Manuscript handled by: R. Camire
Inhibiting the intrinsic pathway of coagulation with a factor XII–targeting RNA aptamer
Article first published online: 15 JUL 2013
© 2013 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 11, Issue 7, pages 1364–1373, July 2013
How to Cite
Inhibiting the intrinsic pathway of coagulation with a factor XII–targeting RNA aptamer. J Thromb Haemost 2013; 11: 1364–73., , , , , .
Final decision: P. H. Reitsma, 14 May 2013
- Issue published online: 15 JUL 2013
- Article first published online: 15 JUL 2013
- Accepted manuscript online: 21 MAY 2013 09:35AM EST
- Manuscript Received: 22 FEB 2013
- National Institutes of H. Grant Number: RO1HL65222
- anticoagulant agents;
- blood coagulation;
- factor XII;
- factor XIIa;
- RNA aptamers
Exposure of the plasma protein factor XII (FXII) to an anionic surface generates activated FXII that not only triggers the intrinsic pathway of blood coagulation through the activation of FXI but also mediates various vascular responses through activation of the plasma contact system. While deficiencies of FXII are not associated with excessive bleeding, thrombosis models in factor-deficient animals have suggested that this protein contributes to stable thrombus formation. Therefore, FXII has emerged as an attractive therapeutic target to treat or prevent pathological thrombosis formation without increasing the risk for hemorrhage.
Using an in vitro directed evolution and chemical biology approach, we sought to isolate a nuclease-resistant RNA aptamer that binds specifically to FXII and directly inhibits FXII coagulant function.
Methods and Results
We describe the isolation and characterization of a high-affinity RNA aptamer targeting FXII/activated FXII (FXIIa) that dose dependently prolongs fibrin clot formation and thrombin generation in clinical coagulation assays. This aptamer functions as a potent anticoagulant by inhibiting the autoactivation of FXII, as well as inhibiting intrinsic pathway activation (FXI activation). However, the aptamer does not affect the FXIIa-mediated activation of the proinflammatory kallikrein-kinin system (plasma kallikrein activation).
We have generated a specific and potent FXII/FXIIa aptamer anticoagulant that offers targeted inhibition of discrete macromolecular interactions involved in the activation of the intrinsic pathway of blood coagulation.