Extracorporeal membrane oxygenation (ECMO) circuits have undergone numerous modifications pertinent to their clinical environment and tasks over time; however, identical anticoagulation strategies have remained. Unfractionated heparin (UFH) is the default anticoagulant for ECMO. Detected in 1916 and made available as a purified substance for human application in the 1930s, UFH is one of the oldest drugs still in use. To reduce the morbidity associated with circuit clotting and subsequent patient coagulopathy, the current institution has routinely been using nitric oxide (NO), which can be safely delivered through the sweep gas to the oxygenator of an ECMO circuit in conjunction with prostacyclin. By preventing platelet adhesion to artificial surfaces, mitigating the systemic inflammatory response and protection against ischaemia–reperfusion injury it may improve oxygen delivery to hypoxic tissue. Bivalirudin, a direct thrombin inhibitor, has also been used to remove or significantly reduce the use of UFH.