title: Probing the coagulation pathway with aptamers identifies combinations that synergistically inhibit blood clot formation.
abstract: Coordinated enzymatic reactions regulate blood clot generation. To explore the contributions of various coagulation enzymes in this process, we utilized a panel of aptamers against factors VIIa, IXa, Xa, and prothrombin. Each aptamer dose-dependently inhibited clot formation, yet none was able to completely impede this process in highly procoagulant settings. However, several combinations of two aptamers synergistically impaired clot formation. One extremely potent aptamer combination was able to maintain human blood fluidity even during extracorporeal circulation, a highly procoagulant setting encountered during cardiopulmonary bypass surgery. Moreover, this aptamer cocktail could be rapidly reversed with antidotes to restore normal hemostasis, indicating that even highly potent aptamer combinations can be rapidly controlled. These studies highlight the potential utility of using sets of aptamers to probe the functions of proteins in molecular pathways for research and therapeutic ends.
authors: Department of Surgery, Duke University Medical Center, DUMC 3704, Durham, North NC 27710, USA; University Program in Genetics and Genomics, Duke University Medical Center, DUMC Box 103855, Durham, NC 27710, USA.
authors: Kristin M
authors: KM
authors: Bompiani
authors: Department of Surgery, Duke University Medical Center, DUMC 3704, Durham, North NC 27710, USA.
authors: Jens L
authors: JL
authors: Lohrmann
authors: Department of Surgery, Duke University Medical Center, DUMC 3704, Durham, North NC 27710, USA.
authors: George A
authors: GA
authors: Pitoc
authors: Department of Surgery, Duke University Medical Center, DUMC 3704, Durham, North NC 27710, USA.
authors: James W
authors: JW
authors: Frederiksen
authors: Department of Anesthesiology-Cardiac Division, Duke University Medical Center, DUMC 3094, Durham, NC 27710, USA.
authors: George B
authors: GB
authors: Mackensen
authors: Department of Surgery, Duke University Medical Center, DUMC 3704, Durham, North NC 27710, USA. Electronic address: bruce.sullenger@duke.edu.
authors: Bruce A
authors: BA
authors: Sullenger
mesh_terms: D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D064368:Healthy Volunteers; D006801:Humans; D011516:Prothrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D052157:Aptamers, Nucleotide; D001779:Blood Coagulation Factors; D011516:Prothrombin