Hemoglobin (Hb) is not solely a passive oxygen transporter but an active molecule with multiple homeostatic and also disease mediating activities. These activities become most apparent when red blood cells (RBC) burst and Hb is released into the circulation. More intensively investigated examples of the non-O2 ligand binding and enzymatic functions of Hb are the avid interaction with nitric oxide (NO) which results in reduced bioavailabilty of this central vasodilator or Hb’s reaction with physiologic oxidants resulting in the generation of oxygen free radicals and accumulation of toxic heme-, protein- and lipid-peroxidation products. Clinical situations likely related to these non-oxygen binding adverse activities of Hb involve vascular complications of hemolytic anemias (i.e. the acute chest syndrome, stroke and pulmonary arterial hypertension in sickle cell disease or related hemolytic anemias). More recently, the evolution of cerebral malaria - one of the most severe complications of plasmodium infection - was causally linked to intravascular free Hb release and heme toxicity.
A unique situation faced to unresolved issues of Hb toxicity involves the administration of artificial oxygen carriers (HBOCs). The rational for HBOCs is found in the unparalleled oxygen transport properties of chemically modified Hb molecules and if once established as save and effective therapeutics HBOCs will serve an unmet need for an oxygen transport agent with immediate and unrestricted availability. Primary fields of potential applications of these therapeutics are severe bleeding when allogenic RBC transfusion is not available or the supplementation of tissue oxygenation during local ischemia (i.e. stroke, myocardial infarction, critical limb ischemia). The current generation of HBOCs is based on the concept that chemical modification of Hb can optimize circulating half live while maintaining the unique O2-binding and transport properties of Hb. Some of these therapeutics have been intensively investigated in large clinical trials. However, although some products might be fairly effective in terms of oxygen transport, overt toxicity directly related to the physiologic adverse effects of cell free Hb preclude their further clinical application. Therefore, reliable strategies to alleviate Hb associated toxicities are needed to revitalize this economically promising field of transfusion medicine.
Physiologic Hb scavenger and detoxification pathways have evolved to clear and detoxifying cell free Hb within the circulation and in Hb exposed tissues. However, it only recently became apparent that these endogenous mechanisms are also highly effective in countering exactly those side effects of free Hb which are also responsible for the complications of hemolysis, cerebral malaria and the failure of current generation HBOCs. It seems thus to be a logic and reasonable approach to explore supplementation of the endogenous Hb scavenger pathways as a novel and global strategy to resolve Hb toxicity in hemolytic diseases and to implement these pathways into a new paradigm for the design of oxygen therapeutics.