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Nika · #1 (**permalink**) 03-28-2005, 09:44 PM

http://www.nataonline.com/Art.php3?NumArticle=3825

Robert M. Winslow, MD
Sangart, Inc., and
Department of Bioengineering
University of California, San Diego
San Diego, California, USA

Safe and effective alternatives to red blood cells for transfusion have been sought for decades.1 In principle, such solutions would alleviate the need to type and crossmatch blood, have prolonged shelf life and could be used immediately in cases of trauma or emergency. Ideally, they would also be inexpensive and readily available. Hemoglobin, the oxygen carrier of red cells, is itself not suited to be administered as a cell-free solution because outside of the red cell the protein rapidly dissociates into monomeric subunits, iron oxidizes, and toxicity in the form of vasoconstriction and tissue damage result. Chemical modification of the protein has been extensively explored, and it is possible to produce derivatized hemoglobin of nearly any size and configuration with prolonged intravascular circulation and stability. While some of these molecules have been tested in human trials, the mechanisms that mediate their toxic effects have not been well understood, and many of the trials have been unsuccessful.

Many, if not all, of the toxic effects of cell-free hemoglobin can be attributed to vasoconstriction, commonly attributed to the capacity of hemoglobin to avidly bind nitric oxide (NO), a potent vasodilator. Recombinant hemoglobin with reduced NO binding kinetics appears to be less vasoactive,2 but NO binding does not explain why other hemoglobins display varying degrees of vasoconstriction.3 Recent studies with polyethylene-glycol (PEG) modified hemoglobins have shown that the interaction of these molecules with local vascular beds can be mediated by manipulation of properties of the hemoglobin to include oxygen binding, viscosity and oncotic pressure. The studies indicate that the mechanisms underlying hemoglobin-based vasoconstriction are more complicated than originally thought, and include local regulation of O2 delivery as well.4

Maleimide-PEG modified human hemoglobin (MP4)5 that is not vasoactive in the hamster skinfold model and releases O2 specifically in hypoxic tissue6 incorporates the lessons learned from these studies and has shown promise in several animal models of hemorrhagic shock and hemodilution. MP4 is now progressing through human clinical trials. It is anticipated that new products that are designed with local tissue needs and circulatory characteristics in mind will be more successful than ones designed to merely duplicate the O2 transport properties of red blood cells. Such products, capable of delivering O2 effectively and safely to tissues, may not be â€œred cell substitutesâ€ in every sense, but may very effectively serve the function of red cells for which they are transfused: tissue oxygenation.

References
1. Winslow RM. Current status of red cell substitutes ("oxygen therapeutics"). In: Stowell CP, Dxik A, eds. Emerging Technologies in Transfusion Medicine. Bethesda, MD: AABB Press; 2003:359-76.
2. Doherty DH, Doyle MP, Curry SR, et al. Rate of reaction with nitric oxide determines the hypertensive effect of cell-free hemoglobin. Nature Biotechnol 1998;16:672-6.
3. Rohlfs RJ, Bruner E, Chiu A, et al. Arterial blood pressure responses to cell-free hemoglobin solutions and the reaction with nitric oxide. J Biol Chem 1998;273:12128-34.
4. Tsai AG, Cabrales P, Winslow RM, Intaglietta M. Microvascular oxygen distribution in awake hamster window chamber model during hyperoxia. Am J Physiol Heart Circ Physiol 2003;285:H1537-45.
5. Vandegriff KD, Malavalli A, Wooldridge J, Lohman J, Winslow RM. MP4, a new nonvasoactive PEG-Hb conjugate. Transfusion 2003;43:509-16.
6. Tsai AG, Vandegriff KD, Intaglietta M, Winslow RM. Targeted O2 delivery by low-P50 hemoglobin: a new basis for O2 therapeutics. Am J Physiol Heart Circ Physiol 2003;285:H1411-9.

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Targeted Oxygen Delivery: A New Alternative to Red Cell Transfusion