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Thromb Haemost 2000; 84(05): 841-848
DOI: 10.1055/s-0037-1614126
Review Article
Schattauer GmbH

Blocking the Initiation of Coagulation by RNA Aptamers to Factor VIIa

Christopher P. Rusconi   *
1   From the Department of Surgery and Genetics, Duke University Medical Center, Durham, N. C., USA
1   From the Department of Surgery and Genetics, Duke University Medical Center, Durham, N. C., USA
,
Alice Yeh   *   *
1   From the Department of Surgery and Genetics, Duke University Medical Center, Durham, N. C., USA
1   From the Department of Surgery and Genetics, Duke University Medical Center, Durham, N. C., USA
,
H. Kim Lyerly
1   From the Department of Surgery and Genetics, Duke University Medical Center, Durham, N. C., USA
1   From the Department of Surgery and Genetics, Duke University Medical Center, Durham, N. C., USA
,
Jeffrey H. Lawson
1   From the Department of Surgery and Genetics, Duke University Medical Center, Durham, N. C., USA
1   From the Department of Surgery and Genetics, Duke University Medical Center, Durham, N. C., USA
,
Bruce A. Sullenger
1   From the Department of Surgery and Genetics, Duke University Medical Center, Durham, N. C., USA
1   From the Department of Surgery and Genetics, Duke University Medical Center, Durham, N. C., USA
2   From the Department of Center for Genetic and Cellular Therapies, Duke University Medical Center, Durham, N. C., USA
› Author AffiliationsWe thank J. Jones and S. Daubendiek for helpful discussion, and the Duke Clinical Coagulation Lab, especially T. Ortel, A. Joyner and L. Estrada for their time, technical assistance and use of equipment and reagents. C.P.R. is a Fellow of the Jane Coffin Childs Memorial Fund for Medical Research. A. Y. was supported by a Claude E. Welch fellowship sponsored through the Department of Surgery at the Massachusetts General Hospital. J.H.L is a supported by a Clinician Scientist Award from the American Heart Association.
Further Information

Publication History

Received 17 February 2000

Accepted after revision 31 May 2000

Publication Date:
13 December 2017 (online)

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Summary

The tissue factor/factor VIIa complex is thought to be the primary initiator of most physiologic blood coagulation events. Because of its proximal role in this process, we sought to generate new inhibitors of tissue factor/factor VIIa activity by targeting factor VIIa. We employed a combinatorial RNA library and in vitro selection methods to isolate a high affinity, nuclease-resistant RNA ligand that binds specifically to coagulation factor VII/VIIa. This RNA inhibits the tissue factordependent activation of factor X by factor VIIa. Kinetic analyses of the mechanism of action of this RNA suggest that it antagonizes factor VIIa activity by preventing formation of a functional factor VII/tissue factor complex. Furthermore, this RNA significantly prolongs the prothrombin time of human plasma in a dose dependent manner, and has an in vitro half-life of ∼15 h in human plasma. Thus, this RNA ligand represents a novel class of anticoagulant agents directed against factor VIIa.

Key words

Factor VIIa - aptamer - FVIIa inhibitors - in vitro selection - thrombosis

* C. P. R. and A. Y. contributed equally to this work


* Present address: Dr. A. Yeh, Department of Surgery, Massachusetts General Hospital, Boston, MA 02115, USA


 

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