Cell-free hemoglobin-based oxygen carriers have been proposed as blood substitutes for transfusions because of their plasma expansion and oxygen transport capabilities. Apart from their use after accidents or major surgery, such substitutes could be employed to alleviate anemia in patients with hematocrits too high to qualify for blood transfusions. Hemoglobin-based blood substitutes have the added advantages that they can be easily purified, stored for relatively long periods of time, and used in patients of all blood types.

Normally hemoglobin in the bloodstream is enclosed in red blood cells, and this tends to stabilize the molecule in its tetrameric form. In addition, the red cells contain a metabolite, 2,3-diphosphoglycerate (2,3-DPG), that both crosslinks the hemoglobin, further promoting its stability, and reduces its oxygen affinity so that it is able to release bound oxygen to the tissue. Red blood cells also contain antioxi-dant enzymes, such as catalase and superoxide dismutase, which catalyze the breakdown of the reactive oxygen species (ROS), hydrogen peroxide (H2O2), and superoxide (O/-). When hemoglobin is released from red cells it rapidly splits up into dimers because these stabilizing factors are no longer present (see Figure 1, stroma-free hemoglobin, SFH). Hemoglobin contained in red cells has a low oxygen affinity, the partial pressure of oxygen needed for 50 percent oxygen saturation, P50, being about 27mmHg. Cell-free hemoglobin, however, has a high oxygen affinity (P50 ~ 8 mmHg), meaning that it will only give up its oxygen to very anoxic tissue.

If free hemoglobin is going to be effective as an oxygen carrier and deliverer, it needs to be stabilized and its oxygen affinity must be reduced. One way to achieve these goals is to cross-link the two a subunits of the hemoglobin molecule with bis(3,5-dibromosalicyl) fumarate. Two such products are diaspirin cross-linked hemoglobin (DCLHb) and its noncommercial analog (DBBF-Hb). Alternatively, hemoglobin can be covalently cross-linked and then conjugated with macromolecules, such as polyethylene glycol (PEG), or it can be polymerized, resulting in inter- and intramolecular cross-linked polymers of various molecular sizes. Some hemoglobins that have been modified in these ways, such as DBBF-Hb, PEG-Hb, PolyHbBv (Oxyglobin), and O-R-PolyHb (Hemolink), have been used in clinical trials. In fact, PolyHbBv (Oxyglobin) is currently FDA-approved for veterinary use in the United States, and its human counterpart has recently been approved for clinical use in humans in South Africa. Studies are also underway to encapsulate modified and nonmodified hemoglobins in liposomes. Further details concerning the properties and physiological effects of these hemoglobins can be found in a review by Alayash [1]. However, transfusion of hemoglobin (Hb)-based blood substitutes, designed for their plasma expansion and oxygen transport capabilities, has resulted in some major problems, such as organ dysfunction, during clinical trials. These events might be linked to deleterious responses occurring in the microvasculature in the presence of the blood substitutes.

Red cell

PM -27 mmHg

Cross-linked tetramer Polymer

Figure 1 Development of hemoglobin solutions as blood substitutes. SFH is either cross-linked, conjugated with macromolecules, or polymerized in order to stabilize the hemoglobin tetramer and enhance its function. SFH are, in some cases, encapsulated within liposomes. (From Ref. [1].)

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