Cardiopulmonary bypass (CPB) elicits derangements to the formed elements of blood because of the physical stresses of extracorporeal flow. Methods of reducing the impact of CPB include circuit surface modification and pharmacological supplementation. The purpose of this study was to examine the effects of aprotinin in combination with surface modification during simulated CPB. Fresh whole bovine blood was used to prime standard CPB circuits divided into four groups (N = 3): control (CTR), aprotinin 300 KIU/mL (APR), Poly (2-methoxyethylacrylate) coating (PMEA), and APR with PMEA (APR–PMEA). Physical stresses included venous reservoir negative pressure (−85 mmHg), arterial line pressure of 150 mmHg at 5 LPM, and air–blood interface, applied over a 90-minute period. Samples were drawn at the following times: 0, 10, 45, and 90 minutes. Endpoints included platelet count (PLT), plasma-free hemoglobin (PFHb), and thromboelastography (TEG). PLT did not change (138.9 ± 15.0 vs. 102.9 ± 21.0, p = ns) throughout the 90-minute experimental periods in any group. PFHb increased significantly (mean of 19- fold) throughout the experiment, but was not affected by any treatment. The TEG index declined in the CTR (3.6 ± 0.4 vs. −16.2 ± 2.9, p < .0003), PMEA (5.9 ± 0.8 vs. −2.7 ± 3.8, p < .02), and APR–PMEA (4.6 ± 1.0 vs. −2.8 ± 0.3 p < .0003) groups, but not in the APR group (3.6 ± 2.2 vs. −1.3 ± 3.3 p = .10). In conclusion, neither APR nor PMEA had an effect on either red cell hemolysis or PLT, but APR treatment alone significantly attenuated the derangements in coagulation induced in this extracorporeal model.