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1
Kor, Daryl J., Camille M. Van Buskirk, and Ognjen Gajic. "Red Blood Cell Storage Lesion." Bosnian Journal of Basic Medical Sciences 9, no. 1 (October 20, 2009): S21—S27. http://dx.doi.org/10.17305/bjbms.2009.2750.
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The past two decades have witnessed increased scrutiny regarding efficacy and risk of the once unquestioned therapy of red blood cell (RBC) transfusion. Simultaneously, a variety of changes have been identified within the RBC and storage media during RBC preservation that are correlated with reduced tissue oxygenation and transfusion-associated adverse effects. These alterations are collectively termed the storage lesion and include extensive biochemical, biomechanical, and immunologic changes involving cells of diverse origin. Time-dependent falls is 2,3-diphosphoglycerate, intracellular RBC adenosine triphosphate, and nitric oxide have been shown to impact RBC deformability and delivery of oxygen to the end-organ. The accumulation of biologic response modifiers such as soluble CD40 ligand (sCD40L), lysophosphatidylcholine (lyso-PC), and Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) have been associated with altered recipient immune function as well. This review will address the alterations occurring within the RBC and storage media during RBC preservation and will address the potential clinical consequence thereof.
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Annan, Edwin, Kristin G. Fless, Nirav Jasani, Frantz Pierre-Louis, Fariborz Rezai, and Paul C. Yodice. "Red Blood Cell Transfusion Practices." ICU Director 4, no. 1 (December 3, 2012): 11–14. http://dx.doi.org/10.1177/1944451612467534.
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Background and Objectives. High-intensity ICU staffing model is associated with quality and outcome improvements. Restrictive red blood cell (RBC) transfusion strategies have been shown to have equivalent mortality to a more liberal strategy in the ICU. We examined the effect of high-intensity staffing on pretransfusion hemoglobin levels, RBC transfusion rates and length of ICU stay. Materials and Methods. The study was a retrospective chart review (n = 196) of all patients admitted to the adult medical/surgical ICU for more than 24 hours one year prior to and after institution of the high-intensity staffing model. Results. Matched for demographics and diagnosis, RBC transfusion rates pre- versus postinstitution of the high-intensity staffing model was 42% versus 27%, respectively, and pretransfusion hemoglobin levels were lower (8.94 to 7.39 g/dL). Length of stay was 4.1 days pre–high-intensity staffing and 4.0 days post–high-intensity staffing. Conclusions. High-intensity ICU staffing resulted in fewer RBC transfusions and lower transfusion thresholds. This restrictive RBC transfusion strategy had no adverse effects on patient ICU length of stay.
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Schrier, S. "Red Blood Cell Diseases (RBC) 1." ASH Image Bank 2002, no. 0605 (June 5, 2002): 100344. http://dx.doi.org/10.1182/ashimagebank-2002-100344.
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Schrier, S. "Red Blood Cell Diseases (RBC) 2." ASH Image Bank 2002, no. 0605 (June 5, 2002): 100345. http://dx.doi.org/10.1182/ashimagebank-2002-100345.
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Colard, Martin, Michaël Dussiot, Anaïs Martinez, Carole Peyssonnaux, Patrick Mayeux, Fleur Samantha Benghiat, Pierre Buffet, Olivier Hermine, and Pascal Amireault. "Erythropoietin Downregulates Red Blood Cell Clearance in Mice." Blood 134, Supplement_1 (November 13, 2019): 3524. http://dx.doi.org/10.1182/blood-2019-126768.
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Purpose Equilibrium between red blood cells (RBC) production and clearance maintains an appropriate circulating RBC biomass. During anemia or hypoxia, a well-characterized hypoxia-dependent induction of erythropoietin (EPO) synthesis leads to an increase in RBC production. At the other extremity of the RBC lifespan, age-related modifications of RBC properties are expected to be recognized by the mononuclear phagocytic system (MPS) and trigger their clearance. We reasoned that, like RBC production, RBC clearance might be physiologically regulated by hypoxia and therefore that its downregulation could contribute to maintain an appropriate RBC biomass. A mouse model was used to explore specific hypotheses on potential regulatory mechanisms involved in RBC clearance. Material and methods Two steps in vivo biotinylation was used to evaluate the impact of EPO on 3 RBC subpopulations: a young subpopulation (<25 days at treatment initiation) representing the RBC produced, one of intermediate age (25-34 days at treatment initiation) which is neither produced nor eliminated, and an old one (> 34 days at treatment initiation) that is steadily cleared. A model of RBC banking (leucocyte depleted and stored in CPDA solution) was used to evaluate the clearance after transfusion of fluorescently-labeled storage-damaged RBC by flow cytometry. Different recipient models were used to evaluate the impact of specific parameters on RBC clearance including: phlebotomy-induced anemia, normobaric hypoxia, erythropoiesis-stimulating agent (ESA) treatment (darbepoietin), splenectomy, doxorubicin-induced inhibition of erythropoiesis and EPO neutralization (anti-EPO rabbit serum) either alone or in combination. Results Decreased clearance of the oldest subpopulation was observed 2 days after ESA treatment and before the increase in RBC production (7 days). After 20 days of treatment, an increased number of RBC from the oldest subpopulation was detected in circulation confirming that senescent RBC clearance is sensitive to EPO signaling. After transfusion, clearance of storage-damaged RBC is reduced by 30% in anemic recipients when compared to non-anemic recipients. RBC clearance is significantly reduced in hypoxic non-anemic recipients, as soon as 6 hours after the initiation of hypoxia, suggesting that hematocrit per se does not affect RBC clearance. In ESA-treated non-anemic non-hypoxic mice, RBC clearance is also reduced showing that EPO signaling is sufficient. To investigate the role of the spleen in this process, splenectomy was combined with the previous models. As expected, RBC clearance was reduced by 20% in splenectomized recipients. RBC clearance is however even more decreased when splenectomy is combined with anemia, hypoxia or ESA treatment compared to splenectomized or control mice, suggesting that EPO downregulation of RBC clearance is not restricted to the spleen. Erythropoiesis inhibition did not alter the anemia-induced downregulation of RBC clearance ruling out the possibility that an erythroid factor is involved in the process. Finally, neutralization of circulating EPO not only abolishes the reduction of RBC clearance observed in anemic recipients, but also increases RBC clearance in both anemic and non-anemic recipients. Taken together these results indicate that EPO regulates RBC clearance during anemia and in steady state (Figure). Conclusion RBC clearance is downregulated during anemia/hypoxia and EPO is sufficient and necessary to mediate this physiological function. RBC clearance downregulation preceded the increase in production rate induced by ESA treatment suggesting it is a very early physiological response to maintain oxygen supply during anemia. The lifespan of a circulating RBC is therefore adaptable and could be regulated by 2 factors: the RBC pro- and anti-phagocytic properties on one side and, on the other side, the MPS level of activity and sensitivity toward these RBC properties. In case of anemia or hypoxia, increased EPO level would act on the RBC itself, on the activity/sensitivity of the MPS or both to downregulate RBC clearance until the equilibrium between oxygen need and supply is restored. Future studies will evaluate if the pathological dysregulation of this mechanism participates in the pathogenesis of anemia or, modulate transfusion efficacy and burden in chronically transfused patients. Figure Disclosures Buffet: Zimmer Biomet: Research Funding. Hermine:Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding. Amireault:Zimmer Biomet: Research Funding.
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Chhetri, Rakchha, Amilia Wee, Romi Sinha, Monika M. Kutyna, Soumya Gupta, Lakshmi Nath, Shriram V. Nath, et al. "Red Cell Alloimmunisation Is Associated with Increased Red Cell Transfusion Requirements in Myelodysplastic Syndrome." Blood 132, Supplement 1 (November 29, 2018): 1826. http://dx.doi.org/10.1182/blood-2018-99-115848.
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Abstract Up to 90% of MDS patients require red blood cell (RBC) transfusions. Literature addressing incidence and impact of alloimmunization in MDS is limited. We previously reported that 11% RBC-transfused MDS patients develop alloantibodies and RBC-transfusion requirement increases following alloimmunization (Singhal et al Haematologica 2017). This study aims to assess mechanism of increased RBC transfusion requirement following alloimmunization in MDS patients by comparing RBC-transfusion requirement following single and multiple alloantibodies, and impact of autoantibody on transfusion requirement. Primary MDS (PMDS), oligoblastic acute myeloid leukemia (AML) and therapy-related myeloid neoplasm (t-MN) patients enrolled in the SA-MDS registry (n=1002) between Nov 1991-Jun 2017, followed up for >3 months, received at least 1 unit of RBC and did not develop alloantibodies before first RBC transfusion were selected for analysis. Cumulative incidence (CI) of RBC-alloimmunization and clinical impact of alloimmunization including autoantibody formation and change in RBC-transfusion requirements was assessed. We also assessed risk factors for alloimmunization using recursive partitioning and Cox-regression. Seven hundred and sixty-two patients (76%) were eligible for analysis; 584 (76.5%) PMDS, 56 (7.3%) oligoblastic AML and 123 (16%) were t-MN. The median age was 72 years (range 18-97) and 489 (64%) were males. According to the Revised International Prognostic Scoring System (IPSS-R), 44.9% and 54.9% patients were classified as IPSS-R Very low/Low risk and Intermediate/High/Very high risk, respectively. The CI of alloimmunization in RBC-transfused patients was 15% (Fig 1A) and alloantibodies were most commonly against K (32%), E (26%), C (18%), Jka (10%) & Duffy (3%) antigens. Interestingly, 53% (53/99) of alloimmunized patients had single alloantibody while 46% (46/99) had multiple alloantibodies detected simultaneously or subsequently. RBC requirement was significantly higher in alloimmunized compared to non-alloimmunized patients (80±95 vs 41±58, p<0.0001; Fig 1B). This difference is unlikely due to difference in overall survival (OS) as median OS of the two groups was not significantly different (27.5 vs 33.7 months; p=0.2). Importantly, RBC requirement of alloimmunized patients significantly increased after alloantibody formation (22±38 vs 57±82, p<0.0001; Fig 1C). This increase is unlikely to be due to difference in follow-up period before and after alloimmunization (12.3 vs 10.7 months; p=0.9). RBC transfusion requirement increased following single (24±44 vs 49±91; p=0.005; Fig 1D) and multiple (21±31 vs 67±70; p<0.0001; Fig 1E) alloantibody formation. RBC requirement prior to alloimmunization was not significantly different between patients with single and multiple alloantibodies (24±44 vs 21±31; p=0.9); however following alloimmunization, it was higher in patients with multiple alloantibodies compared to single alloantibody (49±91 vs 67±70; p=0.06). Increase in RBC requirement following alloimmunization could partly be due to autoantibody formation.The 12-month CI of autoantibody formation was significantly higher in alloimmunized patients compared to non-alloimmunized (31 vs 1.7%; p<0.0001; Fig 1F) and 26% of autoantibodies were detected within 3 months of alloimmunization indicating temporal relation between alloimmunization and autoantibody formation. Within alloimmunized patients, more patients with multiple alloantibodies developed autoantibodies as compared to patients with single alloantibody (67% vs 31%; p<0.001). We then compared impact of autoantibodies on RBC transfusion requirements. Baseline RBC requirement in alloimmunized patients with and without autoantibodies was not significantly different (25.4±34.6 vs 20.4±41.5; p=0.2). However, RBC transfusion requirement following alloimmunization was significantly higher in patients developing autoantibodies compared to patients without autoantibodies (82.51±110 vs 35.61±35.93; p=0.003). In our large cohort of 1002 patients, 15% of RBC transfused patients develop alloantibodies, most commonly against Rh and Kell. The RBC transfusion requirement increases after alloimmunization, most probably due to formation of multiple subsequent alloantibodies and autoantibodies. Hence, we recommend extended phenotype matched RBC transfusion to MDS patients. Disclosures Ross: Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Hiwase:Celgene: Research Funding; Novartis: Research Funding.
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Beerlage, Astrid, Joerg Halter, Sabine Gerull, Michael Medinger, Tanja Ruefli, Georg Stussi, Dominik Heim, et al. "Red Blood Cell Allo-Antibodies after Allogeneic Hematopoietic Stem Cell Transplantation." Blood 132, Supplement 1 (November 29, 2018): 2551. http://dx.doi.org/10.1182/blood-2018-99-116237.
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Abstract Introduction Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) may require red blood cell (RBC) transfusions. AB0 blood group barrier is the clinically most important RBC group in transfusion medicine and HSCT and patients always receive AB0 compatible RBC transfusions. Some patients however develop allo-antibodies against minor RBC antigens. To date there is only limited information about the specificity, immuniser and risk factors for the development of RBC allo-antibodies. In this retrospective single centre study we aimed to identify specificities, risk factors and clinical significance of the development of RBC allo-antibodies in HSCT patients. Methods In this study, we examined the occurrence of RBC alloantibodies in all consecutive patients treated with allogeneic HSCT at the University Hospital Basel between 1996 and 2017 receiving RBC transfusions. RBC and PLT components were all leukocyte depleted. As of 2012, all PLT components were pathogen reduced using the Intercept Blood system. AB0 and extended RBC typing of donor/ recipient pairs, the total number of RBC transfusions and their blood group typing (AB0 and extended RBC antigen typing when available) and the detection of RBC allo-antibodies were analysed and related to clinical outcome parameters. Results 1314 donor/ recipient pairs were analysed. 110 (13%) of patients developed RBC allo-antibodies, 66 patients (5%) prior to HSCT, and 103 (8%) developed the first RBC allo-antibody after HSCT. 8 patients (0.6%) with an RBC allo-antibody before HSCT developed further RBC allo-antibodies after HSCT. Most patients developed only one RBC allo-antibody but in single patients up to 6 antibodies could be detected. The median time between HSCT and the detection of the antibody was 61 days, corresponding to the phase of the most intensive immunosuppressive treatment. In 60% of the patients developing RBC allo-antibodies after HSCT, the antibody was neither directed against the stem cell donor nor the recipient. In these cases, immunization occurred most likely by RBC transfusion. Anti-Rhesus-group antibodies are the most common antibodies (57%). >10 RBC transfusions and the development of GvHD were risk factors for the development of antibodies. There was no significant difference in the occurrence of RBC allo-antibodies between donor type (related vs. unrelated), age or sex of the recipient. Only few patients showed significant haemolysis in the period of the detection of the antibody. The direct antiglobulin test (DAT) was positive in 66% of the cases. Haemolysis defined as an increase of bilirubin, LDH or reticulocytes and a haemoglobin drop of more than 10 g/l could only be reported in 6% of the cases with antibodies detected. The development of RBC allo-antibodies per se has no effect on the survival of patients (1y-survival 70±3% (without antibody) versus 68 ± 9%). However, evidence of haemolysis (even without drop of haemoglobin) in the context of allo-antibodies, is associated with significantly worse survival (1y- survival 75 ± 10% versus 42 ± 20%). Conclusion Allo-Antibodies after HSCT significantly contribute to the difficulties in transfusion management of these patients. Formation of RBC allo-antibodies is not frequent, but patients showing haemolysis after the development of an RBC allo-antibody show decreased survival. Most RBC allo-antibodies appear to be induced by RBC transfusion rather than by minor blood group mismatching between donor/ recipient pairs. Disclosures Heim: Novartis: Research Funding.
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Revskij, Denis, Susanne Haubold, Torsten Viergutz, Claudia Kröger-Koch, Armin Tuchscherer, Hermine Kienberger, Michael Rychlik, et al. "Dietary Fatty Acids Affect Red Blood Cell Membrane Composition and Red Blood Cell ATP Release in Dairy Cows." International Journal of Molecular Sciences 20, no. 11 (June 5, 2019): 2769. http://dx.doi.org/10.3390/ijms20112769.
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Diets of dairy cows are often based on maize silage (MS), delivering lower amounts of n-3 fatty acids (FA) compared to grass silage-based diets. The fatty acid composition of the cell membrane can affect the cell function. We evaluated the effects of an MS-based diet on bovine red blood cell (RBC) membrane FA composition and dietary effects on controlled ATP release of RBC. In trial 1, German Holstein cows were fed an MS-based total mixed ration for 24 weeks. The FA composition of RBC membranes from repeatedly taken blood samples was analysed in addition to the abundance of the RBC membrane protein flotillin-1, which is involved in, for example, cell signalling. In trial 2, four rumen fistulated MS-fed cows were abomasally infused in a 4 × 4 Latin square model with three successively increasing lipid dosages (coconut oil, linseed–safflower oil mix (EFA; rich in n-3 FA), Lutalin®, providing conjugated linoleic acids (CLA) or the combination of the supplements, EFA + CLA) for six weeks, followed by a three-week washout period. In trial 2, we analysed RBC ATP release, flotillin-1, and the membrane protein abundance of pannexin-1, which is involved in ATP release as the last part of a signalling cascade. In trial 1, the total amount of n-3 FA in RBC membranes decreased and the flotillin-1 abundance increased over time. In trial 2, the RBC n-3 FA amount was higher after the six-week infusion period of EFA or EFA + CLA. Furthermore, depending on the dosage of FA, the ATP release from RBC increased. The abundance of flotillin-1 and pannexin-1 was not affected in trial 2. It is concluded that changes of the membrane FA composition influence the RBC function, leading to altered ATP release from intact bovine RBC.
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Risinger, Mary, and Theodosia A. Kalfa. "Red cell membrane disorders: structure meets function." Blood 136, no. 11 (September 10, 2020): 1250–61. http://dx.doi.org/10.1182/blood.2019000946.
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Abstract The mature red blood cell (RBC) lacks a nucleus and organelles characteristic of most cells, but it is elegantly structured to perform the essential function of delivering oxygen and removing carbon dioxide from all other cells while enduring the shear stress imposed by navigating small vessels and sinusoids. Over the past several decades, the efforts of biochemists, cell and molecular biologists, and hematologists have provided an appreciation of the complexity of RBC membrane structure, while studies of the RBC membrane disorders have offered valuable insights into structure–function relationships. Within the last decade, advances in genetic testing and its increased availability have made it possible to substantially build upon this foundational knowledge. Although disorders of the RBC membrane due to altered structural organization or altered transport function are heterogeneous, they often present with common clinical findings of hemolytic anemia. However, they may require substantially different management depending on the underlying pathophysiology. Accurate diagnosis is essential to avoid emergence of complications or inappropriate interventions. We propose an algorithm for laboratory evaluation of patients presenting with symptoms and signs of hemolytic anemia with a focus on RBC membrane disorders. Here, we review the genotypic and phenotypic variability of the RBC membrane disorders in order to raise the index of suspicion and highlight the need for correct and timely diagnosis.
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Alfrey, C. P., M. M. Udden, C. Leach-Huntoon, T. Driscoll, and M. H. Pickett. "Control of red blood cell mass in spaceflight." Journal of Applied Physiology 81, no. 1 (July 1, 1996): 98–104. http://dx.doi.org/10.1152/jappl.1996.81.1.98.
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The effect of spaceflight on red blood cell mass (RBCM), plasma volume (PV), erythron iron turnover, serum erythropoietin, and red blood cell (RBC) production and survival and indexes were determined for six astronauts on two shuttle missions, 9 and 14 days in duration, respectively. PV decreased within the first day. RBCM decreased because of destruction of RBCs either newly released or scheduled to be released from the bone marrow. Older RBCs survived normally. On return to Earth, plasma volume increased, hemoglobin concentration and RBC count declined, and serum erythropoietin increased. We propose that entry into microgravity results in acute plethora as a result of a decrease in vascular space. PV decreases, causing an increase in hemoglobin concentration that effects a decrease in erythropoietin or other growth factors or cytokines. The RBCM decreases by destruction of recently formed RBCs to a level appropriate for the microgravity environment. Return to Earth results sequentially in acute hypovolemia as vascular space dependent on gravity is refilled, an increase in plasma volume, a decrease in hemoglobin concentration (anemia), and an increase in serum erythropoietin.
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Jajosky, Ryan, Connie Arthur, Jerry Allen, Megan Fuller, Patricia E. Zerra, Cheryl Maier, and Sean R. Stowell. "CD47 Regulates Red Blood Cell Alloimmunization in Mice." Blood 134, Supplement_1 (November 13, 2019): 100. http://dx.doi.org/10.1182/blood-2019-131598.
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Background: Exposure to red blood cell (RBC) alloantigens during pregnancy or transfusion can lead to the development of alloantibodies and result in transfusion-related complications, including hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. However, the factors that regulate RBC alloimmunization remain incompletely understood. Several studies suggest that alterations in factors that regulate RBC clearance may impact RBC uptake and antigen presentation, directly influencing the likelihood of RBC alloimmunization. To test this, we directly examined the potential role of CD47, a master regulator of RBC removal previously shown to be altered during RBC senescence and cold storage. To accomplish this, we crossed transgenic mice that express the model HOD antigen (a fusion protein consisting of hen egg lysozyme fused to ovalbumin and human Duffy b) with CD47 knock out (KO) mice to generate HOD RBC donors with wild type, heterozygous or homozygous KO levels of CD47 and used these donors to define the impact of CD47 on antibody formation following RBC transfusion. Methods: HOD transgenic mice expressing the HOD antigen exclusively on RBCs were crossed with CD47-/- mice to produce HOD CD47+/- or HOD CD47-/- mice. HOD and CD47 levels were assessed by flow cytometric analysis using anti-HOD and anti-CD47 antibodies. HOD CD47+/+, HOD CD47+/- or HOD CD47-/- RBCs were transfused into C57BL6 recipients, followed by serum collection on days 14 and 28 post transfusion and evaluation of anti-HOD antibodies by flow cytometry crossmatch. To determine the CD4 T cell response to transfusion, TCR transgenics specific to ovalbumin (OTII) were labeled with CFSE, followed by adoptive transfer, transfusion of HOD CD47+/+, HOD CD47+/- or HOD CD47-/- RBCs and evaluation of T cell proliferation, activation and cytokine secretion. Cellular removal of HOD RBCs was determined by flow cytometric examination of CFSE-labeled HOD RBCs. Finally, antigen levels on HOD RBCs was determined by staining cells with anti-HEL antibodies followed by flow cytometric examination. All three groups were subjected to one-way ANOVA analysis with a p value <0.05 considered significant. Results: While HOD CD47+/+ RBCs expressed levels of CD47 comparable to WT RBCs, HOD CD47+/- RBCs exhibited significantly reduced CD47 levels (nearly half that observed on WT HOD RBCs) and HOD CD47-/-RBCs failed to express any detectable CD47 (p < 0.0001). Following transfusion, HOD CD47+/- and HOD CD47-/- RBCs produced significantly higher levels of IgG anti-HOD antibodies than HOD CD47+/+ RBCs on days 14 and 28 post-transfusion (p < 0.001). However, while HOD CD47-/- RBCs displayed increased clearance consistent with the possible enhancement of a CD4 T cell response (p < 0.0001), HOD CD47+/- RBCs failed to exhibit any different in clearance when compared to HOD CD47+/+ RBCs overtime. To examine the potential impact of differences in HOD RBC clearance on CD4 T cell activation, OTII T cell proliferation was evaluated. While HOD CD47-/- RBC transfusion resulted in significantly increased 33D1+ dendritic cell uptake, OTII proliferation, activation and cytokine secretion (p < 0.05), no difference in 33D1+ dendritic cell uptake or T cell response was observed following HOD CD47+/+ RBC or HOD CD47+/- RBC transfusion. Instead, HOD CD47+/- RBCs exhibited enhanced antigen removal, while also displaying an increased ability to activate HEL specific B cells when compared to HOD CD47+/+ or HOD CD47-/- RBC transfusion. Conclusions: These results demonstrate that alterations in CD47, which occur during normal RBC senescence and cold storage, directly influence RBC alloimmunization through different mechanisms depending on the extent of CD47 loss. While complete loss of CD47 results in enhanced RBC clearance, antigen presentation and CD4 T cell activation, reductions in CD47 to half WT levels failed to impact RBC clearance or T cell activation, but instead enhanced antigen specific B cell activation. These results demonstrate that even partial loss of CD47 is capable of significantly enhancing alloantibody formation completely independent of its role in regulating RBC clearance. In doing so, these findings provide novel insight into the role of CD47 as a key regulator of RBC alloimmunization. Disclosures Stowell: Grifols: Honoraria.
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Puig-de-Morales-Marinkovic, Marina, Kevin T. Turner, James P. Butler, Jeffrey J. Fredberg, and Subra Suresh. "Viscoelasticity of the human red blood cell." American Journal of Physiology-Cell Physiology 293, no. 2 (August 2007): C597—C605. http://dx.doi.org/10.1152/ajpcell.00562.2006.
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We report here the first measurements of the complex modulus of the isolated red blood cell (RBC). Because the RBC is often larger than capillary diameter, important determinants of microcirculatory function are RBC deformability and its changes with pathologies, such as sickle cell disease and malaria. A functionalized ferrimagnetic microbead was attached to the membrane of healthy RBC and then subjected to an oscillatory magnetic field. The resulting torque caused cell deformation. From the oscillatory forcing and resulting bead motions, which were tracked optically, we computed elastic and frictional moduli, g′ and g‴, respectively, from 0.1 to 100 Hz. The g′ was nearly frequency independent and dominated the response at all but the highest frequencies measured. Over three frequency decades, g‴ increased as a power law with an exponent of 0.64, a result not predicted by any simple model. These data suggest that RBC relaxation times that have been reported previously, and any models that rest upon them, are artifactual; the artifact, we suggest, arises from forcing to an exponential fit data of limited temporal duration. A linear range of response was observed, but, as forcing amplitude increased, nonlinearities became clearly apparent. A finite element model suggests that membrane bending was localized to the vicinity of the bead and dominated membrane shear. While the mechanisms accounting for these RBC dynamics remain unclear, methods described here establish new avenues for the exploration of connections among the mechanical, chemical, and biological characteristics of the RBC in health and disease.
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Hendrickson, Jeanne E., and Christopher A. Tormey. "Understanding red blood cell alloimmunization triggers." Hematology 2016, no. 1 (December 2, 2016): 446–51. http://dx.doi.org/10.1182/asheducation-2016.1.446.
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Abstract Blood group alloimmunization is “triggered” when a person lacking a particular antigen is exposed to this antigen during transfusion or pregnancy. Although exposure to an antigen is necessary for alloimmunization to occur, it is not alone sufficient. Blood group antigens are diverse in structure, function, and immunogenicity. In addition to red blood cells (RBCs), a recipient of an RBC transfusion is exposed to donor plasma, white blood cells, and platelets; the potential contribution of these elements to RBC alloimmunization remains unclear. Much attention in recent years has been placed on recipient factors that influence RBC alloantibody responses. Danger signals, identified in murine and human studies alike as being risk factors for alloimmunization, may be quite diverse in nature. In addition to exogenous or condition-associated inflammation, autoimmunity is also a risk factor for alloantibody formation. Triggers for alloimmunization in pregnancy are not well-understood beyond the presence of a fetal/maternal bleed. Studies using animal models of pregnancy-induced RBC alloimmunization may provide insight in this regard. A better understanding of alloimmunization triggers and signatures of “responders” and “nonresponders” is needed for prevention strategies to be optimized. A common goal of such strategies is increased transfusion safety and improved pregnancy outcomes.
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Kumar, Priyatham. "Deep Vein Thrombosis and Pulmonary Embolism in Sickle Cell Disease." Biomedical Research and Clinical Reviews 1, no. 5 (December 4, 2020): 01–04. http://dx.doi.org/10.31579/2692-9406/024.
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Sickle Cell Disease (SCD) is considered a group of genetic red blood cell (RBC) disorders. Healthy red blood cells (RBC) are round in shape and migrates throughout the body to carry oxygen in the small blood vessels. In SCD, the RBC turns into hard and sticky, and the shape is similar to a C-Shaped tool called "SICKLE." Because of the early death of the sickle cells, a constant shortage of red blood cells arises. Because of the typical shape of the sickle cells, their movement in the blood vessel is not as smooth as normal RBC and get stuck and clog the blood flow leading to anemia. The changes in shape make the cells more easily destroyed, causing anemia. Defective hemoglobin is the primary cause of SCD.
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Tomita, M., F. Gotoh, N. Tanahashi, and P. Turcani. "Whole-blood red blood cell aggregometer for human and feline blood." American Journal of Physiology-Heart and Circulatory Physiology 251, no. 6 (December 1, 1986): H1205—H1210. http://dx.doi.org/10.1152/ajpheart.1986.251.6.h1205.
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A whole-blood aggregometer of red blood cells (RBC) is described. It consists of a transparent 0.26-cm ID vinyl tube of approximately 30 cm in length containing freshly drawn heparinized blood and a densitometer head that is attached to the tube. The densitometer head consists of an infrared light source of gallium arsenide and a light detector (silicon photodiode) to monitor changes in optical density of the blood in the tube. The tube and densitometer head were installed in a temperature-controlled box at 37 degrees C. The blood in the tube was first subjected to rapid flow with a solenoid so that the wall shear rate of the blood was approximately 500 s-1. The shear gave rise to a rapid increase in optical density of the blood due to dispersion of the blood corpuscles. The blood was then brought abruptly to a full stop. After the flow had stopped the densitometer head revealed a gradual decrease in optical density in association with RBC aggregate formation. The resultant pattern was termed by us an “RBC aggregogram.” The RBC aggregogram exhibited an exponential decay in its initial part, which was followed by an asymptotic decrease. A simple mathematical procedure was employed to calculate the rate constant of the initial decrease from the two values on the RBC aggregogram at 10 and 20 s. The rate constant k10 was 0.192 +/- 0.028 (5.2 s as time constant; 3.6 s as half time) for feline blood and 0.129 +/- 0.012 (7.7 s as time constant; 5.3 s as half time) for human blood. The RBC aggregation rate varied linearly with the hematocrit below 40%.
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Stussi, Georg, Andreas Buser, and Andreas Holbro. "Red Blood Cells: Exchange, Transfuse, or Deplete." Transfusion Medicine and Hemotherapy 46, no. 6 (2019): 407–16. http://dx.doi.org/10.1159/000504144.
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Erythrocytapheresis, red blood cell (RBC) depletion, and RBC exchange transfusions are apheresis techniques used to rapidly lower the circulating RBC mass or to exchange the patient erythrocyte mass with donor RBC. Automated RBC exchange is performed using an apheresis device, while manual RBC exchange is based on sequential phlebotomies and isovolemic replacement. Compared to simple RBC transfusions, RBC exchange offers several advantages, e.g., a lower risk for iron accumulation and efficient control of pathological erythrocyte populations. Disadvantages are the higher costs of the procedure, the increased use of donor RBC, and the requirement of apheresis devices and trained hospital staff. The most frequent indication for RBC exchange is sickle cell disease (SCD). RBC exchange transfusions are standard treatment in SCD patients with a history of or a risk for acute stroke and are clinical options for other acute complications of SCD. The most common indication for RBC depletion is the removal of donor RBC from the bone marrow grafts in major ABO-incompatible allogeneic hematopoietic stem cell transplantation to avoid immediate hemolysis. Rare indications for RBC exchange are severe infections with intraerythrocytic pathogens such as malaria or babesiosis and severe erythrocytosis or hereditary hemochromatosis where the aim is to rapidly decrease RBC populations or the iron content. However, only few high-quality studies are available looking at the efficacy of RBC exchange in the different disease entities, and treatment is often based on low levels of evidence and should therefore be decided in close collaboration with a transfusion medicine specialist.
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Islamzada, Emel, Kerryn Matthews, Erik Lamoureux, Mark D. Scott, and Hongshen Ma. "Degradation of Red Blood Cell Deformability during Cold Storage in Blood Bags." Blood 138, Supplement 1 (November 5, 2021): 2143. http://dx.doi.org/10.1182/blood-2021-153760.
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Abstract RBC transfusions are a life-saving procedure, aiding both chronic and acute patients in restoring tissue oxygenation. The ability to store collected RBC units for prolonged periods has been one of the most transformative advances in medicine, significantly improving the reliability and the speed of access to blood. However, RBCs undergo a number of metabolic, structural, and biochemical changes during storage, collectively known as the storage lesion, that is detrimental to the quality of the RBC. A major challenge is the ability to evaluate the extent of the storage lesion, and thus the quality of the stored RBC unit directly prior to transfusion. The storage lesion can directly or indirectly reduce the ability of the RBC to deform through the small openings in the microvasculature. Rigid RBCs pose a risk of sequestration in capillaries, impeding blood flow and reducing tissue oxygenation, and are more likely to be cleared out by endothelial macrophages. Studies have shown that there is a loss in RBC deformability during storage and that the rate of RBC deformability loss is donor-dependent. Thus, RBC deformability can be a valuable and reliable biophysical marker of RBC unit quality. Currently, there is a need for a reliable measurement technique that is repeatable and sensitive enough to observe individual differences in RBC deformability in healthy donors, to enable quality control testing of RBC units. We have developed the microfluidic ratchet device, which sorts RBCs based on their deformability, allowing the measurement of both rigid and deformable sup-populations of RBCs within the sample, and generating a unique deformability curve. Here, we use this assay to predict the quality of stored RBC units. We assessed the deformability of 14 healthy donor RBC units through 8 weeks of cold storage at 4°C, which is 2 weeks beyond the Canadian Blood Services approved 6-week standard in Canada. We measured RBC deformability, standard hematological parameters (MCV, MCHC, MCH, and RDW), and hemolysis levels at the time of RBC unit manufacture (week 0), followed by weeks 2, 4, 6, and 8. The microfluidic ratchet device operates by forcing RBCs to deform and travel through rows of tapered constrictions. Constriction size changes from 7.5 to 1.5 µm and is reflective of the microvasculature and vessel opening sizes encountered by RBCs in circulation. RBCs are sorted into 12 distinct outlets based on their deformability. Distribution of RBCs in outlets 1-12 can be quantified and used to calculate the cumulative distribution curve. The cumulative distribution curve provides a distinct deformability signature of each individual RBC sample, which can be defined as rigidity score (RS). RS provides an easy metric to compare the changes in RBC deformability throughout storage (ΔRS) in a single donor as well as across multiple donors. We show that there are both donor- and sex-specific differences in the RBC deformability signatures of stored RBC units. We observed significant inter-donor variability in RBC deformability measured on the day of the RBC unit manufacture, where male donors showed a more stable RBC deformability range (n=8, RS=3.00±0.18) compared to female donors (n=6, RS= 3.29±0.48). The average RS scores were stable between weeks 0-2 (ΔRS 0.07) and showed a reduction in deformability between weeks 1-6 (ΔRS 0.35), with the greatest loss seen between weeks 6-8 (ΔRS 0.42) of cold storage. Interestingly, the response to cold storage is variable, with ΔRS 0.22 to 0.90, suggesting that some donors are more susceptible to storage related changes in RBC deformability than others. Notably, the change in RS over time was donor-specific and did not correlate with RBC deformability at week 0. The majority of RBCs from male donors (ΔRS 0.485, p<0.05), but none of the female donors (ΔRS 0.172) showed changes in deformability during cold storage, suggesting that RBCs from female donors degrade at a slower rate compared to RBCs from male donors. The ability to profile RBC deformability at the individual blood bag level may help identify more stable RBCs for use in chronic and sensitive patients, or RBC units that can be safely stored beyond the 6-week storage window. Disclosures No relevant conflicts of interest to declare.
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Liu, Chang, and Brenda J. Grossman. "Red blood cell transfusion for hematologic disorders." Hematology 2015, no. 1 (December 5, 2015): 454–61. http://dx.doi.org/10.1182/asheducation-2015.1.454.
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Abstract Randomized clinical trials (RCTs) have determined, in surgical and critically ill patients, relatively safe hemoglobin (Hb) thresholds of 7-8 g/dL to guide restrictive transfusion of red blood cells (RBCs). However, in patients with various hematologic disorders, strong evidence in support of such an approach is sparse and the optimal transfusion practice is yet to be defined. This review focuses on RBC transfusion practice in three hematologic diseases and a treatment strategy, including autoimmune hemolytic anemia, thalassemia, myelodysplastic syndrome, and hematopoietic stem cell transplantation. These entities manifest in a broad spectrum of anemia, acute or chronic, in patients with different comorbidities and degrees of transfusion requirement. Thus the nuances in the indications of RBC transfusion and the goals to achieve in these specific situations may have been underappreciated. The limited data available highlight the importance of titrating RBC transfusion based on the clinical context and patient characteristics. Future RCTs are necessary to firmly establish the Hb thresholds associated with improved outcomes relevant to these specific patient populations, which will facilitate the personalized decision-making in RBC transfusion.
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Detterich, Jon, Adam M. Bush, Roberta Miyeko Kato, Rose Wenby, Thomas D. Coates, Herbert Meiselman, and John C. Wood. "Abnormal Red Cell Deformability and Aggregation in Sickle Cell Trait." Blood 120, no. 21 (November 16, 2012): 1001. http://dx.doi.org/10.1182/blood.v120.21.1001.1001.
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Abstract Abstract 1001 Introduction: SCT occurs in 8% of African Americans and is not commonly associated with clinical disease. Nonetheless, the United States Armed Forces has reported that SCT conveys a 30-fold risk of sudden cardiac arrest and a 200-fold risk from exertional rhabdomyolysis. In fact, rhabdomyolysis in athletes with SCT has been the principal cause of death in NCAA football players in the last decade, leading to recently mandated SCT testing in all Division-1 players. In SCT, RBC sickle only under extreme conditions and with slow kinetics. Therefore, rhabdomyolysis most likely occurs in SCT when a “perfect storm” of factors converges to critically imbalance oxygen supply and demand in muscles. We hypothesize that in SCT subjects, abnormal RBC rheology, particularly aggregation and deformability, play an important role in abnormal muscle blood flow supply and distribution to exercising muscle. To test this hypothesis, we examined whole blood viscosity, RBC aggregation, and RBC deformability in 11 SCT and 10 control subjects prior to and following maximum handgrip exercise. Methods: Maximum voluntary contraction (MVC) was assessed by handgrip dynamometer in the dominant arm. Baseline blood was collected for CBC, whole blood viscosity, RBC aggregation, and RBC deformability. Patients then maintained 60% MVC exercise until exhaustion. Following 8 minutes of recovery, a venous blood gas and blood for repeat viscosity assessments was collected from the antecubital fossa of the exercising limb. Whole blood viscosity over a shear rate range of 1–1, 000 1/s was determined by an automated tube viscometer, RBC deformability from 0.5–50 Pa via laser ektacytometry (LORCA) and RBC aggregation in both autologous plasma and 3% dextran 70 kDa using an automated cone-place aggregometer (Myrenne). Aggregation measurements included extent at stasis (M), strength of aggregation (GT min) and kinetics (T ½). Results: Baseline CBC and aggregation values are summarized in Table 1. Both static RBC aggregation in plasma and RBC aggregation in dextran (aggregability) were significantly increased in SCT (Table 1). The rate of aggregation formation trended higher in SCT but the strength of aggregation was not different between the two groups. In SCT subjects, red cell deformability was impaired at low shear stress but greater than controls at higher shear stress (Figure 1). Red cell deformability was completely independent of oxygenation status states in both SCT and control subjects. Whole blood viscosity did not different between the two groups whether oxygenated or deoxygenated and prior to or following handgrip exercise. Discussion: Three important hemorheological differences were observed for SCT subjects versus controls: a) RBC deformability was below control at low stress levels yet greater than control at higher stress; b) The extent of RBC aggregation in autologous plasma was about 40% greater; c) The extent of RBC aggregation for washed RBC re-suspended in an aggregating medium (i.e., 3% dextran 70 kDa) was about 30% higher. RBC deformability is a major determinant of in vivo blood flow dynamics, especially in the microcirculation; decreased deformability adversely affects tissue perfusion. RBC aggregation is also an important determinant since it affects both resistance to blood flow and RBC distribution in a vascular bed (e.g., plasma skimming). The finding of greater aggregability (i.e., higher aggregation in the defined dextran medium) indicates that RBC in SCT have an altered membrane surface in which the penetration of this polymer into the glycocalyx is abnormal. The combined effects of these three rheological parameters is likely to impair in vivo blood flow in SCT, perhaps to a degree resulting in pathophysiological changes of the cardiovascular system. Disclosures: Coates: Novartis: Speakers Bureau; Apopharma: Consultancy. Wood:Ferrokin Biosciences: Consultancy; Shire: Consultancy; Apotex: Consultancy, Honoraria; Novartis: Honoraria, Research Funding.
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Snyder, G. K., and R. D. Sears. "Red blood cell size and the Fåhraeus–Lindqvist effect." Canadian Journal of Zoology 84, no. 3 (March 1, 2006): 419–24. http://dx.doi.org/10.1139/z06-011.
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The reason for the large interspecies variation in vertebrate red blood cell (RBC) size is poorly understood. To test the effect of RBC size on blood viscosity, blood samples from two vertebrates, the dog (Canis familiaris L., 1758) and the greater siren (Siren lacertina L., 1766), with extremely different RBC sizes were examined. In this study, we examined whether RBC size altered the relationship of viscosity and viscometer tube diameter, the well-known Fåhraeus–Lindqvist effect (FLE). We used a glass capillary viscometer that incorporates tubes with a diameter narrow enough to evoke the FLE. At similar RBC concentrations, viscosity of suspensions with the larger siren RBCs were greater than the viscosity of suspensions with the smaller dog RBCs. However, the relationship between viscosity and tube diameter is independent of RBC size. The results of this study allow us to conclude that the FLE is not related to RBC size. While packaging hemoglobin in RBCs appears adaptive by reducing blood viscosity through the FLE, RBC size does not contribute to the reductions in tube-relative viscosity.
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Maier, Cheryl L., Ryan Jajosky, Hans Verkerke, Seema R. Patel, Jerry William Allen, Megan Fuller, and Sean R. Stowell. "Storage Differentially Impacts Immunization to Red Cell Antigens." Blood 138, Supplement 1 (November 5, 2021): 3239. http://dx.doi.org/10.1182/blood-2021-152670.
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Abstract Introduction: The impact of red blood cell (RBC) storage on alloimmunization rates after transfusion remains controversial, with clinical experience demonstrating conflicting results. Indeed, some reports suggest increased rates of alloimmunization associated with longer storage of RBC units, while others suggest no association between alloimmunization rates and length of storage. We hypothesized that this discrepancy may reflect the differential impact of storage on alloimmunization related to each unique antigen and the immune response elicited. Here we define the effect of red cell storage on two distinct antigens, including the Hel-Ova-Duffy (HOD) and KEL antigens, using a preclinical murine model of RBC storage and transfusion. Methods: RBCs singly expressing HOD (HOD RBC) or KEL (KEL RBC) antigens, in addition to those dually expressing both HOD and KEL (HOD x KEL RBC) antigens, were collected from respective transgenic donor mice into CPDA. Units of HOD, KEL or HOD x KEL RBC were generated and used immediately (fresh RBC), or stored for 8 (D8) or 14 (D14) days at 4C before transfusion into wildtype recipients. Recipient cytokine profiles were assessed 2 hours post-transfusion using a multiplex inflammation panel. Donor RBC survival at 24 hours post-transfusion was assessed by flow cytometry. Serum was collected from recipients on days 5 and 14 post-transfusion and analyzed for IgM or IgG development by flow-cytometric crossmatch using HOD or KEL RBC targets. Results: Post-transfusion RBC survival was decreased with increased storage, but was not significantly different between donor cell types (HOD, KEL or HOD x KEL). Recipient cytokine profiles demonstrated a distinct inflammatory profile associated with storage. Development of IgM antibodies against HOD in mice transfused fresh versus D8 or D14 HOD or HOD x KEL RBCs were not significantly different; however, significantly increased (p<0.05) IgG antibodies were detected in recipients transfused with D8 and D14 HOD or HOD x KEL RBCs as compared to those transfused fresh HOD or HOD x KEL RBCs. In contrast, and while the development of anti-KEL IgM antibodies was not significantly different in mice transfused fresh versus D8 or D14 KEL or HOD x KEL RBCs, the IgG response to KEL was abrogated with longer storage, with recipients generating significantly less (p<0.05) anti-KEL IgG following transfusion with stored KEL or HOD x KEL RBCs as compared to fresh HOD or HOD x KEL RBCs. Conclusions: Although the impact of RBC storage on various measures of transfusion efficacy have been determined, the impact of storage on alloimmunization remains incompletely understood. Using a murine model of transfusion, we demonstrate that storage differentially impacts immunization to red cell antigens, increasing the response to certain antigens, like HOD, while decreasing the response to others, like KEL. Although it is unclear whether these findings apply to other RBC antigens and what relevance this holds for human patients, our study provides insight into the impact of storage on red cell alloimmunization and may enlighten future storage protocols. Disclosures Stowell: Argenx: Speakers Bureau; Grifols: Speakers Bureau; Alexion: Consultancy.
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Piyathilake, Chandrika J., Constance B. Robinson, and Phillip Cornwell. "A Practical Approach to Red Blood Cell Folate Analysis." Analytical Chemistry Insights 2 (January 2007): 117739010700200. http://dx.doi.org/10.4137/117739010700200010.
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The measurement of folate in red blood cells (RBCs) is preferred since it reflects long-term folate status in the body compared to plasma/serum folate which may be influenced by recent dietary intake. The commonly accepted technique for RBC folate analysis involves preparation of a hemolysate using a fresh whole blood sample. Hematocrit and plasma folate concentrations are needed to calculate RBC folate values. Because of the need for immediate access to a laboratory where processing can be performed, it may not be practical to assess RBC folate status using this method in field-based epidemiological studies. It is however, feasible to isolate packed RBSs from a blood sample under these conditions. The purpose of this study is to validate RBC folate analysis using packed red cells by comparing the RBC folate values obtained by hemolysate method (routine assay) with those obtained by using packed RBCs (new assay) in the same individuals (n = 50) using the folate microbiological assay. The correlation between plasma folate and the routine RBC folate assay (r = 0.58, p = 0.001) and the correlation between plasma folate and the new RBC folate assay was statistically significant (r = 0.55, p = 0.001). The correlation between RBC folate by the routine assay and new assay was also statistically significant (r = 0.78, p < 0.001). We conclude that measurement of folate in packed RBC is a practical approach in assessing long-term folate status in field-based and or larger scale epidemiological studies where an immediate access to a laboratory is unavailable for necessary sample processing for the routine RBC folate assay.
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Quist, Erin, and Scott Koepsell. "Autoimmune Hemolytic Anemia and Red Blood Cell Autoantibodies." Archives of Pathology & Laboratory Medicine 139, no. 11 (November 1, 2015): 1455–58. http://dx.doi.org/10.5858/arpa.2014-0337-rs.
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Autoimmune hemolytic anemia is a rare disorder caused by autoreactive red blood cell (RBC) antibodies that destroy RBCs. Although autoimmune hemolytic anemia is rare, RBC autoantibodies are encountered frequently and can complicate transfusion workups, impede RBC alloantibody identification, delay distribution of compatible units, have variable clinical significance that ranges from benign to life-threatening, and may signal an underlying disease or disorder. In this review, we discuss the common presenting features of RBC autoantibodies, laboratory findings, ancillary studies that help the pathologist investigate the clinical significance of autoantibodies, and how to provide appropriate patient care and consultation for clinical colleagues. Pathologists must be mindful of, and knowledgeable about, this entity because it not only allows for direct clinical management but also can afford an opportunity to preemptively treat an otherwise silent malignancy or disorder.
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Girelli, G., P. De Fabritiis, G. Menichella, R. Serafini, M. L. Foddai, M. Di Carlo, A. D'Angiolino, and M. Migliaccio. "Multicomponent Collection: The Experience of Regione Lazio." International Journal of Artificial Organs 21, no. 6_suppl (May 1998): 23–25. http://dx.doi.org/10.1177/039139889802106s05.
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Five blood banks of Regione Lazio implemented a multicomponent collection program using apheresis technology. The automated collection of blood components included: red blood cell concentrate and fresh plasma (RBCP), plasma and platelet concentrate (P-PLT), red blood cell and platelet concentrates (RBC-PLT). 334 voluntary blood donors and 30 patients - as autologous donors- were involved. Apheresis collection of RBCP, P - PU, RBC - PLT yielded a standardized product (adequate volume, low residual leucocyte counts, adeguate hematocrit, low platelet contamination) was well tolerated by donors, was performed without technical problems. We conclude that multicomponent collection is a new feasible alternative to conventional whole blood collection.
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Zabeida, Alexandra, Nancy Robitaille, Marc Lebel, and Christian Renaud. "Reevaluating Immunization Delays Post Red Blood Cell Transfusion." Paediatrics & Child Health 23, suppl_1 (May 18, 2018): e58-e58. http://dx.doi.org/10.1093/pch/pxy054.147.
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Abstract BACKGROUND Current Canadian guidelines recommend to delay the measles, mumps, rubella (MMR) and varicella live attenuated vaccines by 6 months following transfusion of unwashed red blood cells (RBC) due to potential interference by serum antibodies. Thus, patients chronically transfused with RBC commonly suffer from a delay or absence of MMR and varicella vaccination. Over the last decades, not only has RBC handling changed, but also fewer blood donors have had natural mumps, measles and rubella infections, resulting in lower blood antibody levels. The recommendations may thus be unfounded and outdated, and prevent valuable vaccination opportunities for children with frequent blood transfusions. OBJECTIVES The primary aim of this project was to determine MMR vaccination immunogenicity in patients chronically transfused with RBC. DESIGN/METHODS Medical charts were reviewed for vaccination and transfusion histories. MMR-specific antibodies were quantified in 25 paediatric patients who received both doses of the MMR vaccine at 12 and 18 months of age while they were on a chronic RBC transfusion program for sickle cell disease, B-thalassemia major, Diamond-Blackfan anemia or pyruvate kinase deficiency. There was no formal control group; long-term immunity rates in the literature are ≥90% for all MMR components. RESULTS Table 1 shows immunogenicity to MMR vaccine components. Delays between vaccination and serology testing averaged 5.9 years (0.3 to 15.8 years). CONCLUSION To the best of our knowledge, this is the first study designed to measure the effect of RBC transfusions on MMR vaccine immunogenicity. Although lower than the rates reported in the literature, the results suggest a high rate of immunogenicity to each component of the MMR vaccine in chronically transfused patients. Weighing the risks and benefits of disease prevention in a highly vulnerable population, a reevaluation of immunization delays post RBC transfusions is called for.
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Kuo, Kevin H. M., and David Barth. "A Comparison of Automated Red Blood Cell Depletion/Exchange to Automated Red Cell Blood Exchange in Sickle Cell Patients." Blood 120, no. 21 (November 16, 2012): 2281. http://dx.doi.org/10.1182/blood.v120.21.2281.2281.
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Abstract Abstract 2281 Introduction: Chronic red blood cell (RBC) exchange transfusion (RBCX) is employed in the prevention and treatment of complications from sickle cell disease (SCD). Although regular automated RBCX by an apheresis device can consistently maintain a low sickle hemoglobin (HbS) percentage at a relatively constant hematocrit level (Hct) with no iron loading, it exposes the patient to significantly more donor erythrocyte units than simple (top-up) transfusion. Since October 2010 the University Health Network, a sickle cell comprehensive care centre in Canada, has started performing automated depletion RBCX with the Caridian Optia Apheresis System. In depletion/exchange, a portion of the patient's RBC is first cytapheresed by the apheresis device prior to the exchange phase of the procedure, with albumin as colloid replacement to maintain intravascular volume and pressure. The clinical effectiveness of depletion/exchange has not been demonstrated in a systematic manner. A retrospective observational cohort study was conducted to investigate the hypothesis that depletion/exchange RBCX, when compared to traditional automated RBCX, will reduce a patient's donor RBC exposure while providing similar hematological and clinical benefit. The laboratory and clinical outcome 1 year before (October 1, 2009) and 1 year after (October 30, 2011) the introduction of depletion/exchange RBCX were compared on a patient-by-patient, rather than on an aggregate, basis. Results: Seven patients, 2 females, 5 males, median age 29 years (range 26 – 38 years), totaling 135 RBCX sessions were examined. Five patients were homozygous for the sickle mutation and 2 were SC compound heterozygotes (HbSC). Stroke was the most prevalent indication (n = 3). Median interval between exchange sessions was 5 weeks (range 4 – 8 weeks). The fraction cell remaining (FCR) was fixed at 20 and did not change when patients were transitioned from non-depleted to depleted exchange. The minimum Hct was reduced to 0.24 in all patients. The inlet speed of the apheresis device and anticoagulant ratio employed were similar across all patients. There was no significant difference in pre-RBCX HbS (or HbS+C in HbSC patients) in 6 patients (P value ranged from 0.0589 to 0.6870). The pre-RBCX HbS was higher with depletion/exchange in 1 patient (P = 0.0071). There was no significant difference in post-RBCX Hct in 5 patients (P value ranged from 0.1056 to 0.8995), and in 2 patients, the mean post-RBCX Hct was lower with depletion/exchange (P = 0.0004 and 0.0148). The mean RBC volume used was reduced by 25 mL/kg/year with depletion/exchange. The mean volume of albumin used was 6.0 ± 2.5 mL/kg per session. Ferritin remained stable throughout the study period (P = 0.2289). None of the patients were on iron chelators. There was no significant difference in mean duration of RBCX session between depletion/exchange and non-depletion exchange in all patients except one. The median duration of one session was 148 ± 51 min. and 147 ± 43 min. in depletion/exchange and non-depletion exchange respectively. A total of 11 adverse events occurred in 135 sessions, with citrate reaction being the commonest (n = 4). There was no significant difference in the rate of adverse event between depletion and non-depletion RBCX (8/74 and 4/61 respectively, P = 0.3874). There was also no incidence of treatment failure, defined as the occurrence of an SCD-related complication in which the RBCX was intended to prevent, in any of the patients during the entire study period, regardless of RBCX method. Conclusion: In this first clinical study of depletion/exchange, this strategy significantly reduced RBC usage in majority of the patients without any negative impact on laboratory and clinical outcome. The use of depletion/exchange reduced RBC usage by 25 mL/kg/year, equivalent to 5 units of packed RBC in a 60 kg person. Further optimization of the technique by modification of the FCR and minimum Hct may yield higher reduction in RBC usage, thereby reducing the risk of exposure to blood products. Disclosures: No relevant conflicts of interest to declare.
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Yasuda, Toshitaka, Akio Funakubo, Kenli Shimokasa, Shahriar Ahmed, Tetsuya Higami, Tsuyoshi Kawamura, and Yasuhiro Fukui. "ESTIMATION OF RED BLOOD CELL (RBC) DAMAGE BY MEASURING RBC AREA." ASAIO Journal 48, no. 2 (March 2002): 191. http://dx.doi.org/10.1097/00002480-200203000-00263.
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Novak, Robert W. "Red Blood Cell Distribution Width in Pediatric Microcytic Anemias." Pediatrics 80, no. 2 (August 1, 1987): 251–54. http://dx.doi.org/10.1542/peds.80.2.251.
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The RBC distribution width has been reported to be of value in the discrimination of iron deficiency anemia from other microcytic anemias, but studies in pediatric populations are lacking. A population of 734 normal children was studied to establish age-appropriate normal values for RBC distribution width. The RBC distribution width of 47 patients with microcytic anemia was then evaluated. RBC distribution width was elevated in 19 of 22 patients with iron deficiency but was also increased in six of 14 patients with thalassemia trait and two of 11 patients with anemia secondary to inflammatory disease. The resulting discrimination was better than that obtained by using Mentzer's index or the discriminant function in the patients studied. The RBC distribution width, albeit a less then perfect tool, can be of value in evaluating pediatric patients with microcytic anemia.
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Bor-Kucukatay, Melek, Rosalinda B. Wenby, Herbert J. Meiselman, and Oguz K. Baskurt. "Effects of nitric oxide on red blood cell deformability." American Journal of Physiology-Heart and Circulatory Physiology 284, no. 5 (May 1, 2003): H1577—H1584. http://dx.doi.org/10.1152/ajpheart.00665.2002.
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In addition to its known action on vascular smooth muscle, nitric oxide (NO) has been suggested to have cardiovascular effects via regulation of red blood cell (RBC) deformability. The present study was designed to further explore this possibility. Human RBCs in autologous plasma were incubated for 1 h with NO synthase (NOS) inhibitors [ N ω-nitro-l-arginine methyl ester (l-NAME) and S-methylisothiourea], NO donors [sodium nitroprusside (SNP) and diethylenetriamine (DETA)-NONOate], an NO precursor (l-arginine), soluble guanylate cyclase inhibitors (1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one and methylene blue), and a potassium channel blocker [triethylammonium (TEA)]. After incubation, RBC deformability at various shear stresses was determined by ektacytometry. Both NOS inhibitors significantly reduced RBC deformability above a threshold concentration, whereas the NO donors increased deformability at optimal concentrations. NO donors, as well as the NO precursor l-arginine and the potassium blocker TEA, were able to reverse the effects of NOS inhibitors. Guanylate cyclase inhibition reduced RBC deformation, with both SNP and DETA-NONOate able to reverse this effect. These results thus indicate the importance of NO as a determinant of RBC mechanical behavior and suggest its regulatory role for normal RBC deformability.
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Grigorev, Georgii V., Alexander V. Lebedev, Xiaohao Wang, Xiang Qian, George V. Maksimov, and Liwei Lin. "Advances in Microfluidics for Single Red Blood Cell Analysis." Biosensors 13, no. 1 (January 9, 2023): 117. http://dx.doi.org/10.3390/bios13010117.
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The utilizations of microfluidic chips for single RBC (red blood cell) studies have attracted great interests in recent years to filter, trap, analyze, and release single erythrocytes for various applications. Researchers in this field have highlighted the vast potential in developing micro devices for industrial and academia usages, including lab-on-a-chip and organ-on-a-chip systems. This article critically reviews the current state-of-the-art and recent advances of microfluidics for single RBC analyses, including integrated sensors and microfluidic platforms for microscopic/tomographic/spectroscopic single RBC analyses, trapping arrays (including bifurcating channels), dielectrophoretic and agglutination/aggregation studies, as well as clinical implications covering cancer, sepsis, prenatal, and Sickle Cell diseases. Microfluidics based RBC microarrays, sorting/counting and trapping techniques (including acoustic, dielectrophoretic, hydrodynamic, magnetic, and optical techniques) are also reviewed. Lastly, organs on chips, multi-organ chips, and drug discovery involving single RBC are described. The limitations and drawbacks of each technology are addressed and future prospects are discussed.
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An, Ran, Yuncheng Man, Erdem Kucukal, Kevin Cheng, William Wulftange, Jane A. Little, and Umut A. Gurkan. "Contribution of Red Blood Cell Derived Extracellular Vesicles to Sickle Red Blood Cell Adhesion Discerned Using an Endothelialized Microfluidic Assay." Blood 136, Supplement 1 (November 5, 2020): 13–14. http://dx.doi.org/10.1182/blood-2020-142176.
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Introduction: Sickle cell disease (SCD) is an inherited hemoglobinopathy, in which the mutation of a single amino acid in the adult beta chain results in sickle hemoglobin (HbS). Upon deoxygenation, HbS polymerizes in red blood cells (RBCs) and provokes a complex pathophysiology of acute and chronic organ damage. Sickle RBCs have reduced deformability, increased adhesion to the endothelium, and are prone to hemolysis, which further contributes to endothelial dysfunction. Chronic inflammatory processes as well as hemostatic alterations and thrombotic events are common in SCD. Cumulatively, thromboinflammation plays a significant pathophysiologic role in SCD, contributing to venous thromboembolism, vaso-occlusion, ischemia-reperfusion, and chronic organ damage, which cumulatively lead to increased morbidity, health care utilization, and a reduced life expectancy. Several pathophysiological processes in SCD result in the activation of RBCs and in the release of sub-micron particles called extracellular vesicles (EVs). EVs are composed of a lipid bilayer, transmembrane proteins, and enclosing intracellular remnants, including cytosolic proteins, RNA, and micro-RNA (miRNA). EVs can serve as vehicles for cellular communication, in near and remote proximity, and can reflect the parent cell's activation state. In SCD, RBC-derived EVs (REVs) comprise the most prevalent (>50%) subtype. REVs express surface phosphatidylserine (PS), contain heme and miRNAs, and are capable of promoting blood coagulation and a pro-inflammatory/pro-adhesive endothelial phenotype. Despite the significant potential role of REVs as candidate biomarkers, REV associated proinflammatory effects are often evaluated using animal models, or by assessing white blood cell adhesion, and thus do not reflect the well-known clinical heterogeneity and the abnormal RBC adhesion amongst SCD patients. Methods: We have developed an in vitro microfluidic assay, the SCD-EV-BioChip, with which to assess RBC adhesion as a biomarker for REV-mediated lung microvascular endothelial dysfunction. The SCD-EV-BioChip contains microfluidic channels lined with human pulmonary microvascular endothelial cells (HPMECs) that are maintained under precise shear stress and oxygen tension at physiologically and clinically relevant levels. HPMECs were incubated with patient-specific or pooled REVs generated in vitro via exposure of RBCs to calcium ionophore (Fig. 1A&B). We assessed RBC adhesion in 4 healthy subjects (HbAA), 10 homozygous SCD patients (HbSS), and 3 patients with HbSC disease for REV proinflammatory effects using HPMCs exposed to patient specific derived REVs. Results and Discussion: In non-patient-specific testing, adhesion assays were performed on samples from 12 individuals with HbSS, using HPMECs that had been exposed to pooled REVs derived from multiple patients, thus reflecting only patient-specific RBC intrinsic adhesion, rather than patient-specific contribution of RBC derived REVs. Patient specific REV activation of HPMCs (Fig. 1C&D) showed that RBC adhesion was greater in HbSS-containing samples, compared with HbSC or HbAA (Fig. 1B&C). In subjects with HbSS, RBC adhesion to HPMC, activated by patient-specific derived REV, was higher in those without, vs. those with a recent transfusion (non-TX vs. TX, Fig. 1D). However, non-TX samples showed intrinsically less adhesion to HPMECs activated by pooled REVs (Fig. 1E), compared with TX samples. Results suggest a paradoxical association between transfusion history and RBC adhesion in patient specific tests vs. non-patient-specific tests. This association suggests that the minority of RBCs containing HbSS in TX subjects generate fewer or less active patient specific REVs, but that these residual HbSS-RBCs are highly adherent when the endothelium is perturbed by pooled non-patient specific REVs. These data highlight that patient-specific contributions from both REVs and RBCs must be accounted for when describing abnormal RBC adhesion in individuals with SCD. Disclosures An: Hemex Health, Inc.: Patents & Royalties. Little:NHLBI: Research Funding; GBT: Membership on an entity's Board of Directors or advisory committees; GBT: Research Funding; Bluebird Bio: Research Funding; BioChip Labs: Patents & Royalties: SCD Biochip (patent, no royalties); Hemex Health, Inc.: Patents & Royalties: Microfluidic electropheresis (patent, no royalties). Gurkan:Dx Now Inc.: Patents & Royalties; Xatek Inc.: Patents & Royalties; BioChip Labs: Patents & Royalties; Hemex Health, Inc.: Consultancy, Current Employment, Patents & Royalties, Research Funding.
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Tormey, Christopher A., and Jeanne E. Hendrickson. "Transfusion-related red blood cell alloantibodies: induction and consequences." Blood 133, no. 17 (April 25, 2019): 1821–30. http://dx.doi.org/10.1182/blood-2018-08-833962.
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Abstract Blood transfusion is the most common procedure completed during a given hospitalization in the United States. Although often life-saving, transfusions are not risk-free. One sequela that occurs in a subset of red blood cell (RBC) transfusion recipients is the development of alloantibodies. It is estimated that only 30% of induced RBC alloantibodies are detected, given alloantibody induction and evanescence patterns, missed opportunities for alloantibody detection, and record fragmentation. Alloantibodies may be clinically significant in future transfusion scenarios, potentially resulting in acute or delayed hemolytic transfusion reactions or in difficulty locating compatible RBC units for future transfusion. Alloantibodies can also be clinically significant in future pregnancies, potentially resulting in hemolytic disease of the fetus and newborn. A better understanding of factors that impact RBC alloantibody formation may allow general or targeted preventative strategies to be developed. Animal and human studies suggest that blood donor, blood product, and transfusion recipient variables potentially influence which transfusion recipients will become alloimmunized, with genetic as well as innate/adaptive immune factors also playing a role. At present, judicious transfusion of RBCs is the primary strategy invoked in alloimmunization prevention. Other mitigation strategies include matching RBC antigens of blood donors to those of transfusion recipients or providing immunomodulatory therapies prior to blood product exposure in select recipients with a history of life-threatening alloimmunization. Multidisciplinary collaborations between providers with expertise in transfusion medicine, hematology, oncology, transplantation, obstetrics, and immunology, among other areas, are needed to better understand RBC alloimmunization and refine preventative strategies.
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Hu, Zheng, Nico Van Rooijen, and Yong-Guang Yang. "Macrophages prevent human red blood cell reconstitution in immunodeficient mice." Blood 118, no. 22 (November 24, 2011): 5938–46. http://dx.doi.org/10.1182/blood-2010-11-321414.
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Abstract An animal model supporting human erythropoiesis will be highly valuable for assessing the biologic function of human RBCs under physiologic and disease settings, and for evaluating protocols of in vitro RBC differentiation. Herein, we analyzed human RBC reconstitution in NOD/SCID or NOD/SCID/γc−/− mice that were transplanted with human CD34+ fetal liver cells and fetal thymic tissue. Although a large number of human CD45−CD71+ nucleated immature erythroid cells were detected in the bone marrow, human RBCs were undetectable in the blood of these mice. Human RBCs became detectable in blood after macrophage depletion but disappeared again after withdrawal of treatment. Furthermore, treatment with human erythropoietin and IL-3 significantly increased human RBC reconstitution in macrophage-depleted, but not control, humanized mice. Significantly more rapid rejection of human RBCs than CD47-deficient mouse RBCs indicates that mechanisms other than insufficient CD47-SIRPα signaling are involved in human RBC xenorejection in mice. All considered, our data demonstrate that human RBCs are highly susceptible to rejection by macrophages in immunodeficient mice. Thus, strategies for preventing human RBC rejection by macrophages are required for using immunodeficient mice as an in vivo model to study human erythropoiesis and RBC function.
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Temprine, Kelsey, Amanda Sankar, Costas Lyssiotis, and Yatrik Shah. "Metabolomic Characterization of Red Blood Cell Differentiation." Blood 136, Supplement 1 (November 5, 2020): 35. http://dx.doi.org/10.1182/blood-2020-137175.
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Background: Erythropoiesis is the highly coordinated multi-step process by which multipotent hematopoietic stem cells differentiate into mature enucleated red blood cells (RBCs). As erythroid cells become more terminally differentiated, they undergo changes in morphology and gene expression, start synthesizing hemoglobin, commit to an irreversible loss of proliferation, and eventually expulse their nuclei and other cytoplasmic organelles. Thus, RBCs must rely on their proteome and metabolome for proper function. The RBC proteome is estimated to contain 2,800 proteins, including a variety of receptors and transporters that allow RBCs to uptake xenobiotics or endogenous metabolites as they circulate for ∼120 days. Furthermore, they are metabolically active with glycolysis, nucleotide catabolism, and glutathione metabolism as the major pathways supporting cell survival and function. However, it is unclear how the metabolome is altered during erythropoiesis, what role metabolites play in normal erythropoiesis, and if dysregulation of metabolites contributes to diseases of ineffective erythropoiesis, such as sickle cell anemia and thalassemia. Methods: Four models of erythropoiesis were used in this study. 1) Mice were treated with phenylhydrazine (Phz) to induce acute hemolysis followed by erythropoietic recovery, leading to an increase in circulating reticulocytes. 2) Mice were lethally irradiated and transplanted with wild-type or sickle cell bone marrow, leading to anemic profiles in sickle cell chimeras. 3) The mouse erythroleukemic (MEL) cell line was treated with DMSO to induce differentiation. 4) The human erythroleukemic (K562) cell line was treated with sodium butyrate to induce differentiation. For the in vivo mouse models, blood was collected from control and treated animals, and complete blood count (CBC) analysis was performed. For the in vitro cell culture models, the mRNA levels of β-globin were measured by Q-RT-PCR in control and differentiated cells, and the degree of hemoglobinization was determined visually and via staining for heme. In addition, metabolites were extracted from the collected RBCs and erythroleukemic cell lines, and a Snapshot LC/MS metabolomic platform was used to identify commonly altered metabolites. Results: We first validated our four models of erythropoiesis. Treatment with Phz decreased the number of total RBCs while increasing the RBC distribution width, indicating an increased number of reticulocytes (more immature RBCs) in circulation. Similar results were seen in the sickle cell chimeras. Treatment of MEL and K562 cells with DMSO and sodium butyrate, respectively, resulted in increased expression of β-globin, increased levels of heme, and increased red color. Then, using our Snapshot metabolomic platform, we identified global changes in RBC metabolism during erythropoiesis. Analyses of the commonly altered metabolites in the in vitro and in vivo models revealed an increase in amino acid, mitochondrial, and urea cycle metabolism during erythropoiesis. L-aspartate levels were particularly upregulated, especially in DMSO-treated MEL cells. We are now investigating the role of aspartate in the regulation of erythropoiesis. Conclusions: We defined how the metabolome was altered in multiple in vitro and in vivo models of erythropoiesis and identified global changes in RBC metabolism between the different models. Specifically, we found that L-aspartate was upregulated during RBC differentiation in all four models. Aspartate is an amino acid that plays a role in many processes in cells, including nucleotide biosynthesis, redox homeostasis, and amino acid biosynthesis. We hypothesize that aspartate metabolism is critical for RBC differentiation and that its dysregulation exacerbates disease of ineffective erythropoiesis, such as sickle cell anemia and β-thalassemia. We are currently testing its role in inducing hemoglobinization and in regulating the commitment of erythroid progenitor cells to an irreversible loss of proliferation. Overall, we believe that understanding the precise mechanisms by which cellular metabolism plays a role in proper RBC differentiation may lead to better therapies for diseases of ineffective erythropoiesis, such as sickle cell anemia and thalassemia. Disclosures No relevant conflicts of interest to declare.
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Zuroidah, Nelly, Arifoel Hajat, and Paulus Budiono Notopuro. "Determining Acute Leukemia Lineage Using Mie Map Red Blood Cell." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 28, no. 1 (December 15, 2021): 1–4. http://dx.doi.org/10.24293/ijcpml.v28i1.1747.
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The determination of myeloid and lymphoid lineage is essential for the diagnosis and therapy of acute leukemia. Immunophenotyping is the gold standard to determine the lineage of acute leukemia, but it is still constrained and relatively expensive. Mie Map RBC in the ADVIA 2120i is a parameter that can give additional information about myeloid and lymphoid lineage but has never been studied before. It is expected that Mie Map RBC can be used to differentiate the lineage of acute myeloid and lymphoid leukemia if immunophenotyping is not present. This study aimed to analyze the diagnostic value of Mie Map RBC with ADVIA 2120i towards immunophenotyping in determining myeloid and lymphoid lineage in acute leukemia. Child and adult patients diagnosed with acute leukemia (n=30) that had peripheral blood smear and bone marrow aspiration with blasts > 20% were examined using ADVIA 2120i. The Mie Map RBC lineage results were compared to the lineage of immunophenotyping. The sensitivity and specificity of the Mie Map RBC myeloid series are respectively 60.00%, 93.33%. The sensitivity and specificity of the Mie Map RBC lymphoid series are respectively 93.33% and 60.00%. The diagnostic accuracy value of Mie Map RBC is 76.67%. The determination of acute leukemia myeloid series lineage has high specificity. If there is no population outside the matrix of Mie Map RBC, it highly suggests myeloid series. On the other hand, the determination of acute leukemia lymphoid series lineage has a relatively low specificity meaning that the population outside the matrix of Mie Map RBC does not always suggest a lymphoid lineage
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Kim, Haewon C. "Red cell exchange: special focus on sickle cell disease." Hematology 2014, no. 1 (December 5, 2014): 450–56. http://dx.doi.org/10.1182/asheducation-2014.1.450.
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Abstract The primary function of red blood cells (RBCs) is to deliver oxygen from the lungs to tissues. Tissue hypoxia occurs when the oxygen-carrying capacity of RBCs is compromised due primarily to 3 causes: (1) a reduction in circulating RBC mass, (2) an increase in circulating RBC mass, or (3) abnormal hemoglobin (Hb) that either does not sufficiently release oxygen to tissues (high-oxygen-affinity hemoglobin) or occludes the microvasculature due to deformed RBCs (sickled RBCs). To improve oxygenation in patients with reduced or increased RBC mass, RBC administration (simple transfusion) or RBC removal (RBC depletion) is performed, respectively. However, for patients with abnormal Hb, RBCs containing abnormal Hb are removed and replaced by healthy volunteer donor RBCs by red cell exchange (RCE). RCE can be performed by manual exchange or by automated exchange using a blood cell separator (erythrocytapheresis). In this review, indications for RCE in sickle cell disease using the evidence-based American Society for Apheresis categories1 are presented and the rationale for RCE in each disorder are discussed. Simple transfusion versus RCE and manual RCE versus automated RCE are compared. Finally, this review briefly presents some of the challenges of performing erythrocytapheresis in small children and discusses various choices for central venous access during RCE.2
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Ramsey, Glenn, and Paul F. Lindholm. "Thrombosis Risk in Cancer Patients Receiving Red Blood Cell Transfusions." Seminars in Thrombosis and Hemostasis 45, no. 06 (August 20, 2019): 648–56. http://dx.doi.org/10.1055/s-0039-1694763.
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AbstractPatients with cancer have increased risk of thrombosis and often need red blood cell (RBC) transfusions. However, RBC transfusions may also promote thrombosis because of raised hematocrit and viscosity, storage-related RBC damage, and exposure to thrombogenic mediators from obsolescent RBCs. The authors conducted a literature survey for studies examining whether RBC transfusions were associated with increased risk of venous thromboembolism (VTE) in cancer patients. In perioperative cancer surgery patients with categorical comparisons of any versus no RBC transfusion, increased risk of VTE with RBC transfusion was found in 11 of 31 studies, 5 by univariate correlation only and 6 in multivariate analysis. All six multivariate-positive studies had intermediate overall rates of thrombosis (1.4–6.0%), and three were in urological surgery series. In the larger studies of > 2,000 patients (range: 2,219–44,656), the maximum odds ratio among the multivariate-positive studies was 1.3. Perioperative RBC transfusion volume was more strongly associated with VTE risk, with a positive association in six of seven studies. One large registry-based study of hospitalized cancer patients, not restricted to the perioperative setting, found an adjusted odds ratio of 1.60 (95% confidence interval: 1.53–1.67) for VTE risk in patients receiving RBCs compared with nontransfused patients.
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Callan, MB, DA Oakley, FS Shofer, and U. Giger. "Canine red blood cell transfusion practice." Journal of the American Animal Hospital Association 32, no. 4 (July 1, 1996): 303–11. http://dx.doi.org/10.5326/15473317-32-4-303.
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Red blood cell (RBC) transfusions in 307 dogs were reviewed. A total of 658 units of RBCs, including 474 (72%) units of packed red blood cells (PRBCs) and 184 (28%) units of whole blood (WB), were administered. Reasons for transfusion included hemorrhage (n = 222), hemolysis (n = 43), and ineffective erythropoiesis (n = 42). The mean pretransfusion packed cell volume (PCV) of dogs with hemolysis (13%) was significantly lower (p less than 0.0001) than the mean pretransfusion PCVs of dogs with hemorrhage (21%) or ineffective erythropoiesis (18%). The mean total volume of PRBCs transfused was significantly greater (p less than 0.03) in dogs with hemolysis. Overall, 187 (61%) of 307 dogs were discharged from the hospital. Cause of anemia, pretransfusion PCV, and total volume of blood administered did not appear to influence survival. However, the mean adjusted posttransfusion PCV of dogs with hemorrhage was significantly higher (p less than 0.001) in dogs that survived. Possible adverse events were observed during or shortly after RBC transfusion in 10 (3.3%) dogs; all reactions were mild and self-limiting, and none were hemolytic.
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Balbuena-Merle, Raisa, Ronald G. Hauser, Matthew Karafin, Sylvia Tan, Bryan R. Spencer, Nareg Roubinian, Yanyun Wu, et al. "The Presence and Persistence of Pregnancy-Associated Red Blood Cell Alloantibodies in Blood Donors." Blood 134, Supplement_1 (November 13, 2019): 2452. http://dx.doi.org/10.1182/blood-2019-121388.
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Background: Females have higher RBC alloantibody prevalence than males, presumably due to exposure to non-self RBC antigens through pregnancy as well as transfusion. Given the lack of routinely available and longitudinal data on lifelong pregnancy and transfusion histories, few studies have been able to distinguish pregnancy versus transfusion as contributing risk factors for RBC alloantibody induction or for the persistence of RBC alloantibody detectability. We hypothesized that pregnancy would be an important source of persistently detected RBC alloantibodies and investigated this in a longitudinal blood donor database. Study Design and Methods: Donor/donation data were obtained from 4 US blood centers from 2012-2016. RBC antibody screen results and antibody identification (using tube, gel, or solid phase), donor demographics, pregnancy history, and transfusion history were evaluated. Blood donors were included in this analysis if they had an RBC alloantibody detected at any given donation as long as they had at least one subsequent blood donation and antibody screen. Anti-D antibodies detected, but present for < 6 months in females <50 years old were presumed due to passive RhIg and were excluded from this analysis. RBC alloantibody persistence was defined as an RBC alloantibody detected at each subsequent donation following its initial identification and RBC alloantibody evanescence was defined as one or more subsequent donations without re-detection of the alloantibody. Rates of donor alloantibody persistence were calculated as blood donors with persistent alloantibodies divided by blood donors with any alloantibody, and patterns of persistence were characterized by donor sex and presumed alloantibody source exposure. Results: 503 blood donors had a detectable RBC alloantibody and a follow-up antibody screen; 374 (74%) were female and 130 (26%) were male. Of the 374 alloimmunized females, 210 (56%) reported prior pregnancy and no transfusion, 124 (33%) reported prior pregnancy and transfusion, 26 (7%) reported no pregnancy or transfusion, and 12 (3%) reported prior transfusion and no pregnancy. 215/334 (64%) of previously pregnant females had RBC alloantibodies that remained detectable throughout the duration of the study. The mean duration of detectability for persistent antibodies in previously pregnant females was 640 days, compared to a mean time to disappearance of 183 days for evanescent antibodies. In contrast, males and all never-pregnant females were less likely to have persistently detectable antibodies, with 52% (87/167) being in this category (chi square p = 0.008). The mean duration of detectability for persistent antibodies in males and never-pregnant females was 576 days, compared to a mean time to disappearance of 290 days for evanescent antibodies. Previously pregnant females with a reported history of prior transfusion (n=124) had the highest rate (77%) of RBC alloantibody persistence. The alloantibody specificities of previously pregnant females included E (96), D (81), K (78), Fy (21), C (47), MNS (38), and Jk (18). Of these, Fy and non-passive D were most likely to be persistent (each 86%), followed by C (79%), K (74%), E (59%), Jk (55%), and MNS (34%). Conclusion: Data from this multi-center blood donor database, with documented life-long pregnancy and transfusion histories, highlight the role that pregnancy plays in RBC alloimmunization. Importantly, pregnancy was an exposure source in almost all studied RBC alloimmunized female healthy blood donors and was the sole reported exposure in the majority of donors. Although these data cannot definitively identify the source of non-self blood group antigen exposure in blood donors with both pregnancy and transfusion histories, they show that antibodies in previously pregnant females are long lasting. It is possible that length of exposure to non-self RBC antigens, the relatively young age of females during childbearing, long standing fetal white blood cell microchimerism in the maternal circulation, or other variables may impact plasma cell longevity and/or antibody production, and thus the persistence of pregnancy (versus transfusion) associated RBC alloantibodies. Given the numbers and persistence of such RBC alloantibodies, we recommend that pregnancy history be taken into consideration in all RBC alloimmunization studies involving females at or beyond childbearing age. Disclosures Spencer: HemaStrat, LLC: Membership on an entity's Board of Directors or advisory committees.
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Dichiera, Angelina M., and Andrew J. Esbaugh. "Red blood cell carbonic anhydrase mediates oxygen delivery via the Root effect in red drum." Journal of Experimental Biology 223, no. 22 (November 15, 2020): jeb232991. http://dx.doi.org/10.1242/jeb.232991.
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ABSTRACTOxygen (O2) and carbon dioxide (CO2) transport are tightly coupled in many fishes as a result of the presence of Root effect hemoglobins (Hb), whereby reduced pH reduces O2 binding even at high O2 tensions. Red blood cell carbonic anhydrase (RBC CA) activity limits the rate of intracellular acidification, yet its role in O2 delivery has been downplayed. We developed an in vitro assay to manipulate RBC CA activity while measuring Hb-O2 offloading following a physiologically relevant CO2-induced acidification. RBC CA activity in red drum (Sciaenops ocellatus) was inhibited with ethoxzolamide by 53.7±0.5%, which prompted a significant reduction in O2 offloading rate by 54.3±5.4% (P=0.0206, two-tailed paired t-test; n=7). Conversely, a 2.03-fold increase in RBC CA activity prompted a 2.14-fold increase in O2 offloading rate (P<0.001, two-tailed paired t-test; n=8). This approximately 1:1 relationship between RBC CA activity and Hb-O2 offloading rate coincided with a similar allometric scaling exponent for RBC CA activity and maximum metabolic rate. Together, our data suggest that RBC CA is rate limiting for O2 delivery in red drum.
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Pasini, Erica M., Hans U. Lutz, Matthias Mann, and Alan W. Thomas. "Red blood cell (RBC) membrane proteomics — Part I: Proteomics and RBC physiology." Journal of Proteomics 73, no. 3 (January 2010): 403–20. http://dx.doi.org/10.1016/j.jprot.2009.06.005.
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DeJong, Kitty, and Frans A. Kuypers. "Enhanced Phosphatidylserine Scrambling in Oxidatively Challenged Red Blood Cells." Blood 110, no. 11 (November 16, 2007): 1718. http://dx.doi.org/10.1182/blood.v110.11.1718.1718.
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Abstract Red blood cells (RBC) that abnormally expose phosphatidylserine (PS) contribute to the pathophysiology of several hemoglobinopathies. PS exposure requires inactivation of the flippase that transports PS from the outer to the inner membrane monolayer, and activation of a phospholipid scrambling process. To evaluate the role of increased oxidative stress in this process, we compared RBC from transgenic sickle mice (Berkeley type) with RBC from peroxiredoxin 2 (prdx) knock-out mice (prdx −/−). These mice lack one of the most prevalent cytosolic antioxidant molecules. This molecule, also known as calpromotin, was previously implicated in membrane abnormalities of the dense sickle RBC population. Mice that lack prdx are slightly anemic, have reduced RBC survival and exhibit a subpopulation of older highly oxidized RBC. The prdx −/− strain did not show a subpopulation of PS-exposing cells in freshly collected blood and the flippase activity, measured by transbilayer kinetics of the fluorescent probe NBD-PS, was normal. In contrast, blood collected from the sickle mice showed a large subpopulation with decreased flippase activity and exhibited a subpopulation of PS-exposing RBC that lack flippase activity. Flippase inhibition induced with vanadate or NEM did not increase the PS exposure of prdx −/− RBC incubated with high levels of Ca2+, indicating that there was no increased Ca2+ influx. In sickle cells, elevated intracellular Ca2+ was evident under similar loading conditions. Loading RBC with 0.1 mM Ca2+, but not lower concentrations, using Ca-ionophore resulted in bilayer scrambling and PS exposure in both strains as well as in normal control mice. The rate of PS scrambling was increased 1.5-fold in sickle mice compared to normal mouse RBC. While the scrambling rate was normal in the young, not oxidized prdx−/− RBC, it was increased 3-fold in the older highly oxidized prdx −/− RBC as compared to normal mouse RBC. The sulfhydryl modifiers NEM or PDA caused flippase inhibition, and altered the PS scrambling rate in normal mouse RBC as reported earlier. Both sickle cells and the older oxidized prdx −/− RBC showed a reduced susceptibility to NEM and PDA, while the younger prdx −/− RBC exhibited a normal sensitivity to these compounds. This suggests that both prdx −/− RBC and sickle cells have sustained similar sulfhydryl damage leading to enhanced scrambling. Exposure to three well-known oxidants (0.1–0.5 mM cumene hydroperoxide, tert-butyl hydroperoxide or hydrogen peroxide) did not increase the percentage of oxidized cells or PS exposure in prdx −/− RBC compared to normal RBC. This indicates that targeted sulfhydryl modification but not general short-term oxidative stress impacts the loss of phospholipid asymmetry. These data confirm that increased oxidative sulfhydryl damage results in a higher propensity for phospholipid scrambling. The presence of active prdx is important to maintain PS asymmetry as it prevents accelerated phospholipid scrambling. In those cells in which the flippase is also inactivated, PS exposure becomes apparent. The loss of flippase activity is much more prevalent in sickle RBC, indicating that prdx does not play an important role in protecting the flippase from inactivation. It can be expected that PS-exposing cells are rapidly removed from the circulation, as they resemble apoptotic cells, which may explain their absence in blood from prdx−/− mice. The presence of PS-exposing RBC in the circulation of sickle mice suggests that the formation of these cells overwhelms their removal.
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Chakmakjian, Carl, and Ed Rappaport. "RBC Histogram Predictive of HE." Blood 106, no. 11 (November 16, 2005): 3706. http://dx.doi.org/10.1182/blood.v106.11.3706.3706.
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Abstract Hereditary elliptocytosis (HE) encompasses a family of inherited erythrocyte disorders characterized by red blood cells with an oval, elongated shape. Diagnosis is most commonly made upon peripheral smear examination. Although the disorder is usually clinically silent, these patients may have some degree of chronic hemolysis that may necessitate splenectomy on occasion. We report a consistent finding in HE common to most electronic cell counters. The red blood cell histogram reliably has a two to three millimeter elevation above baseline at the extreme left of the graph. This “foot” on the histogram is predictive of possible red blood cell elliptocytes. Please see example. Figure Figure
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Morelli, A., M. Grasso, T. Meloni, G. Forteleoni, E. Zocchi, and A. De Flora. "Favism: impairment of proteolytic systems in red blood cells." Blood 69, no. 6 (June 1, 1987): 1753–58. http://dx.doi.org/10.1182/blood.v69.6.1753.1753.
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Abstract Red blood cells (RBC) from favic patients are characterized by (a) severe oxidative damage (contributed by autoxidation of divicine and isouramil, two pyrimidine aglycones present in fava beans) and (b) greatly increased calcium levels. In vitro, both autoxidation of divicine and calcium loading produced marked alterations of proteolytic systems in intact RBC. Specifically, autoxidizing divicine inactivated procalpain, the proenzyme species of calcium-activated cytosolic neutral proteinase, or calpain. Inactivation was much greater with glucose-6-phosphate dehydrogenase (G6PD)-deficient RBC than with normal RBC. On the other hand, loading of normal and G6PD-deficient RBC with calcium resulted in conversion of procalpain to calpain and eventual autoproteolytic inactivation of calpain itself, and extensive release of acid endopeptidase activity from the membranes into the cytosol. Damaged RBC from favic patients had significantly lowered procalpain activity and an abnormal subcellular distribution of acid proteinase activity that was found mostly in the cytosol. When purified calpain was incubated with membranes from acetylphenylhydrazine (APH)-treated RBC, significant proteolysis was observed affecting mostly band 3 and hemoglobin chains, ie, the two proteins involved in the onset of aggregation of Heinz bodies. Moreover, exposure of intact RBC to 20 mmol/L APH induced depletion of procalpain activity for which the time course was inversely related to formation of Heinz bodies. These findings support the role of procalpain in protecting G6PD-deficient RBC from oxidant-induced Heinz body formation and imply that exhaustion of the procalpain-calpain system is an important step in the mechanisms of RBC damage and destruction in favism.
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Morelli, A., M. Grasso, T. Meloni, G. Forteleoni, E. Zocchi, and A. De Flora. "Favism: impairment of proteolytic systems in red blood cells." Blood 69, no. 6 (June 1, 1987): 1753–58. http://dx.doi.org/10.1182/blood.v69.6.1753.bloodjournal6961753.
Full textAbstract:
Red blood cells (RBC) from favic patients are characterized by (a) severe oxidative damage (contributed by autoxidation of divicine and isouramil, two pyrimidine aglycones present in fava beans) and (b) greatly increased calcium levels. In vitro, both autoxidation of divicine and calcium loading produced marked alterations of proteolytic systems in intact RBC. Specifically, autoxidizing divicine inactivated procalpain, the proenzyme species of calcium-activated cytosolic neutral proteinase, or calpain. Inactivation was much greater with glucose-6-phosphate dehydrogenase (G6PD)-deficient RBC than with normal RBC. On the other hand, loading of normal and G6PD-deficient RBC with calcium resulted in conversion of procalpain to calpain and eventual autoproteolytic inactivation of calpain itself, and extensive release of acid endopeptidase activity from the membranes into the cytosol. Damaged RBC from favic patients had significantly lowered procalpain activity and an abnormal subcellular distribution of acid proteinase activity that was found mostly in the cytosol. When purified calpain was incubated with membranes from acetylphenylhydrazine (APH)-treated RBC, significant proteolysis was observed affecting mostly band 3 and hemoglobin chains, ie, the two proteins involved in the onset of aggregation of Heinz bodies. Moreover, exposure of intact RBC to 20 mmol/L APH induced depletion of procalpain activity for which the time course was inversely related to formation of Heinz bodies. These findings support the role of procalpain in protecting G6PD-deficient RBC from oxidant-induced Heinz body formation and imply that exhaustion of the procalpain-calpain system is an important step in the mechanisms of RBC damage and destruction in favism.
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Fazili, Zia, Neelima Papadugula, Phuong Ngac, and Christine M. Pfeiffer. "Folate Forms in Red Blood Cell Lysates and in Intact Washed Red Blood Cells Are Stable for a Few Days During Refrigerated Storage." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 1799. http://dx.doi.org/10.1093/cdn/nzaa067_026.
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Abstract Objectives We investigated whether folate forms are stable in washed red blood cells (RBC) stored refrigerated for up to 9 days relative to RBC-lysates in ascorbic acid under the same storage conditions. Methods We prepared washed RBCs from freshly collected EDTA blood (n = 6 donors). For RBC-lysate 1, we diluted RBCs with saline (1/2 dilution), mixed well and prepared lysates (1/11 dilution) with 1% ascorbic acid (2 vials/time point; n = 12 vials/donor) for storage at 4°C for ≤ 9 days (baseline, 1, 2, 3, 6, and 9). For RBC-lysate 2, we aliquoted ∼0.5 mL washed RBCs (1 vial/time point; n = 5 vials/donor) for storage at 4°C for ≤9 days (1, 2, 3, 6, and 9). When refrigerated storage of samples was completed, RBC lysate 1 samples were frozen at −70°C, while the washed RBCs were diluted with saline (1/2 dilution), mixed well and RBC-lysates 2 were prepared (1/11 dilution) with 1% ascorbic acid (2 vials/time point; n = 10 vials/donor). All samples were stored at −70°C until analysis. At the time of analysis, we processed samples (2 replicates/time point; n = 2 days) for folate polyglutamate deconjugation using recombinant exo γ-glutamyl hydrolase, and conducted sample clean-up by automated solid phase extraction prior to analysis by LC-MS/MS. Results We found negligible losses of major folate forms after overnight refrigerated storage, and folate losses gradually increased over time (∼5% by day 6). The loss of 5-methyltetrahydrofolate and total folate (mean ± SD) after 2 days of storage for RBC lysate 1 was 1.2% ± 1.5% and 1.0% ± 1.3%, and for RBC-lysate 2 was 2.2% ± 1.1% and 2.7% ± 1.9%, respectively. The baseline concentration of non-methyl folate (sum of minor folate forms: 5-formyltetrahydrofolate [<LOD], tetrahydrofolate, and 5, 10-methenyltetrahydrofolate) was small (<3.0 nmol/L) in both sample types, and we noticed a slight increase (∼10%) after overnight storage. 5,10-Methenyltetrahydrofolate appeared to gradually convert to tetrahydrofolate upon storage in RBC-lysate 2 samples. We observed no noticeable changes for MeFox in either sample type. Conclusions Overnight refrigerated storage of RBC-lysates or washed RBCs is feasible and avoids notable losses of folate forms. Prolonged refrigerated storage promotes interconversions of minor folate forms. Funding Sources This work was supported by direct appropriations from U.S. Congress.
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Kanias, Tamir, Jeffrey Isenberg, Grant C. Bullock, Valerie M. Schrott, Donna B. Stolz, and Enrico M. Novelli. "Thrombospondin-1 Stimulates Calcium Influx and Echinocytosis in Sickle Cell-Derived Red Blood Cells." Blood 124, no. 21 (December 6, 2014): 4068. http://dx.doi.org/10.1182/blood.v124.21.4068.4068.
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Abstract Thrombospondin-1 (TSP1) is a secreted matricellular protein found preformed in platelet α-granules and upregulated in the plasma of patients with sickle cell disease (SCD). In preclinical models TSP1 enhances sickle red blood cell (RBC) binding to endothelial cells, while in murine sickle mice TSP1 promotes RBC echinocytosis and vaso-occlusion. Recently we reported elevated plasma TSP1 was associated with vaso-occlusive complications in SCD patients. Herein we tested the hypothesis that TSP1 compromises RBC membrane integrity via enhanced calcium influx leading to morphological changes, such as echinocytosis. RBC were collected via centrifugation of heparinized blood from human HbAA donors (n=3), SCD patients with homozygous HbSS SCD (n=4), and wild type C57BL/6J mice (n=2). Cells were then re-suspended in glucose and calcium-supplemented PBS, and treated with several concentrations of exogenous TSP1 (2.75 nM, 11 nM, 22 nM and 44 nM) for 2 hours at 37°C. RBC morphology was assessed by both light and electron microscopy. TSP1 modulation of RBC calcium influx was studied using the calcium fluorophore Fluo-3, AM. TSP1 treatment, in a dose-dependent manner, stimulated echinocytosis in human SCD and non-SCD RBC and in murine cells. In some instances electron microscopy showed echinocyte membrane projections with a string-of-beads appearance, suggestive of imminent microparticle shedding. TSP1 treatment, again in a dose-dependent manner, also significantly increased calcium influx in SCD (Figure, right panel) and non SCD RBC (Figure, left panel) and murine RBC (not shown). Interestingly, SCD RBC displayed more sensitivity to TSP1-mediated increases in cellular calcium as compared to normal cells. Our results show for the first time that TSP1, at doses found in patient plasma, stimulates significant echinocytosis and calcium influx in both normal and SCD RBC. These data identify a novel role for plasma TSP1 in promoting RBC pathology. Future studies are underway to elucidate this mechanism and its pathogenicity in humans with and without SCD. Figure 1 Figure 1. Disclosures Isenberg: Vasculox: Membership on an entity's Board of Directors or advisory committees; Radiation Control Technologies: Membership on an entity's Board of Directors or advisory committees.
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Brenner, Jacob S., Samir Mitragotri, and Vladimir R. Muzykantov. "Red Blood Cell Hitchhiking: A Novel Approach for Vascular Delivery of Nanocarriers." Annual Review of Biomedical Engineering 23, no. 1 (July 13, 2021): 225–48. http://dx.doi.org/10.1146/annurev-bioeng-121219-024239.
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Red blood cell (RBC) hitchhiking is a method of drug delivery that can increase drug concentration in target organs by orders of magnitude. In RBC hitchhiking, drug-loaded nanoparticles (NPs) are adsorbed onto red blood cells and then injected intravascularly, which causes the NPs to transfer to cells of the capillaries in the downstream organ. RBC hitchhiking has been demonstrated in multiple species and multiple organs. For example, RBC-hitchhiking NPs localized at unprecedented levels in the brain when using intra-arterial catheters, such as those in place immediately after mechanical thrombectomy for acute ischemic stroke. RBC hitchhiking has been successfully employed in numerous preclinical models of disease, ranging from pulmonary embolism to cancer metastasis. In addition to summarizing the versatility of RBC hitchhiking, we also describe studies into the surprisingly complex mechanisms of RBC hitchhiking as well as outline future studies to further improve RBC hitchhiking's clinical utility.
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Prokopchuk-Gauk, Oksana, Nicole L. Prokopishyn, Joanna McCarthy, and Meer-Taher Shabani-Rad. "Red Cell Alloimmunization Rates in Allogeneic Hematopoietic Stem Cell Transplant Recipients." Blood 128, no. 22 (December 2, 2016): 3402. http://dx.doi.org/10.1182/blood.v128.22.3402.3402.
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Abstract Introduction: Donor selection for allogeneic hematopoietic stem cell transplant (allo-HSCT) is dependent on matching with the intended recipient HLA allele profile, but not blood group compatibility. Red blood cell (RBC) phenotype matching is not considered, even if recipient alloantibodies are present pre-HSCT. Historically, up to 3.7% of allo-HSCT recipients have been found to develop new RBC alloantibodies following allo-HSCT. We completed an audit of all adult and pediatric allo-HSCT recipients of the Alberta Bone Marrow and Blood Cell Transplant Program to define the rate of RBC alloimmunization, and evaluate the impact of this RBC alloantibody presence on donor marrow engraftment in our allo-HSCT recipient population. Methods:A retrospective review was completed including all allogeneic pediatric and adult HSCT recipients between January 1, 2007 and January 1, 2015. Data was obtained from review of cellular therapy laboratory electronic records with red cell alloantibody information extracted manually from the transfusion medicine laboratory information system. Results: A total of 674 patients, including 104 pediatric recipients (<18 years old), underwent 697 allo-HSCT procedures (591 peripheral blood, 45 marrow, 61 cord blood). The mean HSCT recipient age was 40 (range 0-66) and most common HSCT indication was acute myeloid leukemia. Myeloablative conditioning was given to all adults and 86% of pediatric recipients. Fully HLA matched grafts were provided to 77% of recipients. ABO compatibility status of allo-HSCT procedures included the following: 362 (52%) ABO identical grafts, 154 (22%) grafts with a minor incompatibility, 143 (21%) grafts with a major incompatibility, and 38 (5.0%) grafts with bidirectional incompatibility. Rh mismatches were present in 165 (24%) of donor-recipient pairs. A total of 47 allo-HSCT recipients, including 3 pediatric and 44 adult patients, were found to have RBC alloantibodies before or after allo-HSCT. A total of 45 (6.4%) of allo-HSCT recipients had detectable RBC alloantibodies pre-HSCT, with 69 individual alloantibodies identified. The most common RBC alloantibody was anti-E (30%). Antibody screen results available on the day of or following HSCT in 43 allo-HSCT recipients found: 12 (28%) with antibody disappearance pre-HSCT and a negative screen on the date of allo-HSCT, 15 (35%) with antibody waning to disappearance after allo-HSCT, and 11 (26%) with persistence of pre-HSCT antibodies following allo-HSCT. New post-HSCT RBC alloantibodies were detected in 3 adult recipients of peripheral blood collected stem cell grafts (anti-D; anti-Kpa; anti-K plus anti-E), with an overall rate of 0.4%. These patients all received myeloablative conditioning and grafts which were ABO identical or had a minor ABO incompatibility. The anti-D antibody developed post-transplant in an Rh positive recipient of an Rh negative graft. Thus, the calculated overall rate of anti-D development in Rh mismatched HSCT recipients was 0.6%. There was no observed impact on neutrophil and platelet engraftment comparing adult allo-HSCT recipients who did and did not have pre-HSCT RBC alloantibodies. Conclusion: The risk of post-HSCT RBC alloantibody development is very low, even in Rh mismatched donor-recipient pairs. ABO incompatibility does not affect the risk of post-HSCT alloantibody development. Allo-HSCT recipients infrequently have pre-HSCT RBC alloantibodies, which may disappear after myeloablative conditioning. The presence of RBC alloantibodies pre-HSCT does not appear to impact donor marrow engraftment. The results of our retrospective study are limited by the availability, timing and frequency of post-HSCT antibody screen investigations. The decision to perform an antibody screen post-HSCT is a clinical one, typically dependent on recipient transfusion needs. Further prospective research is required to more accurately determine the rate of new post-HSCT alloantibody development and duration of alloantibody persistence or disappearance in allo-HSCT recipients. Results of these studies may also help guide RBC transfusion decisions in HSCT recipients known to have pre-HSCT RBC alloantibodies with proven engraftment and a negative post-HSCT antibody screen. Disclosures No relevant conflicts of interest to declare.
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Campbell-Lee, Sally A., Jinhuan Liu, Paul M. Ness, and William M. Baldwin. "Red Blood Cell Alloimmunization Is Affected by Depletion of Donor White Cell Subsets." Blood 110, no. 11 (November 16, 2007): 456. http://dx.doi.org/10.1182/blood.v110.11.456.456.
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Abstract Red blood cell (RBC) alloimmunization leads to therapeutic limitations due to difficulties in obtaining compatible RBC components. Better understanding of immune mechanisms responsible for alloantibody formation are necessary in order to develop ways of preventing or treating alloimmunization in high risk patients. A murine model of RBC alloimmunization was developed using B6CBA-F1-Tg Fyb mice that express the human Fyb blood group as donors, and recipient mice of the B6CBA-F1 strain. RBC were obtained from donor mice that were anesthetized and exsanguinated by cardiac puncture. Donor whole blood was collected into sterile syringes containing CPDA-1 (Sigma Aldrich, St. Louis, MO) and was then centrifuged to produce packed RBCs. Recipient mice were transfused 0.3 mL via the tail vein once a week for two weeks with donor RBC that had 108 spleen cells added which were then depleted of either CD4, CD8, CD19 or natural killer (NK) cell subsets (n=6 in each group). Depletions were performed using immunodensity negative selection with murine anti-CD4, CD8, CD19 and DX5 antibodies (StemCell Technologies, Vancouver, BC). Two control groups were transfused with either washed buffy coat depleted RBC (leukodepletion to fewer than 5 × 106 remaining white blood cells (WBC)) or RBC with spleen cells added that was processed through immunodensity negative selection without the addition of antibody (no leukodepletion with 1 × 108 WBC). Serum was collected from recipient mice once a week for four weeks post-transfusion. Circulating IgG anti-Fyb titers were measured by flow cytometry using donor RBC and staining with fluorescein isothiocyanate conjugated rat anti-mouse IgG (Jackson ImmunoResearch, West Grove, PA); target cells were gated on by size and side scatter parameters using a FACScan flow cytometer (Becton Dickenson, Franklin Lakes, NJ). Serum samples from week 4 post transfusion demonstrated a mean anti-Fyb titer of 64 in the CD4 depleted group. Mean titers of 256, 512 and 512 were observed in the CD8, CD19 and NK depletion groups, respectively. The leukodepletion control group had a mean anti-Fyb titer of 16, and the non-leukodepletion control group showed a mean titer of 64. These results indicate that donor contaminating WBC affect RBC alloimmunization. CD4 cell removal led to an anti-Fyb titer that was the same as the non-leukodepletion control group. CD8, CD19 and NK cell removal increases anti-Fyb titer and may indicate a variety of inhibitory roles of these cell types.