In addition, these protamine/heparin antibodies cross react with protamine-containing insulin preparations [111]. Development of these antibodies predisposes to adverse outcomes after cardiac procedures and may pose risks of anamnestic response on reexposure to protamine [111, 112]. For example, a meta-analysis of the surgical litera- ture showed the risk of a protamine reaction in surgical patients to be 10 to 20 times higher for patients taking protamine-containing insulin compared with control pa- tients not taking insulin preparations [107, 113]. Alternate Agents Used to Reverse Heparin Anticoagulation Reversal of heparin with protamine affects platelet ag- gregation and whole blood clotting [94]. The over- whelming convenience of protamine reversal of heparin makes it the drug of choice for heparin neutralization despite potential adverse effects on platelet and clotting function. There are patients who are unable to receive protamine for various reasons. For this reason, PF4 has been investigated as a heparin reversal agent in ex vivo animal studies and occasional case reports [114 116]. The PF4 is released by activated platelets and has strong 658 Ann Thorac Surg ANTICOAGULATION DURING CARDIOPULMONARY BYPASS 2018;105:650 62 REPORT attraction for heparin. Studies show that recombinant PF4 provides adequate heparin neutralization. However, preformed antibodies against the PF4-heparin complex are important contributors to the pathophysiology of HIT. Patients previously exposed to heparin may have these preformed antibodies, and the addition of exogenous PF4 in the presence of heparin risks an anamnestic response and severe HIT or HIT with thrombosis. More clinical experience is required to validate the safety of PF4 for heparin reversal after CPB [116]. Reports document attempts at using other drugs for heparin neutralization. Methylene blue, hexadimethrine, vancomycin, and heparinase I are among drugs tested for heparin neutralization [115, 117, 118]. 