Circulation and oxygenation of blood outside the body is commonly required during complex surgical interventions involving coronary pulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO). Both CPB and ECMO are life-supporting procedures utilizing a heart-lung machine, which subjects the blood to unphysiological conditions, potentially promoting undesirable blood coagulation. Traditionally, thrombotic complications from CPB and ECMO are resolved by heparin, an inexpensive broad spectrum anticoagulant that prevents blood clotting, but often results in bleeding. Despite hemostatic support therapy and constant monitoring, the lives of patients undergoing CPB and ECMO are often threatened by uncontrolled bleeding. There is an urgent need for novel strategies which provide safe anti-coagulation alternatives during CPB and ECMO procedures. Several non-traditional approaches, including nitric oxide donors as well as various protease and contact activation inhibitors, have been investigated and shown some success. More recently, Larsson et al. isolated a recombinant fully human (3F7) antibody inhibiting Factor XIIa. The antibody was shown to be both an efficacious and safe alternative to heparin. Below we will examine this study in more detail and offer considerations for translation of this novel concept to the clinic.