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Selective phagocytosis of senescent human red blood cells (RBC) requires a molecular alteration on the surface of aging RBC. This cell-age determining signal represents neither a surface-charge density change nor extensive desialylation, as assumed earlier. Since IgG autoantibodies have been detected which specifically bind to senescent RBC, the required surface alteration represents the exposure of a cell-age-specific antigen (CAS antigen). The CAS antigen has been identified as a membrane protein with apparent molecular weights of approximately 100 K or approximately 200 K. Immunoprecipitation of Triton extracts from chymotrypsin-treated RBC as well as preliminary peptide analyses of the surface 125I-iodinated part of a CAS-antigen enriched fraction suggest that the CAS antigen has the protein structure of protein band 3. The CAS-antigenic sites are not formed during senescence but are already present in young RBC. Exposure of the CAS antigen in senescent RBC appears to be due to an increased probability of CAS-antigen dimers. This apparently minor change is sufficient for the following reasons: IgG autoantibody binding to monomeric CAS antigen appears to be monovalent and transient. Thus, CAS antigens may even be exposed rather than cryptic on the surface of young RBC. In contrast, IgG autoantibodies form thermodynamically considerably more stable complexes with dimeric CAS antigen because of a bivalent binding. The dimerization probability of CAS antigens in the plane of the membrane can be increased experimentally by destroying the anchorage between integral membrane proteins and the cytoskeleton. This loss of anchorage is followed by drastically enhanced IgG-autoantibody binding.
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Using the method of inducing spherocytic anemia in the rabbit with antibody serum, we have developed an animal model in which red blood cells (RBCs) can nearly grow synchronously. With this model, we determined that the surface charge density on the RBC membrane decreased with cell aging. The change was not linear, being much more profound in the latter half of RBC life span. There was a positive correlation between the mean RBC density and its "age" (r = 0.847, p < 0.01). However, the density distribution of the RBCs at the same "age" showed a broad range, and the density values for RBC groups with different ages showed considerable overlap. This indicates that the density gradient technique can be used to separate RBC population into fractions with different mean ages, but has a low resolving power for obtaining individual RBCs of a given "age".
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In vivo phagocytosis of senescent red blood cells (RBCs) by macrophages occurs 120 days after their release into the circulation. It depends on two sequential signals that trigger phagocytosis: (1) desialylation of membrane glycoconjugates with the exposure of the penultimate beta-galactosyl residues and (2) exposure of phosphatidylserine in the membrane outer leaflet. Leukodepleted and nonleukodepleted RBCs were compared using flow cytometric procedures to determine whether the in vitro deterioration of RBCs during storage might be attributable to an identical mechanism of desialylation induced by leukocyte neuraminidases, resulting in exposure of beta-galactosyl and subsequently phosphatidylserine residues - signals of senescent RBCs. Without prior leukodepletion, stored RBCs showed an increased population of senescent RBCs (using light scatter measurements), extensive desialylation with the exposure of beta-galactosyl residues (using specific fluorescein isothiocyanate [FITC]-lectins), significant exposure of phosphatidylserine in the outer leaflet of the RBC membrane (using FITC-annexin V), and extensive in vitro phagocytosis (using PKH-26-labeled RBCs). There were minimal changes observed with the leukodepleted RBCs. These results lead to the conclusion that leukocyte enzymes, including neuraminidases, are definitive contributers to the desialylation of RBCs during storage and to the exposure of phosphatidylserine residues. These deleterious effects resulting from highly active leukocyte enzymes are preventable by prior leukodepletion of the stored RBCs. Previously developed flow cytometric procedures to detect in vivo "RBC senescence" have been applied and proved to be reliable criteria to monitor the viability of stored RBCs.
Mice immunized with intact rat red blood cells (RBC) developed serum auto-antibodies (some of which were mouse specific) to the RBC membrane components spectrin and antigens of 100 and 81 kDa as shown by Western blotting and enzyme-linked immunosorbent assay as well as RBC surface-bound autoantibodies detected by the Coombs' test. In order to discover whether these autoantibodies were induced and controlled in similar or different ways, mice were challenged with a variety of rat and mouse RBC preparations. In addition, the ability of recipients given spleen cells from the above donors to generate autoantibody responses to intact rat RBC was measured. It was found that all the autoantibodies were induced in mice challenged with rat RBC ghosts but none following immunization with butanol-extracted rat RBC ghosts or intact mouse RBC. By contrast, mice injected with mouse RBC ghosts made autoantibodies to spectrin and to the 100-kDa band. Spleen cells from mice primed with intact rat RBC, rat RBC ghosts or butanol-extracted rat RBC ghosts curtailed Coombs' autoantibody production of recipient mice challenged with intact rat RBC. Serum from recipients of spleen cells primed with intact rat RBC or the butanol extract generally failed to react with rat or mouse spectrin or with the 81-kDa band, although antibody was detected to the rat 100-kDa band. Recipients of rat RBC ghost-primed spleen cells produced antibody to rat and mouse spectrin and to rat 100-kDa band but not to mouse 100-kDa or rat or mouse 81-kDa bands. Occasionally, suppression of antibody to the rat-specific 38-kDa band was observed in recipients of intact rat RBC-primed spleen cells. It is therefore suggested that regulation of cross-reactive and mouse-specific autoantibodies as well as rat-specific antibodies occurs in an independent, determinant-specific manner.
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UNLABELLED: The separation of whole blood into components is the state-of-the-art in transfusion of allogeneic blood. The main reasons are the negative effects of the buffy coat and the need for FFP. Nevertheless, especially in Germany whole blood is being rejected more and more even as autologous blood. However, most of the negative effects of the buffy coat do not apply to autologous blood. Additionally, these patients usually do not develop coagulation disorders and therefore do not need plasma as a hemostatic component. On the other hand, separation into components of autologous blood leads to an increase of costs and to logistic problems that restrict autologous blood predeposit to a few institutions. Therefore, we have reviewed the literature in order to find a scientific basis for this. METHODS: We analysed all articles listed by MEDLINE during the last 12 years that dealt with the quality of whole blood or red cell concentrates. In addition, all references were included that contributed relevant information to the topic. A total of 135 original articles, abstracts, reviews, letters or editorials were analysed that referred to standard preparations and storage media. In 48 papers the in vivo red cell survival was studied. 28 of which fulfilled the prerequisites to be included into a meta-analysis. The following in vitro parameters were also evaluated: pH, potassium load of the units, ATP and DPG concentration of the red cells. RESULTS AND DISCUSSION: Whole blood (resuspended in CPDA-1) and red cell units (stabilized in CPDA-1 or additive solutions) with a different buffy coat or leucocyte content have comparable pH values and red cell 2,3-DPG and ATP concentrations at the end of the approved storage time. The potassium load of a whole blood unit appears to be higher than red cell concentrates, but this is to some extent caused by the higher plasma content of whole blood and is not thought to be a clinically relevant problem for patients receiving only a few units. A number of studies demonstrate that dependent upon the leucocyte content of a red cell unit, leucocyte metabolites and enzymes are released and accumulate during storage. A detrimental influence on the integrity of the red cell membrane was found in several in vitro studies. Nevertheless, a significant improvement in red cell survival by leucocyte reduction was detected by only one group. Undoubtedly, nonhemolytic febrile transfusion reactions (NHFTR) are generally caused by an antibody-antigen interaction due to the transfusion of allogeneic buffy coat. On the other hand, there is some evidence that non-specific immunological mechanisms such as the release of histamine or cytokines are also capable of causing NHFTR. Thus, these reactions are expected to occur in autologous blood transfusion. However, so far, there are no data about the frequency and severity of these reactions and whether they are more likely to emerge after transfusion of blood units with a particular preparation. Blood transfusions can cause septic complications due to bacterial contamination of the transfused units. These fatal but rare complications may be reduced by pre-storage filtration of blood, but there is no indication that buffy coat reduction is effective. Three cases with septic complications have been reported after autologous transfusion, in two of which red cell concentrates (at least one was free of buffy coat) had been used. Thus, there is no justification for the conclusion that the risk of septic complications is increased by transfusion of whole blood. After all, whole blood and red cell concentrates exhibit only minor differences in relevant in vitro parameters. Hence, a higher incidence of adverse effects following the transfusion of autologous whole blood compared to autologous red cell concentrations is unlikely. Therefore, the 24 h in vivo recovery is considered to be the most valid criterion to assess the quality of red cell preparations.(ABSTRACT TRUNCATED)