Hemoglobin solutions

If hemoglobin solutions were used to replace the oxygen-carrying capacity of 10 per cent of the red blood cell units transfused annually in the United States, 60 000 to 70 000 kg of hemoglobin would be required each year. Possible sources able to provide this amount of hemoglobin are human hemoglobin derived from outdated bank blood, bovine hemoglobin, and genetically engineered recombinant hemoglobin produced by micro-organisms (bacteria, yeasts) ( D.ietz ela/ 1996).

The following problems must be overcome to create a safe and effective hemoglobin solution.

1. Intravascular half-life: when hemoglobin is freed from its intraerythrocytic environment, its tetrameric structure of two a chains and two b chains dissociates into a and b dimers or single a and b monomers. Both dimers and monomers are rapidly filtered by the kidneys, reducing their intravascular retention time.

2. Oxygen affinity: removal of hemoglobin from red blood cells is associated with loss of the regulatory function of 2,3-diphosphoglycerate. At low oxygen partial pressures (PO2), oxygen liberation from hemoglobin is hindered. The P50 value (PO2 at which 50 per cent of hemoglobin is saturated with oxygen) is lowered and the oxygen-hemoglobin dissociation curve is shifted to the left. Because of the higher oxygen affinity of free hemoglobin in the absence of 2,3-diphosphoglycerate, there is less diffusion of oxygen to the tissues, despite an adequate PO2 gradient (arterial PO2, 90-100 mmHg; tissue PO2, 30-40 mmHg). This results in reduced availability of hemoglobin-bound oxygen at the tissue level.

3. Renal toxicity: renal damage occurs when filtered hemoglobin dimers or monomers precipitate in the ascending limb of the loop of Henle. Insufficient purification of the hemoglobin solution from red cell stromal debris may contribute to the renal damage.

4. Vasoconstriction: this phenomenon was observed in the first animal experiments dating from the early 1930s, when a solution of bovine hemoglobin in saline was used for exchange transfusion. Vasoconstriction and the consecutive rise in systemic vascular resistance, mean aortic pressure, and left ventricular oxygen requirements remain uncontrolled side-effects of hemoglobin solution. The most probable explanation of the immediate onset of vasoconstriction upon infusion of hemoglobin solutions is scavenging of nitric oxide (a potent endogenous vasodilator) by the hemoglobin molecule. Upregulation of endothelin and sympathoadrenergic receptors has also been suggested. Additionally, the hemoglobin molecule itself may possess vasoconstricting properties.

Great efforts have been made by pharmaceutical manufacturers to develop new hemoglobin preparations which do not have these problems. The intravascular persistence of hemoglobin has been successfully prolonged by chemical approaches. It is possible to cross-link, polymerize, or conjugate hemoglobin dimers or monomers, thus creating larger molecules with an intravascular half-life prolonged to 6 to 8 h. At the same time renal damage due to filtered monomers and dimers is avoided. Production of hemoglobin solutions based on bovine hemoglobin takes adventage of the fact that the P5C value of bovine hemoglobin is similar to that of human hemoglobin and is not controlled by 2,3-diphosphoglycerate but by ionic chloride, which is present in large concentrations in plasma. It is expected that genetic engineering will allow structural modifications of the hemoglobin molecule. The tertiary structure of the binding sites for the nitric oxide molecule might be changed and the vasoconstrictive effect of hemoglobin molecules modified in this way might be reduced. Liposome encapsulation of modified hemoglobin molecules imitates the membrane structure of the red blood cells, allowing incorporation of 2,3-diphosphoglycerate (physiological P50) and prolongation of intravascular half-life.

Despite definite progress in producing effective and safe oxygen-carrying blood substitutes based on hemoglobin, serious limitations on the general use of such compounds still remain. The use of bovine hemoglobin may be seriously endangered by possible interspecies transmission of infectious diseases such as bovine spongiform encephalitis. With better organization of blood banks and a shrinking donor pool, fewer red blood cell units become outdated; hence this source of hemoglobin may become unrealistic. It is unclear at present whether recombinant DNA technology will allow cost-effective provision of the required amounts of hemoglobin and whether complete elimination of bacterial components from the hemoglobin will be achieved. Finally, the use of hemoglobin solutions for the treatment of a broad range of patients requires control of the vasoconstrictor effect of these compounds to satisfy concerns about safety.

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