Antidote-controlled antithrombotic therapy targeting factor IXa and von Willebrand factor.
Thrombotic disorders and their common clinical phenotypes of acute myocardial infarction, ischemic stroke, and venous thromboembolism are the proximate cause of substantial morbidity, mortality, and health care expenditures worldwide. Accordingly, therapies designed to attenuate thrombus initiation and propagation, reflecting integrated platelet-mediated and coagulation protease-mediated events, respectively, represent a standard of care. Unfortunately, there are numerous inherent limitations of existing therapies that include target nonselectivity, variable onset and offset of pharmacodynamic effects, a narrow efficacy-safety profile, and the absence of a safe and reliable platform for either accurate titration, based on existing patient-specific, disease-specific, and clinical conditions, or active reversibility. Herein, we summarize our experience with oligonucleotide antithrombotic agents and their complementary antidotes, targeting the platelet adhesive protein von Willebrand factor and the pivotal coagulation protease factor IXa.
Division of Hematology , Duke University School of Medicine, Duke Clinical Research Institute, Biosignatures Program, Durham, North Carolina 27701, USA. richard.becker@duke.edu
Richard C
RC
Becker
Sabah
S
Oney
Kristian C D
KC
Becker
Bruce
B
Sullenger
D000931:Antidotes / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D001792:Blood Platelets / Q000378:metabolism; D015949:Factor IXa / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D009843:Oligoribonucleotides / Q000627:therapeutic use*; D052156:SELEX Aptamer Technique; D013927:Thrombosis / Q000628:therapy*; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors*
D000931:Antidotes; D052157:Aptamers, Nucleotide; D005343:Fibrinolytic Agents; D009843:Oligoribonucleotides; D014841:von Willebrand Factor; D015949:Factor IXa