HbXL99 alpha: a hemoglobin derivative that is cross-linked between the alpha subunits is useful as a blood substitute.
Under deoxygenated conditions, bis(3,5-dibromosalicyl) fumarate reacts with hemoglobin selectively to cross-link the alpha subunits between Lys-alpha 1 99 and Lys-alpha 2 99. We have characterized further the properties of this recently described hemoglobin and have demonstrated its utility as a blood substitute. The oxygen transport characteristics of the cross-linked derivative are very similar to those of whole blood. Under physiological conditions, the partial pressure of oxygen at half-saturation of hemoglobin is increased to 29 mm Hg (1 mm Hg = 133.3 kPa), compared to 12 mm Hg for hemoglobin A, fully compensating for the absence of 2,3-bisphosphoglycerate outside of the erythrocyte. The Hill coefficient is 2.9. The dependence of the oxygen affinity of HbXL99 alpha on CO2 is also identical to that of hemoglobin A. The cross-link between the alpha subunits blocks dissociation of oxyhemoglobin into alpha beta dimers and thereby prevents renal excretion of the modified hemoglobin. In the rat, the half-life of HbXL99 alpha in plasma, at a 15% volume exchange, is increased to 3.3 hr, compared to 90 min for hemoglobin A. Cross-linking HbXL99 alpha intermolecularly with bis(sulfosuccinimidyl) suberate to form predominantly a mixture of dimers and trimers further increased the half-life of the hemoglobin within the circulation by about 2-fold. The rate of autooxidation of the transfused hemoglobin was found to be markedly reduced because of the presence of an endogenous reducing system in plasma.
D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives; D001802:Blood Substitutes / Q000378:metabolism* / Q000493:pharmacokinetics; D001803:Blood Transfusion; D003432:Cross-Linking Reagents; D006207:Half-Life; D006443:Hemoglobin A2 / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism* / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010108:Oxyhemoglobins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D001802:Blood Substitutes; D003432:Cross-Linking Reagents; D006454:Hemoglobins; D010108:Oxyhemoglobins; C053936:hemoglobin XL99alpha; C021630:bis(3,5-dibromosalicyl)fumarate; D008706:Methemoglobin; D006443:Hemoglobin A2; D001241:Aspirin; D010100:Oxygen