Two studies provide convincing evi- dence that when the ratio of protamine to heparin (protamine mg per 100 units heparin) is above 5:1, platelet aggregation and function are impaired [94, 95]. In addi- tion, Mochizuki and associates [94] demonstrated that at ratios above 2.6:1, the ACT signi cantly increases. The European Association of Cardiothoracic Surgery identi- ed a ratio of 2.6:1 of protamine to heparin as risking excessive bleeding. Their guidelines recommend limiting protamine, preferably using a titration method, after the completion of CPB [96]. Ann Thorac Surg 2018;105:650 62 ANTICOAGULATION DURING CARDIOPULMONARY BYPASS REPORT Class IIb Recommendation  Heparin rebound: Because of the risk of heparin rebound in patients requiring high doses of heparin and with prolonged CPB times, low-dose protamine infusion (25 mg/h) for as long as 6 hours after the end of CPB may be considered as part of a multi- modality blood conservation program. (Level of Ev- idence C) Heparin rebound occurs when detectable heparin blood levels are present at some remote time after apparently adequate heparin reversal with protamine. That likely occurs because of the ability of large molecules of heparin to sequester in fat stores and plasma proteins, with eventual reappearance in the blood at some time after protamine neutralization. Heparin dosing in excess of 400 IU/kg can result in heparin rebound. High heparin dosing during CPB results in higher doses of protamine required for reversal. Randomized comparisons of high-dose and low-dose heparin for CPB suggest that heparin rebound increases with high-dose heparin [21]. One study suggests that 10% to 15% of patients receiving usual heparin doses for CPB will have detectable heparin levels 2 hours after prot- amine reversal [97]. 