Artificial Oxygen Carriers: Hemoglobin-Based Oxygen Carriers – Current Status 2004

Abstract

Because of an impending shortfall of allogeneic blood products within the next decades and ongoing problems associated with relevant costs for testing and storage of banked red blood cell (RBC) units, the development of alternatives has been intensified during the last 15 years. Modern chemically modified hemoglobin- based oxygen carriers (HBOC) are free of RBC membrane remnants, renal toxicity, and ABO antigens which allows transfusion without knowledge of the respective blood group of a patient. Bovine polymerized cell-free hemoglobin can be stored at room temperature for 3 years. In contrast to the perfluorocarbon solutions, HBOC can be applied at room air oxygen concentrations. Animal experiments have shown that HBOC can compensate for intravascular volume deficits in hemorrhagic shock, including restoration of colloid osmotic pressure and organ perfusion, and deliver oxygen to organs and tissues during nearly complete blood exchange. Chemical modifications of HBOC are able to reduce the vasoconstrictive side effect of HBOC which is caused by NO scavenging. In spite of vasoconstriction, the increased oxygen extraction in presence of HBOC in combination with the plasmatic oxygen transport provides enhanced tissue oxygenation even in post-stenotic tissues. HBOC seem to improve the diffusive oxygen transport at the microcirculatory site, thus decreasing tissue damage in acute pancreatitis and tissue injury in the heart and brain after ischemia/reperfusion. Clinical studies showed that the perioperative use of different HBOC (Hemopure®, PolyHeme®, Hemolink®, HemAssist®) can reduce the number of allogeneic RBC units and increase the avoidance rate of allogeneic transfusion in emergency bleeding as well as in vascular, cardiac and noncardiac surgery. Polymerized HBOC appear to have a lower potential of side effects in comparison to intramolecularly crosslinked preparations. However, HBOC-201 (Hemopure) is the only substance which has been licensed for the treatment of patients until now.

Protein–protein coupling and its application to functional red cell substitutes

“…It was clear that serious side effects in the clinical trials resulted from administration of the added HBOC and not from their breakdown products. 59,60 During the course of the studies on HBOCs, the importance of nitric oxide as a signaling species for vasodilation became widely recognized and the effects of hemoglobin on nitric oxide concentration became a serious concern. [61][62][63] It is well-known that hemoglobin has a high affinity for nitric oxide and that it can displace oxygen from its heme binding site.…”

Mass Spectrometry in the Study of Hemoglobin: from Covalent Structure to Higher Order Assembly

“…They can also be produced recombinantly in yeast, tobacco plants or from different animal species. Some HBOCs are chemically modified hemoglobins, in which the Hb intravascular halflife has been prolonged by intramolecular crosslinking [124][125][126], by the conjugation of macromolecules such as polyethylene glycol to the Hb tetramer [127], or by inter-molecular cross-linking to produce a polymerized hemoglobin solution [128,129].…”

Immune recognition of exposed xenoantigens on the surface of PEGylated bovine red blood cells

“…HBOCs possess several disadvantages, which has sparked a movement to investigate modifications of the intact RBC by conjugating methoxypolyethylene glycol (mPEG) to the surface of human RBCs (Bradley et al, 2002;Davey, 2004;Garratty, 2004;Nacharaju et al, 2005;Tan et al, 2006). Although transfusion of mPEG-hRBCs may decrease the probability of an adverse immunological reaction, it is still reliant on human blood donors, which are already in low supply (Riess, 2001;Standl, 2004;Stollings and Oyen, 2006).…”