Abstract
Intense efforts have been made by both industry and academia over the last three decades to produce viable hemoglobin (Hb)-based oxygen carriers (HBOCs), also known as “blood substitutes”. Human trials conducted so far by several manufactures in a variety of clinical indications, including trauma, and elective surgeries have failed and no product has gained the Food and Drug Administration approval for human use. Safety concerns due to frequent incidences of hemodynamic, cardiac events, and even death led to the termination of some of these trials. Several second generation HBOC products that have been chemically and/or genetically modified (or in some cases ligated with carbon monoxide (CO)) found a new clinical application in conditions as complex as sickle cell disease (SCD). By virtue of higher oxygen affinity (P50) (R-state), and smaller size, HBOCs may be able to reach the microvasculature unload of oxygen to reverse the cycles of sickling/unsickling of the deoxy-sickle cell Hb (HbS) (T-state), thus preventing vaso-occlusion, a central event in SCD pathophysiology. However, biochemically, it is thought that outside the red blood cell (due to frequent hemolysis), free HbS or infused HBOCs are capable of interfering with a number of oxidative and signaling pathways and may, thus, negate any benefit that HBOCs may provide. This review discusses the advantages and disadvantages of using HBOCs in SCD.
Highlights
Growing interest in the production of artificial blood over the last three decades has resulted in several products that would have revolutionized the practice of blood transfusion
Changes introduced onto the hemoglobin (Hb) molecule by chemical or genetic modifications presented considerable barriers to the full understanding of how these molecules operate in a cell-free environment
We have recently shown that free HbS is prone to oxidative changes in presence of oxidants such as peroxide (H2 O2 ) and that Hb becomes more damaging to itself but to other biological molecules and organelles such as the mitochondria
Summary
Growing interest in the production of artificial blood over the last three decades has resulted in several products that would have revolutionized the practice of blood transfusion. Blood transfusion in the United States is considered a safe practice, concerns regarding the acquired immune deficiency syndrome epidemic and human immunodeficiency virus contaminated blood (or other infectious agents) have stimulated both industry, as well as the military in developing products as alternatives to blood donation [2,3] The development of these products has stalled because of problems with their safety and efficacy. Three major biochemical mechanisms were put forward by researchers to explain the basis of free Hb-mediated toxicity that would otherwise been suppressed inside the red blood cell. These are: (1) scavenging of endothelial nitric oxide (NO), a vasodilator;. The multiplicity of these biochemical hypotheses and conflicting experimental data have complicated the interpretation of many preclinical animal studies that have failed to predict the adverse outcome, observed in the clinical investigations of these therapeutics [11]
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