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This prospective randomized study compares full and reduced heparinization on novel hyaluronan-based heparin-bonded circuits vs. uncoated controls under challenging clinical setting including biomaterial evaluation.100 patients undergoing reoperation for coronary artery bypass grafting were allocated into two equal groups (n = 50): Group one was treated with hyaluronan-based heparin bonded preconnected circuits (Vision HFOGBS, Gish, California, USA) and Group two with identical uncoated controls (Vision HFO, Gish, USA). In the study group, half of the patients (n = 25) received low-systemic heparin (125 IU/kg, ACT >250 s) or full dose like control group. Blood samples were collected after induction of anesthesia (T1) and heparin administration before cardiopulmonary bypass (CPB) (T2), 15 min after initiation of CPB (T3), before cessation of CPB (T4), 15 min after reversal with protamine (T5), and the first postoperative day at 08: 00 h (T6).Platelet counts were preserved significantly better at T5, T6 in hyaluronan groups (P < 0.05 vs. control). Serum IL-2 levels were significantly lower at T4, T5 in both hyaluronan groups and C3a levels at T4 and T5 only in low-dose group (P < 0.05). Troponin-T levels in coronary sinus blood demonstrated well preserved myocardium in hyaluronan groups. No significant differences in thrombin–antithrombin levels were observed between full and low-dose heparin groups at any time point. Amount of desorbed protein was 1.41 ± 0.01 in full and 1.43 ± 0.01 in low dose vs. 1.78 ± 0.01 mg/dl in control (P < 0.05).Hyaluronan-based heparin-bonded circuits provided better clinical outcome and less inflammatory response compared with uncoated surfaces. Reduced systemic heparinization combined with hyaluronan-based heparin-bonded circuits is feasible and clinically well tolerated.