Characterization of the molecular mechanisms of silicon uptake in coccolithophores.

Coccolithophores are an important group of calcifying marine phytoplankton. Although coccolithophores are not silicified, some species exhibit a requirement for Si in the calcification process. These species also possess a novel protein (SITL) that resembles the SIT family of Si transporters found in diatoms. However, the nature of Si transport in coccolithophores is not yet known, making it difficult to determine the wider role of Si in coccolithophore biology. Here, we show that coccolithophore SITLs act as Na+ -coupled Si transporters when expressed in heterologous systems and exhibit similar characteristics to diatom SITs. We find that CbSITL from Coccolithus braarudii is transcriptionally regulated by Si availability and is expressed in environmental coccolithophore populations. However, the Si requirement of C. braarudii and other coccolithophores is very low, with transport rates of exogenous Si below the level of detection in sensitive assays of Si transport. As coccoliths contain only low levels of Si, we propose that Si acts to support the calcification process, rather than forming a structural component of the coccolith itself. Si is therefore acting as a micronutrient in coccolithophores and natural populations are only likely to experience Si limitation in circumstances where dissolved silicon (DSi) is depleted to extreme levels.

Prospective, open-label, multicenter clinical study to assess the performance of a new donation system for the collection of source plasma.

BACKGROUND: Safe, efficient, and reliable innovations among donation systems are needed to meet the growing global demand for source plasma. This study assessed the ability of a new donation system to collect appropriate product weights based on the US Food and Drug Administration nomogram for source plasma collections. Procedure duration and safety endpoints were also collected. STUDY DESIGN AND METHODS: The Rika Plasma Donation System (Terumo BCT, Inc., Lakewood, CO) was evaluated in a prospective, open-label, multicenter study. Healthy adults meeting FDA and Plasma Protein Therapeutics Association requirements for source plasma donor eligibility were consented and enrolled in the study resulting in 124 evaluable products. RESULTS: The target product collection weights (ie, including plasma and anticoagulant) by participant weight category were: 705 g (110-149 lbs), 845 g (150-174 lbs), and 900 g (≥175 lbs). The mean reported product collection weights by participant weight category were 705.0 ± 0.00, 845.0 ± 0.20, and 899.9 ± 0.31 g, respectively. The mean overall procedure time was 31.5 ± 5.41 minutes. The mean procedure times by participant weight category were 25.6 ± 3.13, 30.5 ± 4.45, and 33.7 ± 4.80 minutes, respectively. Procedure-emergent adverse events (PEAEs) occurred in five participants. All PEAEs were consistent with known risks for apheresis donation, and none were related to the donation system. CONCLUSIONS: The new donation system collected the target product collection weight in 100% of evaluable products. The mean procedure collection time was 31.5 minutes. The system is a new efficient platform that consistently collects the appropriate weight of the source plasma.

An in vitro comparison of intra-operative isohemagglutinin and human leukocyte antigen removal techniques in pediatric heart transplantation.

BACKGROUND: Highly sensitized pediatric patients awaiting heart transplantation experience longer wait times and thus higher waitlist mortality. Similarly, children less than 2 years of age have increased waitlist times and mortality when compared to their older peers. To improve the likelihood of successful transplantation in these patients, various strategies have been utilized, including peri-operative plasmapheresis. However, limited data exists comparing plasmapheresis techniques for antibody reduction. This study's aim was to compare the in vitro magnitude of isohemagglutinin titers (IT) and human leukocyte antigen (HLA) antibody removal and the time required between membrane-based plasmapheresis (MP) and centrifuge-based plasmapheresis (CP) incorporated into the extracorporeal (EC) circuit. METHODS: Two MP (Prismaflex) and two CP (Spectra Optia, Terumo BCT) circuits were incorporated into four separate EC circuits primed with high titer, highly sensitized type O donor whole blood. Assays were performed to determine baseline IT and anti-HLA antibodies and then at 30-minute increments until completion of the run (two plasma volume exchanges) at two hours. RESULTS: There was a decrease in anti-A and anti-B IgM and IgG titers with both MP and CP. Mean anti-A and anti-B titer reduction was by 4.625 titers (93.7% change) and 4.375 titers (93.8% change) using MP and CP, respectively. At 2 h of apheresis, CP reduced 62.5% of all ITs to ≤ 1:4, while MP reduced 50% of ITs to ≤ 1:4. Additionally, reduction of anti-HLA class II antibody to mean fluorescence intensity (MFI) <3000 was achieved with both MP and CP. At 2 h of apheresis, CP reduced MFI by 2-3.5 fold and MP reduced MFI by 1.7-2.5 fold. Both demonstrated similar hemolytic and thrombotic profiles. CONCLUSIONS: In this in vitro plasmapheresis model of IT and anti-HLA antibody reduction, both MP and CP incorporated into the EC circuit can be used quickly and effectively to reduce circulating antibodies. While CP may have some greater efficiency, further study is necessary to verify this in vivo.

Large Anterior Mediastinal Mass and Cardiac Infiltration at Diagnosis in a Child With T-cell Acute Lymphoblastic Leukemia.

While anterior mediastinal masses are a common presenting feature of T-cell acute lymphoblastic leukemia, cardiac leukemic infiltration is an exceedingly rare extramedullary manifestation. We report a 4-year-old female with new-onset T-cell acute lymphoblastic leukemia who was found to have a large interventricular septal mass upon initial presentation. This patient required a unique management approach with serial echocardiograms, continuous telemetry, and hemodynamic monitoring with close surveillance for ventricular ectopy. Given a good response to traditional leukemia therapy, the cardiac mass was presumed to have been a focal infiltrate of leukemic cells.

Lessons learned from the use of convalescent plasma for the treatment of COVID-19 and specific considerations for immunocompromised patients.

Coronavirus disease 2019 (COVID-19) convalescent plasma (CovCP) infusions have been widely used for the treatment of hospitalized patients with COVID-19. The aims of this narrative review were to analyze the safety and efficacy of CovCP infusions in the overall population and in immunocompromised patients with COVID-19 and to identify the lessons learned concerning the use of convalescent plasma (CP) to fill treatment gaps for emerging viruses. Systematic searches (PubMed, Scopus, and COVID-19 Research) were conducted to identify peer-reviewed articles and pre-prints published between March 1, 2020 and May 1, 2021 on the use of CovCP for the treatment of patients with COVID-19. From 261 retrieved articles, 37 articles reporting robust controlled studies in the overall population of patients with COVID-19 and 9 articles in immunocompromised patients with COVID-19 were selected. While CovCP infusions are well tolerated in both populations, they do not seem to improve clinical outcomes in critically-ill patients with COVID-19 and no conclusion could be drawn concerning their potential benefits in immunocompromised patients with COVID-19. To be better prepared for future epidemics/pandemics and to evaluate potential benefits of CP treatment, only CP units with high neutralizing antibodies (NAbs) titers should be infused in patients with low NAb titers, patient eligibility criteria should be based on the disease pathophysiology, and measured clinical outcomes and methods should be comparable across studies. Even if CovCP infusions did not improve clinical outcomes in patients with COVID-19, NAb-containing CP infusions remain a safe, widely available and potentially beneficial treatment option for future epidemics/pandemics.

Role of silicon in the development of complex crystal shapes in coccolithophores.

The development of calcification by the coccolithophores had a profound impact on ocean carbon cycling, but the evolutionary steps leading to the formation of these complex biomineralized structures are not clear. Heterococcoliths consisting of intricately shaped calcite crystals are formed intracellularly by the diploid life cycle phase. Holococcoliths consisting of simple rhombic crystals can be produced by the haploid life cycle stage but are thought to be formed extracellularly, representing an independent evolutionary origin of calcification. We use advanced microscopy techniques to determine the nature of coccolith formation and complex crystal formation in coccolithophore life cycle stages. We find that holococcoliths are formed in intracellular compartments in a similar manner to heterococcoliths. However, we show that silicon is not required for holococcolith formation and that the requirement for silicon in certain coccolithophore species relates specifically to the process of crystal morphogenesis in heterococcoliths. We therefore propose an evolutionary scheme in which the lower complexity holococcoliths represent an ancestral form of calcification in coccolithophores. The subsequent recruitment of a silicon-dependent mechanism for crystal morphogenesis in the diploid life cycle stage led to the emergence of the intricately shaped heterococcoliths, enabling the formation of the elaborate coccospheres that underpin the ecological success of coccolithophores.

COVID-19 convalescent plasma donor characteristics, product disposition, and comparison with standard apheresis donors.

BACKGROUND: With coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) offering an early treatment option for COVID-19, blood collectors needed to quickly overcome obstacles to recruiting and qualifying eligible donors. We provide attributes of CCP donors and products and compare to standard donors and products. STUDY DESIGN AND METHODS: Information on CCP donors was gathered from the American Red Cross qualification website through product collection. Data from 2019 for standard plasma/platelet apheresis (SA) and whole blood (WB) donor demographics and SA donations including product disposition and reactions were used for comparison. RESULTS: Of almost 59 000 donors registering on the website, 75% reported an existing COVID-19 diagnostic polymerase chain reaction or an antibody test. The majority (56.2%) of 10 231 CCP donors were first-time donors in contrast to SA or WB donor populations, which were only 3.0% and 30.6%, respectively, first-time donors. The number of female donors was 12% higher than SA donors. Older (≥ 65 years) and younger (16-19 years) were comparatively underrepresented in CCP donors. Deferral (10.2%) and Quantity Not Sufficient rates (6.4%) for presenting CCP donations were higher than SA (8.2% and 1.1%, respectively). Human leukocyte antigen antibody reactivity was the highest cause of product loss for CCP donations vs SA donations (9.6% vs 1.3%). Acute adverse events also occurred at a higher rate among both first-time and repeat CCP donations compared to SA. CONCLUSIONS: CCP donors were more likely to be first-time and female donors than WB or SA donors. CCP donations had a higher rate of donor adverse reactions, deferrals, and product loss than SA donations.

Neonatal and pediatric blood bank practice in the United States: Results from the AABB pediatric transfusion medicine subsection survey.

BACKGROUND: There are limited standards guiding the selection and processing of blood components specific for neonatal and pediatric transfusions. Therefore, blood banks (BBs) and transfusion services must create their own policies and procedures. STUDY DESIGN AND METHODS: The American Association of Blood Banks (AABB) Pediatric Transfusion Medicine Subsection Committee developed a 74-question survey to capture neonatal and pediatric BB practices in the United States. RESULTS: Thirty-five centers completed the survey: a response rate 15.8%. Responses indicated that most carry a mixed inventory of red blood cells (RBCs); 94.2% allow more than one type of RBC product for small-volume (SV) and large-volume (LV) transfusions to neonatal and pediatric patients. Many had storage age thresholds for RBCs transfused to neonates (SV = 60%, LV = 67.7%) but not older pediatric patients. The use of Group O for nonurgent RBC transfusion in neonates was common (74.2%). Responses related to special processing of RBCs and platelets indicated that 100% RBC and platelets are leukocyte-reduced (LR) for neonates and 97% for non-neonates. Irradiation of RBCs and platelets was commonly performed for neonatal transfusion (88.6%). Providing cytomegalovirus (CMV) seronegative products, volume reduction, and washing were variable. All centers transfused single-donor apheresis platelets; 20% allowed pathogen reduction (PR). The majority of centers have strategies limiting the amount of incompatible plasma transfused; however, few titrate ABO isoagglutinins in plasma-containing products (20% for platelets and 9.1% for plasma). CONCLUSIONS: Variability exists in BB practice for neonatal and pediatric transfusion. Future studies are needed to understand and define best BB practices in these patient populations.

Survey of newborn direct antiglobulin testing practice in United States and Canadian transfusion services.

BACKGROUND: We hypothesized that variability in practice exists for newborn immunohematology testing due to lack of consensus guidelines. We report the results of a survey assessing that variability at hospitals in the United States and Canada. STUDY DESIGN AND METHODS: An AABB Pediatric Subsection working party developed and validated a survey of newborn immunohematology testing practice. The survey was sent electronically to transfusion service leadership at teaching institutions. RESULTS: The response rate was 67% (61/91); 56 surveys meeting inclusion criteria were analyzed. Approximately 90% (50/56) were from birth hospitals and 16.1% (9/56) were from pediatric hospitals. Newborn immunohematology testing is ordered as a panel by 66.0% (33/50) of birth hospitals. ABO group and DAT is mandated before discharge in 14/56 (25.0%) and 13/56 (23.2%), respectively. About 76.8% (43/56) selectively perform a DAT according to blood blank or clinical parameters. The most common DAT practices include anti-IgG only testing by 73.2% (41/56) and use of umbilical cord specimen type by 67.9% (38/56). A positive DAT is a critical value for 26.8% (15/56) and followed with eluate testing when a maternal antibody screen is positive for 48.2% (27/56). In the setting of a non-ABO maternal red cell antibody, 55.4% (31/56), phenotype neonatal red cells when the DAT is positive. Group O RBC are transfused irrespective of the DAT result for 82.1%, (46/56). CONCLUSION: There is variability in newborn immunohematology testing and transfusion practice and potential overutilization of the DAT. Evidence-based consensus guidelines should be developed to standardize practice and to improve safety.

Selecting COVID-19 convalescent plasma for neutralizing antibody potency using a high-capacity SARS-CoV-2 antibody assay.

BACKGROUND: Efficacy of COVID-19 convalescent plasma (CCP) is hypothesized to be associated with the concentration of neutralizing antibodies (nAb) to SARS-CoV-2. High capacity serologic assays detecting binding antibodies (bAb) have been developed; nAb assays are not adaptable to high-throughput testing. We sought to determine the effectiveness of using surrogate bAb signal-to-cutoff ratios (S/Co) in predicting nAb titers using a pseudovirus reporter viral particle neutralization (RVPN) assay. METHODS: CCP donor serum collected by three US blood collectors was tested with a bAb assay (Ortho Clinical Diagnostics VITROS Anti-SARS-CoV-2 Total, CoV2T) and a nAb RVPN assay. Prediction effectiveness of various CoV2T S/Co criteria was evaluated for RVPN nAb NT50 titers using receiver operating characteristics. RESULTS: Seven hundred and fifty-three CCPs were tested with median CoV2T S/Co and NT50 of 71.2 of 527.5. Proportions of donors with NT50 over target nAb titers were 86% ≥1:80, 76% ≥1:160, and 62% ≥1:320. Increasing CoV2T S/Co criterion reduced the sensitivity to predict NT50 titers, while specificity to identify those below increased. As target NT50 titers increase, the CoV2T assay becomes less accurate as a predictor with a decline in positive predictive value and rise in negative predictive value. CONCLUSION: Selection of a clinically effective nAb titer will impact availability of CCP. Product release with CoV2T assay S/Co criterion must balance the risk of releasing products below target nAb titers with the cost of false negatives. A two-step testing scheme may be optimal, with nAb testing on CoV2T samples with S/Cos below criterion.

Use of therapeutic plasma exchange for pediatric neurological diseases.

Therapeutic plasma exchange is used to treat neurological diseases in the pediatric population. Since its first use in pediatric patients with hepatic coma in the form of manual whole blood exchange, therapeutic plasma exchange has been increasingly used to treat these disorders of the nervous system. This expansion is a result of improved techniques and apheresis instruments suitable for small children, as well as the recognition of its applicability to many diseases in the pediatric population. This review provides a historical overview of the use of therapeutic apheresis in children and highlights the most common applications for therapeutic plasma exchange to treat neurological disorders in children.

Update to the ASFA guidelines on the use of therapeutic apheresis in ANCA-associated vasculitis.

Since 1986, the American Society for Apheresis (ASFA) has published practice guidelines on the use of therapeutic apheresis in the Journal of Clinical Apheresis (JCA) Special Issue. Since 2007, updated guidelines have been published every 3 years to reflect current evidence based apheresis practice with the most recent edition (8th) published in 2019. With each edition, the guidelines are reviewed and updated based on any newly published literature since the last review. The PEXIVAS study, an international, randomized controlled trial comparing therapeutic plasma exchange (TPE) vs no TPE and standard vs reduced dose steroid regimen on the primary composite outcome of end stage renal disease or death in patients with ANCA-associated vasculitis (AAV), was published in February 2020. This study represents the largest study on the role of therapeutic apheresis in AAV published to date and prompted the JCA Special Issue Writing Committee to reassess the current AAV fact sheet for updates based on this newly available evidence. This interim fact sheet summarizes current ASFA recommendations for the evidence-based use of therapeutic apheresis in AAV and supersedes the recommendations published in the 2019 guidelines.

Health literacy and knowledge of chronic transfusion therapy in adolescents with sickle cell disease and caregivers.

BACKGROUND: Patients with sickle cell disease (SCD) may require chronic transfusion therapy (CTT) for prevention of stroke or other complications. Limited health literacy (HL) is common and is associated with poor health-related knowledge and outcomes in chronic disease. We sought to assess HL and transfusion knowledge in patients with SCD on CTT and their caregivers. METHODS: A cross-sectional study of patients was conducted in outpatient hematology clinics. Forty-five pairs of adolescent patients and caregivers and 20 caregivers of pre-adolescent patients completed the Newest Vital Sign HL assessment and answered questions assessing SCD and transfusion knowledge. Community-level median income and unemployment rates were estimated from Census data. We computed the correlation of HL with knowledge and compared each to Census variables, payor status, educational attainment, and stroke. RESULTS: HL was inadequate in 22 (34%) caregivers and 31 (69%) adolescents. Adequate caregiver HL was associated with higher educational attainment but not community-level socioeconomics or payor status. Mean knowledge score was lower in adolescents than in caregivers and correlated with age in adolescents (r = 0.42, P = .004). HL correlated with knowledge (r = 0.46, P < .0001). There were no significant correlations of HL or knowledge between adolescents and their caregivers. Neither HL nor knowledge was associated with prior stroke. The greatest knowledge was demonstrated for iron overload and SCD genotype, whereas knowledge gaps existed in alloimmunization, indication for CTT, and SCD curative therapy. CONCLUSIONS: Enhanced educational resources in transfusion therapy, alloimmunization, and curative therapy are needed for patients with SCD and caregivers of all HL levels.

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue.

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Eighth Edition of the JCA Special Issue continues to maintain this methodology and rigor in order to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Eighth Edition, like its predecessor, continues to apply the category and grading system definitions in fact sheets. The general layout and concept of a fact sheet that was introduced in the Fourth Edition, has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease entity or medical condition. The Eighth Edition comprises 84 fact sheets for relevant diseases and medical conditions, with 157 graded and categorized indications and/or TA modalities. The Eighth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.

The Influence of Social Media on Intrapartum Decision Making: A Scoping Review.

Social media has been influential in decision making regarding a number of health concerns. However, comparatively little has been examined with regard to its effects on pregnant women. The goal of this scoping review was to examine the literature and identify the role of social media in intrapartum decision making. A scoping review of the literature published between January 1990 and June 2018 was performed using PubMed, CINAHL, EMBASE, PsychINFO, Web of Science, and Cochrane databases. Of the initial 1951 records reviewed, 5 met inclusion criteria. Two of the 5 were quantitative in design, 1 was qualitative, and 2 used mixed methods. Internationally widespread, studies largely took place in developed nations including the United States, the United Kingdom, Canada, Australia, New Zealand, and Finland. Women are using the Internet, including social media, consistently as a source of pregnancy information, for example, 97% of 2400 participates in 1 exploratory study. This knowledge seeking was found to increase women's confidence and self-assurance in making decision during labor and birth. Studies identified issues surrounding women's ability to appraise available information. While it is clear that social media has an influence on women's intrapartum decision making, it is not clear exactly how. Further studies are needed to determine the content of the social media being appraised, the accuracy of the information, and the resulting decision as it affects the intrapartum experience. In addition, efforts should be made to open lines of communication between patients and care providers. This may foster a greater clinical understanding of social media consumption and its influences.

Epidemiology of therapeutic apheresis with a multidisciplinary approach at a high volume pediatric center.

INTRODUCTION: Therapeutic apheresis (TA) is used inconsistently in pediatric populations. We seek to define our multidisciplinary institutional practice. METHODS: We conducted a retrospective chart review of patients receiving TA from January 1, 2012 through October 31, 2015. Data collected included demographics, American Society of Apheresis (ASFA) indication, complications, and mortality. RESULTS: Over 46 months, 1198 TA procedures were conducted on 289 patients ranging in age from 5 months to 21 years with weights ranging from 4.76 to 170.3 kg (16 procedures in patients <10 kg). The procedures were 86% therapeutic plasma exchange, 10% red blood cell exchange, 4% extracorporeal photopheresis, and 5 leukocytapheresis procedures. TA was initiated in different clinical environments: 41% outpatient, 37% intensive care, 15% general inpatient, and 7% operating room. The ASFA category (6th edition) indications for the 1198 procedures included: 44% category I, 25% category II, 23% category III, a single category IV procedure, and the remainder (8%) uncategorized by ASFA. The rate of procedure failure and procedure-related mortality are 1 and 0%, respectively. Case mortality rate was 4%. CONCLUSION: At a large volume pediatric hospital, TA is commonly used and can be performed safely in a variety of settings by a multidisciplinary team. This demographic review catalogs the number and type of procedures performed as a second-line therapy or on the basis of limited evidence. Additional collaborative investigation is needed to evaluate unique implications of TA in pediatrics to maximize efficacy while preserving safety.

Blood Group Antigen Matching Influence on Gestational Outcomes (AMIGO) study.

BACKGROUND: Red blood cell (RBC) antigen matching policies to prevent alloimmunization in females of childbearing potential (FCP) vary between centers. To inform transfusion centers responsible for making decisions about matching policies for FCPs, the causal stimulus of the antibodies implicated in severe hemolytic disease of the fetus and newborn (HDFN) must be determined. STUDY DESIGN AND METHODS: We conducted a multinational retrospective study of women with offspring affected by severe HDFN requiring neonatal exchange transfusion and/or intrauterine transfusion. Mothers treated at centers that provide extended antigen-negative RBCs (MATCH, five centers) and those that do not (NoMATCH, nine centers) were compared. RESULTS: A total of 293 mothers had at least one affected pregnancy: 179 at MATCH centers and 114 at NoMATCH centers. Most alloimmunization (83%) was attributed to previous pregnancy: 3% to transfusion (two cases at MATCH, six at NoMATCH centers) and 14% undetermined (both antecedent transfusion and pregnancy). Only 50 mothers had received transfusions; 13 had HDFN due to anti-K at MATCH and four at NoMATCH centers. Most (12/13, 92%) of the anti-K HDFN cases at MATCH centers had K+ paternal antigen status. Mothers at the MATCH centers do not appear to be protected from HDFN due to K, C, c, and E antibodies, although the low number of FCPs who received transfusions precluded drawing firm conclusions. CONCLUSION: The causal stimulus of antibodies that cause HDFN is predominantly from previous pregnancy. Although extended RBC matching for FCPs may impart some protection from allosensitization, we were unable to show a positive effect, possibly because matching policies are not uniform and there was a small number of mothers who previously received transfusions.

Innate immunity against molecular mimicry: Examining galectin-mediated antimicrobial activity.

Adaptive immunity provides the unique ability to respond to a nearly infinite range of antigenic determinants. Given the inherent plasticity of the adaptive immune system, a series of tolerance mechanisms exist to reduce reactivity toward self. While this reduces the probability of autoimmunity, it also creates an important gap in adaptive immunity: the ability to recognize microbes that look like self. As a variety of microbes decorate themselves in self-like carbohydrate antigens and tolerance reduces the ability of adaptive immunity to react with self-like structures, protection against molecular mimicry likely resides within the innate arm of immunity. In this review, we will explore the potential consequences of microbial molecular mimicry, including factors within innate immunity that appear to specifically target microbes expressing self-like antigens, and therefore provide protection against molecular mimicry.

Impact of red blood cell alloimmunization on sickle cell disease mortality: a case series.

BACKGROUND: Although red blood cell (RBC) transfusion represents an integral component of sickle cell disease (SCD) care, transfusion support for some patients can result in alloimmunization to RBC antigens. Alloimmunized patients with SCD appear to experience worse survival compared to nonalloimmunized patients. While this difference in mortality may in part be due to underlying immunologic differences related to disease severity, it may also reflect direct clinical consequences of RBC alloimmunization. Alloimmunized patients have an increased risk of serious hemolytic transfusion reactions (HTRs) and may not receive adequate RBC transfusion support due to lack of compatible RBC units. CASE REPORT: This study reports on five RBC alloimmunized patients with SCD who died, to illustrate the concept that RBC alloimmunization itself contributes to premature death. RESULTS: The clinical course for each of the reported patients provides insight into the direct and indirect consequences of RBC alloimmunization, where patients experienced delayed HTRs or did not receive needed RBC transfusions. CONCLUSION: Future work examining the clinical impact of RBC alloimmunization should not only consider HTRs but should also address the potential consequences associated with difficulties in obtaining compatible blood.