Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits.

Abstract

Central venous catheter thrombosis can cause venous obstruction and pulmonary embolism. To determine the extent to which catheter thrombosis is triggered by the contact or extrinsic pathway of coagulation, we used antisense oligonucleotides (ASOs) to selectively knock down factor (f)XII, fXI, or high-molecular-weight kininogen (HK), key components of the contact pathway, or fVII, which is essential for the extrinsic pathway. Knockdown of contact pathway components prolonged the activated partial thromboplastin time and decreased target protein activity levels by over 90%, whereas fVII knockdown prolonged the prothrombin time and reduced fVII activity to a similar extent. Using a rabbit model of catheter thrombosis, catheters implanted in the jugular vein were assessed daily until they occluded, up to a maximum of 35 days. Compared with control, fXII and fXI ASO treatment prolonged the time to catheter occlusion by 2.2- and 2.3-fold, respectively. In contrast, both HK and fVII knockdown did not significantly prolong the time to occlusion, and dual treatment with fVII- and fXI-directed ASOs produced a time to occlusion similar to that with the fXI ASO alone. These findings suggest that catheter thrombosis is triggered via the contact pathway and identify fXII and fXI as potential targets to attenuate this complication.

• Authors: Jonathan W Yau, Peng Liao, James C Fredenburgh, Alan R Stafford, Alexey S Revenko, Brett P Monia, Jeffrey I Weitz
• Journal: Blood (Blood) Vol. 123 Issue 13 Pg. 2102-7 (Mar 27 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24501216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Oligonucleotides, Antisense
• Factor XII
• Factor XI

Topics

• Animals
• Catheter Obstruction
• Catheters (adverse effects)
• Disease Models, Animal
• Factor XI (antagonists & inhibitors, genetics)
• Factor XII (antagonists & inhibitors, genetics)
• Gene Expression Regulation (drug effects)
• Genetic Therapy (methods)
• Male
• Oligonucleotides, Antisense (pharmacology)
• RNA Interference (physiology)
• Rabbits
• Substrate Specificity (drug effects, genetics)
• Thrombosis (genetics, prevention & control)