Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?

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.

Manipulating hemoglobin oxygenation using silica nanoparticles: a novel prospect for artificial oxygen carriers

“…13 However, other studies suggested a potential renal toxicity of polymerized Hb systems associated with oxidative stress. 14,15 Despite great efforts and recent progress for the development of new blood substitutes, no HBOCs have yet been approved for clinical use in Europe or in the United States.…”

Study on Oxidation Stability and Oxygen Affinity of Hemoglobin During Storage

“…Hemoglobin‐based oxygen carriers (HBOCs) are blood substitutes derived from bovine, pig, or outdated human blood . The potential benefits of HBOCs include universal compatibility without the need for cross‐matching of donated blood, availability, and no infection risks .…”

Use of the blood substitute HBOC‐201 in critically ill patients during sickle crisis: a three‐case series

“…Physicians are faced with a significant challenge when treating life-threatening anemia in patients unwilling to accept blood for religious reasons or for whom safe blood is not available due to extensive alloimmunization or lack of supply in some developing countries. 3,6,[15][16][17][18][19] Unfortunately, survival of patients with life-threatening anemia for whom RBC transfusion is not an option has not improved over the past 20 or 30 years. 20,21 Administration of HBOCs may represent a therapeutic alternative to reduce mortality for both medical and surgical patients in this population.…”

“…In cases where hemoglobin (Hb) levels are insufficient to fulfill metabolic needs, red blood cell (RBC) and exchange transfusion are often utilized. However, Jehovah's Witnesses (JWs) typically refuse blood products or compatible RBCs may not be available or safe . Cell‐free Hb substitutes have improved over the past 30 years, with significant improvements in the safety profiles and clinical outcomes of second‐generation Hb‐based oxygen carriers (HBOCs) .…”

“…However, Jehovah's Witnesses (JWs) typically refuse blood products 1,[3][4][5] or compatible RBCs may not be available or safe. 6 Cellfree Hb substitutes have improved over the past 30 years, 7,8 with significant improvements in the safety profiles and clinical outcomes of second-generation Hbbased oxygen carriers (HBOCs). 9 HBOC-201 is cell-free polymerized bovine Hb (Hb glutamer-250 [bovine]) with a P50 (oxygen pressure at which 50% of oxygen-binding sites are saturated) of 40 (66) mmHg, compared to 27 mmHg for native human Hb, and concentration of 130 g/ L, originally developed by Biopure Corporation.…”