TY - JOUR
T1 - Pilot study of the efficacy of a thrombin inhibitor for use during cardiopulmonary bypass
AU - DeAnda, Abe
AU - Coutre, Steven E.
AU - Moon, Marc R.
AU - Vial, Conrad M.
AU - Griffin, Linda C.
AU - Law, Veronica S.
AU - Komeda, Masashi
AU - Leung, Lawrence L.K.
AU - Miller, D. Craig
N1 - Funding Information:
Supported by grants from the National Heart, Lung and Blood Institute (HL-29589), the Veterans Administration Medical Research Service, and Gilead Sciences, Foster City, CA. Doctors DeAnda, Moon, and Komeda are Carl and Leah McConnell Cardiovascular Surgical Research Fellows. Doctors Moon and DeAnda were also supported by NHLBI Individual National Research Service Awards HL-08532 and HL-08928, respectively.
PY - 1994/8
Y1 - 1994/8
N2 - 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. The calculated plasma aptamer elimination half-life increased from 1.9 minutes during baseline conditions to 7.7 minutes during total bypass, suggesting that the pulmonary vasculature plays a role in aptamer clearance. Importantly, the coagulation profile returned to normal levels within 5 minutes of halting aptamer infusion. There was no difference in platelet or fibrinogen consumption versus those of heparin. Postoperative bleeding (chest tube output) was minimal (95 to 150 mL over a 2-hour period), and serum chemistry profiles were normal. These preliminary pilot data indicate that this thrombin aptamer is both safe and, using conventional measures of anticoagulation, effective as an anticoagulant in this short-term canine CPB model, and that its pharmacokinetics are predictable. Furthermore, the pulmonary circulation appears to play a major role in the clearance of the aptamer.
AB - 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. The calculated plasma aptamer elimination half-life increased from 1.9 minutes during baseline conditions to 7.7 minutes during total bypass, suggesting that the pulmonary vasculature plays a role in aptamer clearance. Importantly, the coagulation profile returned to normal levels within 5 minutes of halting aptamer infusion. There was no difference in platelet or fibrinogen consumption versus those of heparin. Postoperative bleeding (chest tube output) was minimal (95 to 150 mL over a 2-hour period), and serum chemistry profiles were normal. These preliminary pilot data indicate that this thrombin aptamer is both safe and, using conventional measures of anticoagulation, effective as an anticoagulant in this short-term canine CPB model, and that its pharmacokinetics are predictable. Furthermore, the pulmonary circulation appears to play a major role in the clearance of the aptamer.
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U2 - 10.1016/0003-4975(94)92206-3
DO - 10.1016/0003-4975(94)92206-3
M3 - Article
C2 - 8067830
AN - SCOPUS:0027956461
SN - 0003-4975
VL - 58
SP - 344
EP - 350
JO - The Annals of Thoracic Surgery
JF - The Annals of Thoracic Surgery
IS - 2
ER -