy and immunohistochemistry. Mice were pretreated with either factor XI antisense or nonsense oligonucleotides (50 mg/kg) to lower factor XI plasma levels. A tail bleeding assay was used to determine the safety. On plaque rupture, initial platelet adhesion and platelet plug formation were not impaired in animals treated with factor XI antisense oligonucleotides. However, the ensuing thrombus formation and fibrin deposition were significantly lower after 5 to 10 minutes (P<0.05) in factor XI antisense oligonucleotide-treated animals without inducing a bleeding tendency. Furthermore, thrombi from antisense-treated animals were less stable than thrombi from placebo-treated animals. Moreover, macrophage infiltration and collagen deposition were lower in the carotid arteries of factor XI antisense-treated animals. No neutrophils were present.

Conclusions: Factor XI antisense oligonucleotides safely prevent thrombus formation on acutely ruptured atherosclerotic plaques in mice. Furthermore, perturbed carotid arteries from factor XI antisense-treated animals show a less severe inflammatory response.

Keywords: atherosclerosis; blood coagulation; factor XI; thrombosis.

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Comment in

  • New targets for atherothrombosis.
    Mackman N. Mackman N. Arterioscler Thromb Vasc Biol. 2014 Aug;34(8):1607-8. doi: 10.1161/ATVBAHA.114.304005. Arterioscler Thromb Vasc Biol. 2014. PMID: 25031326 Free PMC article. No abstract available.

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