PILOT-STUDY OF THE EFFICACY OF A THROMBIN INHIBITOR FOR USE DURING CARDIOPULMONARY BYPASS

Heparin is normally used for anticoagulation during cardiopulmonary by pass (CPB), but its use is contraindicated in patients with a history of heparin-induced thrombocytopenia, heparin-provoked thrombosis, or b oth. Heparin therapy can also be ineffective due to heparin resistance . A short-acting, oligonucleotide-based thrombin inhibitor (thrombin a ptamer) may potentially serve as a substitute for heparin in these and other clinical situations. We tested a novel thrombin aptamer in a ca nine CPB pilot study to determine its anticoagulant efficacy, the resu ltant changes in coagulation variables, and the aptamers clearance mec hanisms 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 char acterize the baseline coagulation status), with partial CPB and hemodi lution, during 60 minutes of total CPB, and, finally, after a 2-hour r ecovery period. At a 0.5 mg.kg(-1).min(-1) dose, the activated clottin g time rose with aptamer infusion from 106 +/- 12 seconds to 187 +/- 8 seconds (+/- 1 standard deviation) (p = 0.014), increased further wit h hemodilution (to 259 +/- 41 seconds; p = 0.017), and was even more p rolonged during total CPB (> 1,500 seconds; p < 0.001). This later inc rease in the activated clotting time paralleled a rise in the plasma c oncentration of the thrombin aptamer during total CPB, as determined b y high-performance liquid chromatography. The calculated plasma aptame r elimination half-life increased from 1.9 minutes during baseline con ditions to 7.7 minutes during total bypass, suggesting that the pulmon ary vasculature plays a role in aptamer clearance. Importantly, the co agulation profile returned to normal levels within 5 minutes of haltin g aptamer infusion. There was no difference in platelet or fibrinogen consumption versus those of heparin. Postoperative bleeding (chest tub e output) was minimal (95 to 150 mL over a 2-hour period), and serum c hemistry profiles were normal. These preliminary pilot data indicate t hat this thrombin aptamer is both safe and, using conventional measure s of anticoagulation, effective as an anticoagulant in this short-term canine CPB model, and that its pharmacokinetics are predictable. Furt hermore, the pulmonary circulation appears to play a major role in the clearance of the aptamer.