Abstract 633: Aptamer to Factor IXa and Matched Antidote improve Cardiac Function after Cardiopulmonary Bypass in Rats; an Alternative to Heparin and Protamine
To date, heparin is the standard anticoagulant during cardiopulmonary bypass (CPB) for cardiac surgery, largely because protamine can be used to reverse its activity. Unfortunately, this anticoagulant-antidote pair is associated with immunologic reactions precipitating thromboembolic complications and hemodynamic changes, all resulting in increased perioperative morbidity and mortality. The search for a safe and specific anticoagulant-antidote pair without these side effects continues. Previously, we have described an RNA ligand, 9.3tC that specifically inhibited Factor IXa in-vitro and a second RNA molecule, 5–2 that reversed the activity of the 9.3tC molecule. We hypothesized that the immunologic profile and hemodynamic effects of this aptamer-antidote pair in the setting of CPB might be favorable compared to heparin and protamine. Using a previously described rat CPB model, twenty-four rats were anticoagulated and subjected to 60 minutes of CPB, followed by reversal of the drug by its antidote and subsequent monitoring for 3 hr. Rats (n=12 per group) received either heparin (600IU/kg) and protamine (1.25 mg/100IU) or aptamer 10 μg/kg and 50 μg/kg antidote. Coagulation assays and IL (IL-1β, IL-6, IL-10 and TNF-α) levels were determined throughout the procedure. Global left ventricular performance was assessed echocardiographically at 3 hr post CPB. Using the transthoracic midpapillary short-axis view the shortening fraction was calculated based on three different loops using the following equation: enddiastolic diameter (EDD) minus endsystolic diameter (ESD) divided by EDD, times100. Both anticoagulation protocols allowed for sufficient anticoagulation during CPB and reversal afterwards with no noticeable thrombus formation in the CPB circuit. There were no differences in levels of inflammatory markers between the two treatment groups. Shortening fraction was 42 ± 8 % in the heparin-protamine group and 60 ± 16 % (p = 0.01) in the aptamere group. We conclude that anticoagulation for experimental CPB surgery with aptamer 9.3tC and reversal with its antidote is feasible and results in improved cardiac performance when compared to conventional heparin and protamine administration.