Blood substitutes: Haemoglobin therapeutics in clinical practice

A number of oxygen-carrying alternatives to blood have been in clinical evaluation since Amberson [1] administered haemoglobin-saline solutions in clinical trials. Fourteen patients received an injection of a haemoglobin-saline solution. Of these, five patients with secondary anaemia due to haemorrhage or infection received multiple injections, and three of these patients showed clinical improvement, consisting of increased haemoglobin and haematocrit values and reticulocytosis. The use of these early haemoglobin solutions had a number of drawbacks, however, including signs of renal impairment, resulting from short intravascular persistence and impurities of the haemoglobin introduced during preparation. The first generation of haemoglobin therapeutics has addressed the infectious disease risk, storage, stability and typing issues. These solutions have the potential to augment the oxygen-carrying capacity of patients' red blood cells temporarily and help avoid allogenic transfusion.Early approaches to the development of oxygen carriers involved the use of stroma-free haemoglobin solutions [2]. These solutions did not require blood typing or cross-matching and could be stored for long periods. It was discovered, however, that removal of haemoglobin from red cells leads to the loss of 2,3-diphosphoglycerate and diminished oxygen-delivery characteristics. Furthermore, haemoglobin tetramers tend to dissociate into dimers, which have a short intravascular persistence (due to rapid renal excretion) and a nephrotoxic action secondary to dimer precipitation in the proximal tubule [3]. Therefore, in recent years, a variety of methods have been developed to prevent these problems by chemically modifying and stabilizing the haemoglobin molecule. Several haemoglobin therapeutics are now in clinical trials as temporary alternatives to blood or as therapeutic agents for ischaemia. The various haemoglobin products under development are derived from three principal sources: human,