title: Pilot study of the efficacy of a thrombin inhibitor for use during cardiopulmonary bypass.
abstract: Heparin is normally used for anticoagulation during cardiopulmonary bypass (CPB), but its use is contraindicated in patients with a history of heparin-induced thrombocytopenia, heparin-provoked thrombosis, or both. Heparin therapy can also be ineffective due to heparin resistance. A short-acting, oligonucleotide-based thrombin inhibitor (thrombin aptamer) may potentially serve as a substitute for heparin in these and other clinical situations. We tested a novel thrombin aptamer in a canine CPB pilot study to determine its anticoagulant efficacy, the resultant changes in coagulation variables, and the aptamer's clearance mechanisms and pharmacokinetics. Seven dogs were studied initially: Four received varied doses of the aptamer (to establish the pharmacokinetic profile) and 3 received heparin. Subsequently, 4 other dogs underwent CPB, receiving a constant infusion of the aptamer before CPB (to characterize the baseline coagulation status), with partial CPB and hemodilution, during 60 minutes of total CPB, and, finally, after a 2-hour recovery period. At a 0.5 mg.kg-1.min-1 dose, the activated clotting time rose with aptamer infusion from 106 +/- 12 seconds to 187 +/- 8 seconds (+/- 1 standard deviation) (p = 0.014), increased further with hemodilution (to 259 +/- 41 seconds; p = 0.017), and was even more prolonged during total CPB (> 1,500 seconds; p < 0.001). This later increase in the activated clotting time paralleled a rise in the plasma concentration of the thrombin aptamer during total CPB, as determined by high-performance liquid chromatography.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Cardiovascular and Thoracic Surgery, Standford University School of Medicine, CA 94305-5247.
authors.forename: A
authors.initials: A
authors.lastname: DeAnda
authors.forename: S E
authors.initials: SE
authors.lastname: Coutre
authors.forename: M R
authors.initials: MR
authors.lastname: Moon
authors.forename: C M
authors.initials: CM
authors.lastname: Vial
authors.forename: L C
authors.initials: LC
authors.lastname: Griffin
authors.forename: V S
authors.initials: VS
authors.lastname: Law
authors.forename: M
authors.initials: M
authors.lastname: Komeda
authors.forename: L L
authors.initials: LL
authors.lastname: Leung
authors.forename: D C
authors.initials: DC
authors.lastname: Miller
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide; D001777:Blood Coagulation; D002315:Cardiopulmonary Bypass; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000008:administration & dosage; D007262:Infusions, Intravenous; D009841:Oligonucleotides; D010865:Pilot Projects; D011119:Polynucleotides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011517:Prothrombin Time; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D052157:Aptamers, Nucleotide; D009841:Oligonucleotides; D011119:Polynucleotides; C081676:thrombin aptamer; D006493:Heparin; D013917:Thrombin