[157]. Although A‐to‐O conversion is possible, some A determinants remained on the carbohydrate, and this work was halted. Clinical trials of enzymatically converted B type RBCs on healthy volunteers reported no signs of hemolysis [157].
Masking ABO antigens
A different approach to altering the RBC membrane to convert group A or B red cells into group O red cells is to mask the antigens to produce “stealth” red cells. Polyethylene glycol has been used to covalently bond to red cells to mask blood group antigens, such as ABO, Rh, Kell, and Kidd [159]. Small studies in animals suggest that there is little in vitro damage to the red cells and that they have a normal survival, although such studies have not yet been carried out in humans. It is not clear whether development of this process will continue.
5.11 Blood substitutes
The functions of blood can be grouped generally as maintenance of intravascular volume, delivery of oxygen to tissues, provision of coagulation factors, provision of some defense mechanisms, and transportation of metabolic waste products. Considerable effort has been made to develop blood substitutes or artificial blood, but these products deal only with the oxygen‐delivery function. Thus, more appropriate terms are hemoglobin or red cell substitutes [160].
The ideal acellular red cell substitute would not require crossmatching or blood typing, could be stored preferably at room temperature for a long period, would have a reasonable intravascular life span and thereafter be excreted promptly, and would be free of toxicity or disease transmission. Two approaches have been used: perfluorocarbons, compounds in which oxygen is highly soluble, and free hemoglobin solutions using either human or animal hemoglobin [161]. Hemoglobin chemically binds oxygen, whereas perfluorocarbons have a carbon backbone with fluorine substitutions that have solubility for oxygen 20 times greater than water. The physiologic benefit of this high solubility for oxygen has been demonstrated dramatically by the survival of mice completely immersed in a solution of well‐oxygenated perfluorocarbons.
Hemoglobin can be prepared in solution by lysis of red cells. If the remaining cell stroma is removed, the stroma‐free hemoglobin is nonantigenic. However, stroma‐free hemoglobin in solution has a short intravascular life span and has a low P50 (the point at which 50% is saturated). Thus, research has focused on modifying the structure of the hemoglobin molecule (cross‐linking or polymerization) or binding hemoglobin to other molecules to overcome these two problems [161]. Outdated human red cells, bovine hemoglobulin, and recombinant DNA‐produced hemoglobin have been used as sources of hemoglobin. The potential difficulties with hemoglobin‐based oxygen carriers are rapid clearance of the hemoglobin, hypertensive effects, change in the oxygen dissociation curve, hemoglobin metabolites, immunogenicity, and bacterial sepsis [161].
Five products are or have undergone clinical trials: Polyheme (Northfield Laboratories, Evanston, IL, USA), HemAssist (Baxter Healthcare Corporation, Round Lake, IL, USA), Hemopure (Biopure Corporation, Cambridge, MA, USA), Hemolink (Hemosol, Mississauga, ON, Canada), and Sanguinate (Prolong Pharmaceuticals, LLC, South Plainfield, NJ, USA) [162, 163].
Development of HemAssist has been discontinued after randomized trials demonstrated safety problems [164, 165]. Hemopure was used successfully in a patient with severe autoimmune hemolytic anemia [166] and in a patient with sickle cell disease with acute chest syndrome who refused blood transfusion [167]. However, clinical trials of these products have come to a stop [168, 169]. Currently, the FDA has approved expanded access study for Hemopure (compassionate use) for patients with life‐threatening anemia when a transfusion is not an option [170, 171].
In a careful study, 8 patients with severe anemia (hemoglobin levels of 1.2–4.5 g/dL) who refused a blood transfusion received the perfluorocarbon product and were compared with 15 patients who did not [172]. The amount of oxygen delivered by the perfluorocarbon was not clinically significant, and the patients did not benefit. The major observation in this study was the ability of all the patients to tolerate remarkably low hemoglobin levels and the lack of the need for increased arterial oxygen content in the 15 control patients who had hemoglobin levels of approximately 7 g/dL. Fluosol products are not available, nor are they undergoing clinical trial.
Potential clinical uses and impact of hemoglobin substitutes
If a hemoglobin‐based oxygen carrier was developed, it is not likely that it will replace most red cell transfusions. The substitutes might be used for immediate restoration of oxygen delivery, such as in trauma or in other urgent situations involving massive blood loss where red cells are not available quickly, but the short intravascular half‐life of these substitutes makes them impractical for long‐term red cell replacement (for instance, in patients with chronic anemia). Because blood typing and crossmatching would not be necessary, the substitutes might be carried in emergency vehicles, stocked in emergency departments, or used by the military or civilians in situations where access to blood is limited. Other potential uses of hemoglobin substitutes include organ perfusion and preservation prior to transplantation and improving oxygen delivery to tissues that have an impaired blood supply. Unfortunately, it does not appear that a hemoglobin‐based blood substitute [24] will be available soon, and the long‐awaited “blood substitute” is not close to reality.
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