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E D I T O R I a L Editorial E D I T O R I A L EDITORIAL Universal RBCs ntigens on RBCs have been a problem for blood RBCs; products such as Hb-based oxygen carriers are also transfusion right from the start. In the mid-17th universal, in that they can be transfused to any patient.) century, Jean Denis in France and Richard Lower Two general approaches could be used to make a uni- in England attempted animal-to-human blood versal RBC. The RBC antigens can be removed permanently Atransfusions, only to be foiled by (among many factors) the from the RBC surface, or they can be masked to avoid rec- presence of incompatibilities between the animal RBCs and ognition by the immune system. This recognition by the human serum. James Blundell’s use of human-to-human immune system could lead to an immediate reaction via blood transfusions in the early 19th century lowered the im- preexisting antibodies in the recipient against antigens on munologic barrier, but major RBC antigenic differences be- donor RBCs or to later alloimmunization to these antigens. tween humans led to hemolytic reactions. With Landsteiner’s There has been substantial progress along both of these discovery of the ABO blood group antigens on RBCs and research directions, yielding RBC products of differing associated serum isoagglutinins a century ago,1 the major characteristics and different potential uses in transfusion cause of this immune reaction had been found, and suc- medicine. cessful blood transfusion could be achieved. Blood samples from donor and patient were each tested and classified into ENZYMATICALLY CONVERTED one of the four phenotypes—O, A, B, or AB—which allowed GROUP O CELLS the donor and patient phenotypes to be matched. At the turn of this new century, typing of ABO antigens still re- Work in the 1950s and 1960s by Morgan, Watkins, Kabat, and mains the critical step in RBC transfusion, necessitated by others elucidated the carbohydrate structures of the ABO anti- the presence of preexisting antibodies to A and/or B anti- gens on glycolipids and glycoproteins (reviewed by Hakomori2). gens in individuals lacking these antigens. The entire sys- It was shown that these antigens differed only in the termi- tem of blood collection, distribution, and transfusion re- nal monosaccharide attached to the precursor H oligosac- volves around the ABO blood groups. Elimination of this charide antigen: N-acetylgalactosamine for group A, galac- need for typing, by the creation of a universal RBC for trans- tose for group B, and no added monosaccharide for group fusion, would bring about a revolution in blood banking O (remains H antigen). This raised the possibility that A and akin to that which followed Landsteiner’s discovery of the B antigens could be converted back to H antigen by the re- ABO blood group system. So what are the potential meth- moval of the terminal monosaccharide unit by an appropri- ods with which to accomplish this task? Will universal RBCs ate exoglycosidase, α-N-acetylgalactosaminidase for group be coming to neighborhood blood centers and hospitals A and α-galactosidase for group B. Pioneering studies by the anytime soon? late Jack Goldstein and colleagues3 at the New York Blood The term “universal RBC” could have several mean- Center demonstrated that this process of enzymatic con- ings. Group O persons are considered universal RBC donors version of group B RBCs to group O could be carried out because they lack the antigens of the ABO blood group sys- with the enzyme coffee bean α-galactosidase under condi- tem, and thus their RBCs can be transfused to any recipi- tions that leave the RBCs physically and functionally intact and ent without concern for preexisting ABO antibodies. Blood suitable for transfusion. Studies in group O or group A vol- donor and recipient are also matched for D antigen, despite unteer recipients showed that these enzymatically converted the lack of anti-D in nonimmunized recipients, because the group O (ECO) cells functioned essentially identically to immunization rate is greater than 50 percent upon expo- group O RBCs; there was no evidence of acute transfusion sure of D– recipients to the D antigen. Thus, O– could be reactions or hemolysis, and RBC survival in the recipients considered the universal RBC. Finally, a small percentage was normal.4 Multi-unit or second transfusions were also of patients have preexisting antibodies to one or more of the well tolerated.5,6 An occasional serologic finding in the re- several hundred additional antigens described on RBCs, so cipients of these ECO cells was an increase in the titer of a truly universal RBC would have to be negative for all of anti-B or an incompatibility of recipient serum with ECO these antigens. (This discussion is limited to universal cells. As there was no evidence of associated clinical prob- lems, the meaning of these serologic results was not clear. TRANSFUSION 2000;40:1285-1289. Volume 40, November 2000 TRANSFUSION 1285 EDITORIAL In this issue of TRANSFUSION, Kruskall and col- matically converted to group O RBCs, which would increase leagues7 extend these studies by reporting a Phase II trial the blood supply, the ECO technology would not be eco- of the transfusion of ECO (B-to-O) RBCs to transfusion-de- nomically viable if used solely for this purpose. pendent patients of group O or A. In this crossover study of For ECO RBCs to become a universal blood supply, there 24 patients of group O or A, the patients were given either must be a process for A-to-O conversion. The original hope ECO or group O RBCs; 18 patients subsequently received a that this could be accomplished in a fashion parallel to the transfusion with the alternate product. Overall, the trans- B-to-O process by the use of an α-N-acetylgalactosamin- fusions of ECO RBCs appeared safe and effective; there were idase enzyme for A-to-O conversion has been dashed by the no acute transfusion reactions or evidence of hemolysis, biochemical complexity of the A antigen (see Fig. 1 in the and chromium survival studies showed that the lifespans article by Kruskall et al.7 in this issue of TRANSFUSION). of the transfused ECO and group O RBCs were equal. How- Epitopes of A can exist at both the terminal positions of the ever, a number of in vitro serologic abnormalities were oligosaccharide chains, where they can be removed by an noted, which were similar to observations in the previous α-N-acetylgalactosaminidase enzyme, and at internal po- studies of ECO RBC transfusions to normal volunteers.4,5 sitions, where they would be resistant to this exoglycosidase Five of 19 patients who received ECO RBCs had significant enzyme. Research aimed at the removal of all A epitopes is increases in anti-B titers, and 2 of these patients had incom- ongoing, but until this problem yields a biochemical solu- patible antiglobulin crossmatches with ECO RBCs.7 While tion, one must be guarded in predicting the future of a uni- the rising anti-B titers most certainly reflect an immune versal ECO blood supply. response to a small residual number of B epitopes on the Let us take a look at what future blood banking would ECO RBCs (compared to the original levels of approx. 0.8 × be like if the A-to-O conversion were accomplished and led 106/RBC), this weak antigen expression did not appear to to a totally group O blood supply, a mixture of ECO and cause measurable hemolysis in these patients. The incom- group O RBCs. It would be a completely different world, in patible crossmatches with ECO RBCs found with the serum which many of the daily activities in blood centers and from two patients is potentially concerning. Despite the hospitals would simply vanish. No more ABO to track for reassuring finding of normal transfusion results in these donors and patients. No more worries for recruiters at blood patients, additional work must be done to deduce the tar- centers about meeting separate targets for individual blood get of this antibody (residual B? neoantigen?) and its clini- groups, which can lead to overcollection to meet higher cal significance. Otherwise, the finding in this study7 that group O needs. No longer would inventory managers have 20 percent of group A patients and 40 percent of group O to ship blood around the country to redress the misalign- patients had incompatible crossmatches with ECO RBCs ment of blood group targets among regions. Nor would (often, weak reactions detectable only in the antiglobulin hospital transfusion services (or blood centers at each in- phase) would, at the least, introduce complicating serologic termediate transfer) have to reconfirm the ABO type of results into the testing protocol with an ECO blood supply, blood units. ABO transfusion errors, the most serious and and, more worrisome, might lead to reduced ECO RBC sur- life-threatening of transfusion reactions, would not occur. vival in vivo. These questions require further study. (But a caveat must be inserted here. Currently, ABO-incom- Nonetheless, it is fair to state that this overall research patible RBC transfusions occur because of error at some program has produced very strong and convincing data sup- stage of patient or blood unit identification, at an estimated porting the proposal that an ECO RBC produced by B-to-O rate of 1 in 33,000 transfusions, 6 percent of which have fatal conversion would serve as a universal RBC suitable for trans- outcomes.8 In a universal ECO blood supply, ABO identifi- fusion. Is this of any practical use to the blood supply? Sim- cation is no longer a problem, but the treatment process ply put, the answer is no.
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