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Inhibition of coagulation by a phosphorothioate oligonucleotide
S P Henry1, W Novotny, J Leeds
1Department of Toxicology, Isis Pharmaceuticals, Inc., Carlsbad, CA 92008, USA.
Antisense & Nucleic Acid Drug Development
|November 15, 1997
Summary
Phosphorothioate oligodeoxynucleotides can transiently prolong clotting times. This effect, observed with ISIS 2302 in monkeys, involves the intrinsic pathway and is dose-dependent, controllable by managing plasma concentrations.
Area of Science:
- Pharmacology
- Biochemistry
- Antisense Therapeutics
Background:
- Phosphorothioate oligodeoxynucleotides (oligos) exhibit hybridization-independent effects.
- Transient prolongation of clotting times is a known effect of high-dose oligos.
Purpose of the Study:
- To characterize the time course of activated partial thromboplastin time (APTT) and plasma oligo concentrations after ISIS 2302 infusion.
- To investigate the in vitro mechanism of clotting time inhibition by ISIS 2302.
Main Methods:
- Intravenous infusion of ISIS 2302 in cynomolgus monkeys.
- In vitro addition of ISIS 2302 to citrated blood.
- Assays for APTT, plasma oligo concentrations, and clotting factor activity.
Main Results:
- ISIS 2302 transiently prolonged APTT, correlating with plasma oligo levels.
- The intrinsic clotting pathway (APTT) was more sensitive to inhibition than the extrinsic pathway (PT).
- Oligos with phosphodiester or 2'-propoxy linkages showed less inhibition; mechanism differed from heparin.
Conclusions:
- Clotting time prolongation by ISIS 2302 is transient, dose-dependent, and linked to plasma concentrations.
- The inhibition mechanism may involve selective targeting of intrinsic and common clotting pathways, potentially via fibrinogen interaction.
- Managing peak plasma oligo levels can control the extent of APTT prolongation.