Factor xi regulates pathological thrombus formation on acutely ruptured atherosclerotic plaques

  • Van Montfoort M
  • Kuijpers M
  • Knaup V
 et al. 
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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
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.

Author-supplied keywords

  • Atherosclerosis
  • Blood coagulation
  • Factor XI
  • Thrombosis

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Authors

  • Maurits L. Van Montfoort

  • Marijke J E Kuijpers

  • Véronique L. Knaup

  • Sanjay Bhanot

  • Brett P. Monia

  • Joris J T H Roelofs

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