title: Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates.
abstract: OBJECTIVE
  During coagulation, factor IX (FIX) is activated by 2 distinct mechanisms mediated by the active proteases of either FVIIa or FXIa. Both coagulation factors may contribute to thrombosis; FXI, however, plays only a limited role in the arrest of bleeding. Therefore, therapeutic targeting of FXI may produce an antithrombotic effect with relatively low hemostatic risk.
  
  
  RESULTS
  We have reported that reducing FXI levels with FXI antisense oligonucleotides produces antithrombotic activity in mice, and that administration of FXI antisense oligonucleotides to primates decreases circulating FXI levels and activity in a dose-dependent and time-dependent manner. Here, we evaluated the relationship between FXI plasma levels and thrombogenicity in an established baboon model of thrombosis and hemostasis. In previous studies with this model, antibody-induced inhibition of FXI produced potent antithrombotic effects. In the present article, antisense oligonucleotides-mediated reduction of FXI plasma levels by ≥ 50% resulted in a demonstrable and sustained antithrombotic effect without an increased risk of bleeding.
  
  
  CONCLUSIONS
  These results indicate that reducing FXI levels using antisense oligonucleotides is a promising alternative to direct FXI inhibition, and that targeting FXI may be potentially safer than conventional antithrombotic therapies that can markedly impair primary hemostasis.
authors.affiliation: Department of Antisense Drug Discovery, ISIS Pharmaceuticals, Inc, Carlsbad, CA, USA. jcrosby@isisph.com
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Crosby
authors.forename: Ulla
authors.initials: U
authors.lastname: Marzec
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Revenko
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhao
authors.forename: Dacao
authors.initials: D
authors.lastname: Gao
authors.forename: Anton
authors.initials: A
authors.lastname: Matafonov
authors.forename: David
authors.initials: D
authors.lastname: Gailani
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
authors.forename: Erik I
authors.initials: EI
authors.lastname: Tucker
authors.forename: Andras
authors.initials: A
authors.lastname: Gruber
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hanson
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001166:Arteriovenous Shunt, Surgical; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D003094:Collagen; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005172:Factor XI / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000633:toxicity; D006470:Hemorrhage / Q000139:chemically induced; D008252:Macaca fascicularis; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000633:toxicity; D010215:Papio; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D016376:Oligonucleotides, Antisense; D003094:Collagen; D005172:Factor XI; D013917:Thrombin
keywords: antisense oligonucleotide; factor XI; platelets; thrombus formation; vascular graft
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