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BackgroundThe Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P) Epidemiology, Surveillance and Preparedness of the Novel SARS-CoV-2 Epidemic (RESPONSE) seroprevalence study conducted monthly cross-sectional testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in blood donors in 6 US metropolitan regions to estimate the extent of SARS-CoV-2 infections over time.MethodsDuring March-August 2020, approximately ≥1000 serum specimens were collected monthly from each region and tested for SARS-CoV-2 antibodies using a well-validated algorithm. Regional seroprevalence estimates were weighted based on demographic differences compared with the general population. Seroprevalence was compared with reported coronavirus disease 2019 (COVID-19) case rates over time.ResultsFor all regions, seroprevalence was

The use of blood products to support patients undergoing the large variety of medical and surgical interventions requiring such support has continued to escalate very significantly over time. Relevantly, significant practice variation in the use of blood products exists among practitioners and institutions, largely because of the lack of robust clinical trial data, in many instances, which are critical for providing practitioners with evidence-based guidelines for appropriate blood product utilization. Recognizing this gap, the National Heart, Lung, and Blood Institute recently established a State-of-the-Science Symposium to help define areas of clinical trial research that would enhance the opportunity for developing appropriate practice guidelines for both Transfusion Medicine and Hemostasis/Thrombosis. Such a Symposium was held in September 2009 to identify important clinical trial research issues in these 2 subject areas of endeavor. The aims of this Symposium were to specifically identify phase 2 and 3 clinical trials that, if conducted over the next 5 to 10 years, could impact the treatment of patients with hemostatic and other disorders as well as to optimize the use of blood products in patients who need such interventions. This article reports on the deliberations that were held relating to the various clinical trial concepts developed by 7 Transfusion Medicine subcommittees. This Symposium generated a rich assortment of clinical trial proposals that will undergo further refinement before final implementation into pilot or full randomized clinical trials. The various proposals identified many opportunities for clinical trial research and most importantly underscored the ongoing need for well-developed evidence-based clinical trial research in the field of Transfusion Medicine. [ABSTRACT FROM AUTHOR]

Bacterial contamination of blood products has emerged as a serious problem in transfusion medicine in the past 20 years and is second only to ABO-mismatch in causing transfusion-associated death.Data from 1985 - 1999 showed that 11% (77/694) of transfusion-associated fatalities reported to the FDA were caused by bacterially contaminated products leading to sepsis.As platelets are stored at room temperature, and in a large volume of plasma and a bag that allows oxygen diffusion, it is platelet products that are the most frequently implicated in transfusion-associated fatalities due to bacterial contamination. [ABSTRACT FROM AUTHOR]

Emergence of new infectious diseases raises concern about the safety of the blood supply in the United States.This article will briefly review these emerging and enduring transfusion-transmitted infections.This article also reviews the different procedures and tests that blood banks implement to screen for these infections. [ABSTRACT FROM AUTHOR]

Red blood cell (RBC) antigen matching beyond ABO and RhD is commonly recommended for patients with sickle cell disease (SCD) and thalassaemia. We present an updated systematic literature review to inform evidence-based guidelines on RBC matching. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool was used to develop recommendations. Six new observational studies (4 prospective, 2 retrospective) were identified. The six studies reported on 583 patients in total, including cross-over designs, with sample sizes from 10 to 343. Studies were heterogeneous, utilising varying degrees of RBC matching and different definitions for 'extended' matching. All reported on alloimmunisation. One study reported on molecular matching. The reported prevalence of alloimmunisation using limited matching was 0%-50% and with extended matching was 0%-24%. Eighty-two patients were alloimmunised before study entry. The risk of bias across studies was moderate to critical. The guideline panel recommends that ABO, RhDCcEe, and K-compatible RBCs are selected for individuals with SCD and thalassaemia, even in the absence of alloantibodies, and that RBCs which are antigen-negative to already existing clinically significant antibodies are chosen. There is a need for comparative research to define the benefit, impact, cost-effectiveness, and feasibility of extended RBC matching strategies to prevent alloimmunisation., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Blood transfusions, crucial in managing anemia and coagulopathy in intensive care unit (ICU) settings, require accurate prediction for effective resource allocation and patient risk assessment. However, existing clinical decision support systems have primarily targeted a particular patient demographic with unique medical conditions and focused on a single type of blood transfusion. This study aims to develop an advanced machine learning-based model to predict the probability of transfusion necessity over the next 24 h for a diverse range of non-traumatic ICU patients. Methods: We conducted a retrospective cohort study on 72,072 non-traumatic adult ICU patients admitted to a high-volume US metropolitan academic hospital between 2016 and 2020. We developed a meta-learner and various machine learning models to serve as predictors, training them annually with 4-year data and evaluating on the fifth, unseen year, iteratively over 5 years. Results: The experimental results revealed that the meta-model surpasses the other models in different development scenarios. It achieved notable performance metrics, including an area under the receiver operating characteristic curve of 0.97, an accuracy rate of 0.93, and an F1 score of 0.89 in the best scenario. Conclusion: This study pioneers the use of machine learning models for predicting the likelihood of blood transfusion receipt in a diverse cohort of critically ill patients. The findings of this evaluation confirm that our model not only effectively predicts transfusion reception but also identifies key biomarkers for making transfusion decisions., Competing Interests: Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Alireza Rafiei et al.)

Background: Pediatric Patient Blood Management (PBM) programs require continuous surveillance of errors and near misses. However, most PBM programs rely on passive surveillance methods. Our objective was to develop and evaluate a set of automated trigger tools for active surveillance of pediatric PBM errors., Materials and Methods: We used the Rand-UCLA method with an expert panel of pediatric transfusion medicine specialists to identify and prioritize candidate trigger tools for all transfused blood products. We then iteratively developed automated queries of electronic health record (EHR) data for the highest priority triggers. Two physicians manually reviewed a subset of cases meeting trigger tool criteria and estimated each trigger tool's positive predictive value (PPV). We then estimated the rate of PBM errors, whether they reached the patient, and adverse events for each trigger tool across four years in a single pediatric health system., Results: We identified 28 potential triggers for pediatric PBM errors and developed 5 automated trigger tools (positive patient identification, missing irradiation, unwashed products despite prior anaphylaxis, transfusion lasting >4 hours, over-transfusion by volume). The PPV for ordering errors ranged from 38-100%. The most frequently detected near miss event reaching patients was first transfusions without positive patient identification (estimate 303, 95% CI: 288-318 per year). The only adverse events detected were from over-transfusions by volume, including 4 adverse events detected on manual review that had not been reported in passive surveillance systems., Discussion: It is feasible to automatically detect pediatric PBM errors using existing data captured in the EHR that enable active surveillance systems. Over-transfusions may be one of the most frequent causes of harm in the pediatric environment.

Few data describe pediatric patients who receive massive transfusion for life-threatening hemorrhage (LTH) while on extracorporeal membrane oxygenation (ECMO). We present a retrospective secondary analysis of a multicenter prospective observational study to describe resource utilization and mortality in pediatric patients with LTH while on ECMO. Children who were on ECMO during an LTH were compared to children with LTH who were not on ECMO. Primary outcomes were volumes of blood products administered and 28 day mortality. Comparisons were assessed by two-sided Fisher's exact test or Wilcoxon rank sum test. A total of 449 children, including 36 on ECMO, were included. Compared to those not on ECMO, children on ECMO received a higher volume of blood products (110 [50-223] vs . 59 [28-113]) ml/kg, p = 0.002) and were more likely to receive antifibrinolytic therapy (39% vs . 10%, p < 0.001). Blood product ratios were similar. Extracorporeal membrane oxygenation patients had higher 28 day mortality (64% vs. 35%, p = 0.001), although 24 hour mortality was similar (17% vs . 23%, p = 0.5). In conclusion, children on ECMO with LTH experience high resource utilization and 28 day mortality. Studies are needed to identify children at risk for LTH and to evaluate ECMO-specific treatment strategies., Competing Interests: Disclosure: M.E.S. is a consultant for Medtronic education services; P.C.S. is a consultant for Cerus, Hemanext, CSL Behring, and Haima and is founder and chief medical officer for Kalocyte. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Objectives: To assess sex-specific differences in the association between pre-transfusion haemoglobin values and early neurodevelopmental function., Design: Observational follow-up of infants with birth weights <1000 g and gestational ages 22-28 weeks who were enrolled in the NICHD Neonatal Research Network Transfusion of Prematures (TOP) Trial at 19 U.S. sites, 2012-2017., Main Outcome Measures: Pretransfusion haemoglobin values were obtained longitudinally through 36 weeks' postmenstrual age. The infant's mean pretransfusion haemoglobin was used as a marker of degree of anaemia (n=1655 measures). Measures of brain function were obtained at 22-26 months' corrected age using the Bayley Scales of Infant & Toddler Development, third edition (BSID-III) (n=1290 BSID-III scores). Sex-specific estimates for the linear relation between pretransfusion haemoglobin and BSID-III scores were obtained from repeated-measures regression analysis, adjusted for gestational age, birth weight, study site, clinical characteristics, and demographic covariates., Results: The relation of pretransfusion haemoglobin with 24-month BSID-III scores showed significant, independent interactions with both (1) sex (p=0.046) and (2) retinopathy of prematurity (ROP; p=0.004). In 614 males, BSID-III scores were higher by 1.07 points per g/dL (95% CI 1.58 to 4.33; p=0.008), not differing significantly among the three subscales (cognitive, language and motor; p=0.94). In 247 infants with ROP, BSID-III scores were higher by 2.95 points per g/dL (95% CI 0.28 to 1.87; p<0.0001), uniformly across subscales (p=0.73). These associations were non-significant in 676 females (p=0.96) and 1043 infants without ROP (p=0.81)., Conclusions: This study demonstrates sex-specific associations between mean pretransfusion haemoglobin (a marker of the severity of anaemia throughout the neonatal intensive care unit [NICU] hospitalisation) and early neurodevelopmental function at 22-26 months' corrected age., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Post-transfusion survival of donor red blood cells (RBCs) is important for effective chronic transfusion therapy in conditions including sickle cell disease (SCD). Biotin labeling RBCs allows direct in vivo measurement of multiple donor RBC units simultaneously post-transfusion., Study Design and Methods: In an observational trial of patients with SCD receiving monthly chronic transfusion therapy, aliquots of RBCs from one transfusion episode were biotin-labeled and infused along with the unlabeled RBC units. Serial blood samples were obtained to measure RBC survival. Donor units were tested for RBC indices, hemoglobin fractionation, and glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. For microcytic donor RBCs (MCV < 70 fL), HBA1 and HBA2 genetic testing was performed on whole blood., Results: We present one recipient, a pediatric patient with SCD and splenectomy who received two RBC units with aliquots from each unit labeled at distinct biotin densities (2 and 18 μg/mL biotin). One donor unit was identified to have microcytosis (MCV 68.5 fL after biotinylation); whole blood sample obtained at a subsequent donation showed 2-gene deletion alpha-thalassemia trait (ɑ- 3.7kb /ɑ- 3.7kb ) and normal serum ferritin. G6PD activity was >60% of normal mean for both. The RBCs with alpha-thalassemia RBC had accelerated clearance and increased surface phosphatidylserine post-transfusion, as compared with the normocytic RBC (half life 65 vs. 86 days, respectively)., Discussion: Post-transfusion RBC survival may be lower for units from donors with alpha-thalassemia trait, although the impact of thalassemia trait donors on transfusion efficacy requires further study., (© 2024 AABB.)

Importance: Observational studies often report that anemia and red blood cell (RBC) transfusions are associated with a higher risk of necrotizing enterocolitis (NEC) among extremely low-birthweight (ELBW) infants., Objective: To evaluate whether there is a temporal association between 72-hour hazard periods of exposure to RBC transfusions and NEC among ELBW infants randomized to either higher or lower hemoglobin transfusion thresholds., Design, Setting, and Participants: This post hoc secondary analysis of 1690 ELBW infants who survived to postnatal day 10 enrolled in the Transfusion of Prematures (TOP) randomized multicenter trial between December 1, 2012, and April 12, 2017, was performed between June 2021 and July 2023., Exposures: First, the distribution of RBC transfusions and the occurrence of NEC up to postnatal day 60 were examined. Second, 72-hour posttransfusion periods were categorized as hazard periods and the pretransfusion periods of variable duration as control periods. Then, the risk of NEC in posttransfusion hazard periods was compared with that in pretransfusion control periods, stratifying the risk based on randomization group (higher or lower hemoglobin transfusion threshold group)., Main Outcomes and Measures: The primary outcome was incidence of NEC stage 2 or 3. Secondary outcomes included the incidence rates of NEC within five 10-day intervals, taking into account the number of days at risk., Results: Of 1824 ELBW infants randomized during the TOP trial, 1690 were included in the present analysis (mean [SD] gestational age, 26.0 [1.5] weeks; 899 infants [53.2%] were female). After categorizing 4947 hazard periods and 5813 control periods, we identified 133 NEC cases. Fifty-nine of these cases (44.4%) occurred during hazard periods. Baseline and clinical characteristics of infants with NEC during hazard periods did not differ from those of infants with NEC during control periods. The risk of NEC was 11.9 per 1000 posttransfusion hazard periods and 12.7 per 1000 control periods (adjusted risk ratio, 0.95; 95% CI, 0.68-1.32; P = .74). This risk did not differ significantly between randomization groups, but the incidence rate of NEC per 1000 days peaked between postnatal days 20 and 29 in the lower hemoglobin transfusion threshold group., Conclusions and Relevance: The findings of this post hoc analysis suggest that, among ELBW infants with the hemoglobin ranges occurring in the TOP trial, exposure to RBC transfusions was not temporally associated with a higher risk of NEC during 72-hour posttransfusion hazard periods. Given that the incidence rate of NEC peaked between postnatal days 20 and 29 among infants with lower hemoglobin values, a more in-depth examination of this at-risk period using larger data sets is warranted., Trial Registration: ClinicalTrials.gov Identifier: NCT01702805.

Introduction: Transfusion may increase the risk of organ failure through immunomodulatory effects. The primary objective of this study was to assess for patient or transfusion-related factors that are independently associated with the risk of acute kidney injury (AKI) and acute respiratory distress syndrome (ARDS) in a cohort of children with life-threatening bleeding from all etiologies., Methods: In a secondary analysis of the prospective observational massive transfusion in children (MATIC) study, multivariable logistic regression was performed in an adjusted analysis to determine if blood product ratios or deficits were independently associated with AKI or ARDS in children with life-threatening bleeding., Results: There were 449 children included with a median (interquartile range, IQR) age of 7.3 years (1.7-14.7). Within 5 days of the life-threatening bleeding event, AKI occurred in 18.5% and ARDS occurred in 20.3% of the subjects. Every 10% increase in the platelet to red blood cell transfusion ratio is independently associated with a 12.7% increase in the odds of AKI (adjusted odds ratio 1.127; 95% confidence interval 1.025-1.239; p-value .013). Subjects with operative or medical etiologies were independently associated with an increased risk of AKI compared to those with traumatic injury. No transfusion-related variables were independently associated with the risk of developing ARDS., Conclusion: The use of increased platelet to red blood cell transfusion ratios in children with life-threatening bleeding of any etiology may increase the risk of AKI but not ARDS. Prospective trials are needed to determine if increased platelet use in this cohort increases the risk of AKI to examine possible mechanisms., (© 2024 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Background: Recent data suggest female sex imparts a survival benefit after trauma in adults. The independent associations between patient sex and age with outcomes have not been examined in children with life-threatening hemorrhage (LTH) from all etiologies., Study Design and Methods: In a secondary analysis of a multicenter prospective observational study of children with LTH, Massive Transfusion in Children (MATIC), we analyzed if patient sex and age were associated with differences in severity of illness, therapies, and outcomes. Primary outcomes were 24 hour mortality and weight-adjusted transfusion volume during LTH. Kruskal-Wallis, chi-square testing, and multivariable linear regression were used for adjusted analyses., Results: Of 449 children, 45% were females and 55% were males. Females were more commonly younger, white, and with less trauma as the etiology of LTH compared to males. Markers of clinical severity were similar between groups, except injury severity score (ISS) was higher in females in the trauma subgroup. In terms of resuscitative practices, females received greater weight-adjusted total transfusion volumes compared to males (76 (40-150) mL/kg vs. 53 (24-100) mL/kg), as well as increased red blood cells (RBCs), plasma, and platelets compared to males. After adjustment for confounders, female sex and age 0-11 years were independently associated with increased transfusion volume during LTH. There were no differences in mortality or adverse outcomes according to patient sex., Conclusion: Patient sex and age may impact factors associated with LTH and therapies received. Studies in developmental hemostasis are needed to determine the optimal transfusion strategy for LTH according to patient sex and age., (© 2024 AABB.)

Background: Red blood cell (RBC) antibodies are common in multiply transfused patients with sickle cell disease (SCD). Unlike RBC alloantibodies, the potential of autoantibodies to cause post-transfusion hemolysis may be uncertain. Biotin-labeling provides a direct measurement of red cell survival (RCS) over time, thus can be used to assess the clinical significance of RBC antibodies. Antibodies to biotinylated RBC (B-RBC) occasionally are detected after exposure, which may impact B-RBC survival in subsequent RCS studies., Study Design and Methods: Pediatric patients with SCD receiving monthly chronic transfusions underwent RCS studies, receiving aliquots of allogeneic RBC labeled at distinct densities of biotin (2-18 μg/mL). B-RBC survival was followed for 4 months post-transfusion, and B-RBC antibody screening for 6 months. Patients with warm autoantibodies (WAA) or B-RBC antibodies are reported here., Results: RBC antibodies were detected during RCS in four patients: one with WAA, one with WAA followed by B-RBC-specific antibodies, and two with transient B-RBC antibodies within the first 5 weeks of exposure. B-RBC half-lives (T 50 ) ranged 37.6-61.7 days (mean 47.8 days). There was no evidence of increased hemolysis or accelerated B-RBC clearance in the presence of WAA or B-RBC antibodies., Discussion: Biotinylation of allogenic RBC can be used to assess the possible effects of RBC antibodies on transfusion survival in individual cases, particularly when it is uncertain if the detected antibodies may result in hemolysis. In the cases presented here, neither WAA nor B-RBC antibodies were associated with significant shortening of B-RBC survival in individuals with SCD., (© 2024 AABB.)

Purpose: Balanced blood product resuscitation with red blood cells, plasma, and platelets can be achieved using whole blood (WB) or component therapy (CT). However, balanced resuscitation of younger children with severe traumatic hemorrhage may be complicated by delays in delivering all blood components and concerns regarding multiple product exposures. We hypothesized that WB achieves balanced resuscitation faster than CT, with fewer product exposures and improved clinical outcomes., Methods: Children younger than 12 years receiving balanced resuscitation within 4 hours of arrival were identified from the 2017 to 2019 Trauma Quality Improvement Program database. Time to balanced resuscitation was defined as the time of initiation of WB or all three components. Patient characteristics, resuscitation details, and outcomes were compared between WB and CT groups. Time to balanced resuscitation was compared using Kaplan-Meier analysis and Cox regression modeling to adjust for covariates. Additional multivariable regression models compared number of transfusion exposures, intensive care unit (ICU) length of stay, and mortality., Results: There were 390 patients (109 WB, 281 CT) with median age 7 years, 12% penetrating mechanism, 42% severe traumatic brain injury, and 49% in-hospital mortality. Time to balanced resuscitation was shorter for WB versus CT (median, 28 vs. 87 minutes; hazard ratio [HR], 2.93; 95% confidence interval [CI], 2.31-3.72; p < 0.0001). Whole blood patients received fewer transfusion exposures (mean, 3.2 vs. 3.9; adjusted incidence rate ratio, 0.82; 95% CI, 0.72-0.92; p = 0.001) and lower total product volumes (50 vs. 85 mL/kg; p = 0.01). Intensive care unit stays trended shorter for WB versus CT (median, 10 vs. 12 days; adjusted HR, 1.32; 95% CI, 0.93-1.86), while in-hospital mortality was similar (50% vs. 45%; adjusted odds ratio, 1.11; 95% CI, 0.65-1.88)., Conclusion: In critically injured preadolescent children receiving emergent transfusion, WB was associated with faster time to balanced resuscitation, fewer transfusion exposures, lower blood product volumes, and a trend toward shorter ICU stays than CT., Level of Evidence: Prognostic and Epidemiological; Level III., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

There is little formal guidance to direct neonatal blood banking practices and, as a result, practices vary widely across institutions. In this vulnerable patient population with a high transfusion burden, considerations for blood product selection include freshness, extended-storage media, pathogen inactivation, and other modifications. The authors discuss the potential unintended adverse impacts in the neonatal recipient. Concerns such as immunodeficiency, donor exposures, cytomegalovirus transmission, volume overload, transfusion-associated hyperkalemia, and passive hemolysis from ABO incompatibility have driven modifications of blood components to improve safety., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Red blood cell (RBC) transfusion is a common clinical intervention used to treat patients with acute and chronic anemia. The decision to transfuse RBCs in the acute setting is based on several factors but current clinical studies informing optimal RBC transfusion decision making (TDM) are largely based upon hemoglobin (Hb) level. In contrast to transfusion in acute settings, chronic RBC transfusion therapy has several different purposes and is associated with distinct transfusion risks such as iron overload and RBC alloimmunization. Consequently, RBC TDM in the chronic setting requires optimizing the survival of transfused RBCs in order to reduce transfusion exposure over the lifespan of an individual and the associated transfusion complications mentioned. This review summarizes the current medical literature addressing optimal RBC-TDM in the acute and chronic transfusion settings and discusses the current gaps in knowledge which need to be prioritized in future national and international research initiatives., Competing Interests: Declaration of Competing Interest RMF serves on medical advisory boards for Global Blood Therapeutics, Forma Therapeutics, and Cerus, and receives research funding from Forma Therapeutics and Cerus. RMF also serves as a consultant for REDSIV-Pediatric which is funded by the NIH/NHLBI. AD has no conflicts relevant to this publication. SRS serves as a consultant for Novartis, Alexison, Cereus, Grifols, Cellics, and Argenx. PCS serves as a consultant for Hemanext. JLC serves as the principal investigator of the NIH sponsored Myocardial Ischemia and Transfusion (MINT) trial, and is the Chair of DSMB for Cerus. CLM has no conflicts relevant to this publication. CDJ serves as a consultant for Westat, Immuocr, and has an unrestricted grant through Medtronics. DJT serves on the medical advisory board for Fresenius Kabi., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The optimal use of prophylactic platelet transfusion remains uncertain in a number of clinical scenarios. Platelet count thresholds have been established in patients with hematologic malignancies, yet thresholds backed by scientific data are limited or do not exist for many patient populations. Clinical scenarios involving transfusion thresholds for thrombocytopenic patients with critical illness, need for surgery or invasive procedures, or those involving specials populations like children and neonates, lack clear evidence for discerning favorable outcomes without undue risk related to platelet transfusion. In addition, while prophylactic platelet transfusions are administered with the goal of enhancing hemostasis, increasing evidence supports critical nonhemostatic roles for platelets related to innate and adaptive immunity, inflammation, and angiogenesis, which may impact patient responses and outcomes. Here we review several recent studies conducted in adult or pediatric patients that highlight the limitations in our current understanding of prophylactic platelet transfusion. Together, these studies underscore the need for additional research, especially in the form of robust randomized clinical trials and integrating additional parameters beyond the platelet count. Future research at the basic, translational, and clinical levels will best define the optimal role for prophylactic transfusion across the lifespan and its broader impact on health and disease., Competing Interests: Declaration of Competing Interest CLM is the recipient of an National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) career development award related to platelet transfusion. SJS is an employee of NHSBT, who manufacturers platelets, and is in receipt of multiple research grants for studies of platelet transfusions, including trials discussed in this article. MS-V serves as a consultant for Johnson and Johnson and has laboratory equipment on loan from Sysmex America, Inc DK serves on the advisory board for CSH Behring and receives royalties from UpToDate and consulting fees from NIH/NHLBI for the Recipient Epidemiology and Donor Evaluation Study (REDSIV-Pediatric). AEM receives research funding from Novo Nordisk and has received honoraria for serving on Novo Nordisk Advisory Boards. CDJ serves as a consultant for Westat. DJT serves on the medical advisory board for Fresenius Kabi. MEN serves as a consultant for REDSIV-Pediatric and is funded by the NIH/NHLBI. RF has no relevant disclosures., (Copyright © 2023. Published by Elsevier Inc.)

Antibodies against fetal red blood cell (RBC) antigens can cause hemolytic disease of the fetus and newborn (HDFN). Reductions in HDFN due to anti-RhD antibodies have been achieved through use of Rh immune globulin (RhIg), a polyclonal antibody preparation that causes antibody-mediated immunosuppression (AMIS), thereby preventing maternal immune responses against fetal RBCs. Despite the success of RhIg, it is only effective against 1 alloantigen. The lack of similar interventions that mitigate immune responses toward other RBC alloantigens reflects an incomplete understanding of AMIS mechanisms. AMIS has been previously attributed to rapid antibody-mediated RBC removal, resulting in B-cell ignorance of the RBC alloantigen. However, our data demonstrate that antibody-mediated RBC removal can enhance de novo alloimmunization. In contrast, inclusion of antibodies that possess the ability to rapidly remove the target antigen in the absence of detectable RBC clearance can convert an augmented antibody response to AMIS. These results suggest that the ability of antibodies to remove target antigens from the RBC surface can trigger AMIS in situations in which enhanced immunity may otherwise occur. In doing so, these results hold promise in identifying key antibody characteristics that can drive AMIS, thereby facilitating the design of AMIS approaches toward other RBC antigens to eliminate all forms of HDFN., (© 2023 by The American Society of Hematology.)

Background: Injured children with severe hemorrhage often receive blood product transfusions with ratios of plasma and platelets to packed red blood cells (PRBCs) approaching 1:1:1. Whether blood product ratios vary during pediatric resuscitation is unknown. This study (1) described precise timing of pediatric blood product administration, (2) characterized changes in blood product ratios over time, and (3) evaluated the association of blood products with early mortality while incorporating time-varying factors., Methods: Pediatric (younger than 18 years) trauma patients receiving high-volume transfusion (>40 mL/kg total products or >2 U PRBC or whole blood, during first 4 hours) were obtained from the 2017 to 2019 Trauma Quality Improvement Program database. The time of each individual product transfusion was recorded, along with demographics, injury details, and times of death. Patients were assigned to blood product groups at 15-minute intervals: high plasma/PRBC ratio (>1:1) with platelets, high plasma/PRBC ratio (>1:1) without platelets, low plasma/PRBC ratio (<1:1), PRBC only, and whole blood. Cox proportional hazards modeling for 24-hour mortality was performed, including blood product group as a time-varying variable and adjusting for relevant covariates., Results: Of 1,152 included patients (median age, 15 years; 32% penetrating, 28% severe traumatic brain injury [sTBI]), 18% died within 24 hours. During the resuscitation period, the number of patients in high-ratio groups increased over time, and patients switched blood product groups up to six times. There was no significant difference in mortality by blood product group. Among patients with sTBI, there was a strong trend toward lower mortality among high plasma/PRBC without platelets versus high plasma/PRBC with platelets (hazard ratio, 0.55; p = 0.07)., Conclusion: No significant association of high ratios or whole blood with mortality was seen when time-varying factors were incorporated. The impact of balanced resuscitation strategies, particularly platelet transfusion, may be greatest among patients with sTBI. Optimizing balanced resuscitation for children requires appropriately designed prospective studies., Level of Evidence: Therapeutic/Care Management; Level IV., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Among the risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ABO(H) blood group antigens are among the most recognized predictors of infection. However, the mechanisms by which ABO(H) antigens influence susceptibility to COVID-19 remain incompletely understood. The receptor-binding domain (RBD) of SARS-CoV-2, which facilitates host cell engagement, bears significant similarity to galectins, an ancient family of carbohydrate-binding proteins. Because ABO(H) blood group antigens are carbohydrates, we compared the glycan-binding specificity of SARS-CoV-2 RBD with that of galectins. Similar to the binding profile of several galectins, the RBDs of SARS-CoV-2, including Delta and Omicron variants, exhibited specificity for blood group A. Not only did each RBD recognize blood group A in a glycan array format, but each SARS-CoV-2 virus also displayed a preferential ability to infect blood group A-expressing cells. Preincubation of blood group A cells with a blood group-binding galectin specifically inhibited the blood group A enhancement of SARS-CoV-2 infection, whereas similar incubation with a galectin that does not recognize blood group antigens failed to impact SARS-CoV-2 infection. These results demonstrated that SARS-CoV-2 can engage blood group A, providing a direct link between ABO(H) blood group expression and SARS-CoV-2 infection., (© 2023 by The American Society of Hematology.)

Background: Anemia in very low birth weight (VLBW) infants is common and frequently managed with red blood cell (RBC) transfusions. We utilized a linked vein-to-vein database to assess the role of blood donors and component factors on measures of RBC transfusion effectiveness in VLBW infants., Study Design and Methods: We linked blood donor and component manufacturing data with VLBW infants transfused RBCs between January 1, 2013 and December 31, 2016 in the Recipient Epidemiology Donor Evaluation Study-III (REDS III) database. Using multivariable regression, hemoglobin increments and subsequent transfusion events following single-unit RBC transfusion episodes were examined with consideration of donor, component, and recipient factors., Results: Data on VLBW infants (n = 254) who received one or more single-unit RBC transfusions (n = 567 units) were linked to donor demographic and component manufacturing characteristics for analysis. Reduced post-transfusion hemoglobin increments were associated with RBC units donated by female donors (-0.24 g/dL [95% confidence interval (CI) -0.57, -0.02]; p = .04) and donors <25 years old (-0.57 g/dL [95% CI -1.02, -0.11]; p = .02). For RBC units donated by male donors, reduced donor hemoglobin levels were associated with an increased need for subsequent recipient RBC transfusion (odds ratio 3.0 [95% CI 1.3, 6.7]; p < .01). In contrast, component characteristics, storage duration, and time from irradiation to transfusion were not associated with post-transfusion hemoglobin increments., Conclusion: Donor sex, age, and hemoglobin levels were associated with measures of RBC transfusion effectiveness in VLBW infants. Mechanistic studies are needed to better understand the role of these potential donor factors on other clinical outcomes in VLBW infants., (© 2023 AABB.)

Antibodies against red blood cell (RBC) alloantigens can increase morbidity and mortality among transfusion recipients. However, alloimmunization rates can vary dramatically, as some patients never generate alloantibodies after transfusion, whereas others not only become alloimmunized but may also be prone to generating additional alloantibodies after subsequent transfusion. Previous studies suggested that CD4 T-cell responses that drive alloantibody formation recognize the same alloantigen engaged by B cells. However, because RBCs express numerous antigens, both internally and externally, it is possible that CD4 T-cell responses directed against intracellular antigens may facilitate subsequent alloimmunization against a surface RBC antigen. Here, we show that B cells can acquire intracellular antigens from RBCs. Using a mouse model of donor RBCs expressing 2 distinct alloantigens, we demonstrate that immune priming to an intracellular antigen, which would not be detected by any currently used RBC compatibility assays, can directly influence alloantibody formation after exposure to a subsequent distinct surface RBC alloantigen. These findings suggest a previously underappreciated mechanism whereby transfusion recipient responders may exhibit an increased rate of alloimmunization because of prior immune priming toward intracellular antigens., (© 2023 by The American Society of Hematology.)

Background: Firearm injury (FI) is the leading cause of death in children and adolescents in the United States (US). We describe the epidemiology of pediatric FI-associated emergency department (ED) visits and hospitalizations in the US stratified by race and ethnicity., Methods: Data on pediatric (0-17-year-olds) FI were analyzed using the 2019 Nationwide Emergency Department Sample (NEDS) and Kids' Inpatient Database (KID), the largest all-payer databases in the US for ED visits and pediatric hospitalizations, respectively. FI encounters were stratified by race and ethnicity. Poisson regression was used to identify factors associated with in-hospital mortality. Sampling weights were applied to generate nationally representative estimates., Findings: There were 7017 pediatric ED visits with FI (NEDS); 85.0% (5961/7017) were male and 73.0% (5125/7017) were adolescents (15-17 years). Overall, 5.5% (384/7017) died in the ED; 53.1% (3727/7017) of ED encounters did not result in hospitalization. There were 2817 pediatric FI hospitalizations (KID); 84.1% (2369/2817) were male and 71.6% (2018/2817) were adolescents; 51.4% (1447/2817) of FI were unintentional, 42.8% (1207/2817) were assault-related, and 5.8% (163/2817) were self-inflicted. Black children had the highest proportion (52.6%; 1481/2817) of hospitalizations among all race and ethnicities (p < 0.0001 vs. White). White children had the highest proportion of hospitalizations for self-inflicted injuries (16.6% [91/551] vs. 4.9% [25/504; p < 0.0001] in Hispanics and 1.7% [24/1481] in Blacks; p < 0.0001). The majority (56.5%; 1591/2817) of hospitalizations were patients from low-income zip codes (median annual-household-income <$44,000); 70% (1971/2817) had Medicaid as the primary insurance payer. Overall, 8.0% (225/2817) died during FI-associated hospitalizations. Self-inflicted injuries had the highest in-hospital mortality (prevalence ratio = 8.20, 95% CI = 6.06-11.10 vs. unintentional)., Interpretation: Black children and children with lower household incomes were disproportionately impacted by FI resulting from assaults and accidents, while White children had the highest proportion of self-inflicted FI injuries. Public health and legal policy interventions are needed to prevent pediatric FI., Funding: US National Institutes of Health., Competing Interests: All authors signed an Author Statement Form, and completed an individual ICMJE COI Form. Dr. Gehrie received payments or honoraria from Grifols Diagnostics, Cerus Corporation, Instrumentation Laboratories, and Wiley. No other authors have declared any relevant conflicts of interest., (© 2023 The Author(s).)

Background: Antifibrinolytic medications have been associated with reduced mortality in pediatric hemorrhage but may contribute to adverse events such as acute kidney injury (AKI)., Study Design and Methods: We conducted a secondary analysis of the MAssive Transfusion in Children (MATIC), a prospectively collected database of children with life-threatening hemorrhage (LTH), and evaluated for risk of adverse events with either antifibrinolytic treatment, epsilon aminocaproic acid (EACA) or tranexamic acid (TXA). The primary outcome was AKI and secondary outcomes were acute respiratory distress syndrome (ARDS) and sepsis., Results: Of 448 children included, median (interquartile range) age was 7 (2-15) years, 55% were male, and LTH etiology was 46% trauma, 34% operative, and 20% medical. Three hundred and ninety-three patients did not receive an antifibrinolytic (88%); 37 (8%) received TXA and 18 (4%) received EACA. Sixty-seven (17.1%) patients in the no antifibrinolytic group developed AKI, 6 (16.2%) patients in the TXA group, and 9 (50%) patients in the EACA group (p = .002). After adjusting for cardiothoracic surgery, cyanotic heart disease, preexisting renal disease, lowest hemoglobin pre-LTH, and total weight-adjusted transfusion volume during the LTH, the EACA group had increased risk of AKI (adjusted odds ratio 3.3 [95% CI: 1.0-10.3]) compared to no antifibrinolytic. TXA was not associated with AKI. Neither antifibrinolytic treatment was associated with ARDS or sepsis., Conclusion: Administration of EACA during LTH may increase the risk of AKI. Additional studies are needed to compare the risk of AKI between EACA and TXA in pediatric patients., (© 2023 AABB.)

Objective: Growing evidence suggests multiple pathophysiological mechanisms linking red blood cells (RBC) transfusions to thrombosis. This study examined blood donor, component, and recipient factors which may be associated with thromboembolic outcomes following RBC transfusion., Methods: We utilized the Recipient Epidemiology Donor Evaluation Study-III (REDS-III) database on patients transfused in 12 hospitals between 2013-2016. Stratified Cox proportional hazards regression models with time-dependent exposures were used to examine associations of donor and component modification characteristics on venous thromboembolism (VTE) in patients transfused RBC units., Results: 59,603 patients were transfused 229,500 RBC units during 79,298 hospitalizations with post-transfusion VTE occurring in 1869 (2.4%) of patients. In adjusted regression analyses, a per RBC-unit risk of VTE was present for gamma irradiation (HR = 1.03; 95% CI: 1.02-1.03), female donor sex (HR = 1.01; 95% CI: 1.00-1.01), storage duration greater than 5 weeks (HR = 1.01; 95% CI: 1.01-1.02), AS-1 storage solution (HR = 1.01; 95% CI: 1.00-1.01), and apheresis-derived collections (HR = 1.01; 95% CI: 1.01-1.02). Among recipient factors, male sex (HR = 1.03; 95% CI: 1.02-1.04), pre-transfusion hemoglobin level (HR = 0.94; 95% CI: 0.94-0.94), body mass index strata (HR = 1.11; 95% CI: 1.08-1.14), and principal diagnoses including malignancy (HR = 1.13; 95% CI: 1.10-1.16), cardiac arrest (HR = 1.38; 95% CI:1.07-1.77) and hip fracture (HR = 1.59; 95% CI:1.53-1.66) were associated with VTE in adjusted analyses., Discussion: We identified several donor, component, and recipient-specific factors associated with VTE in transfused hospitalized adult patients. In adjusted models, the dose-dependent associations of donor and component-specific factors with VTE were modest and unlikely to be clinically significant in the majority of transfused patients. Additional mechanistic and clinical studies linking blood donor and component factors with thrombotic outcomes are needed., (© 2023 AABB.)

Background: Hypofibrinogenemia is an important risk factor for poor outcomes in children with severe bleeding. There is a paucity of data on the impact of cryoprecipitate transfusion on outcomes in pediatric patients with life-threatening hemorrhage (LTH)., Study Design and Methods: This secondary analysis of a multicenter prospective observational study of children with LTH investigated subjects who were categorized by receipt of cryoprecipitate during their resuscitation and according to the etiology of their bleeding: trauma, operative, and medical. Bivariate analysis was performed to identify variables associated with 6-h, 24-h, and 28-day mortality. Cox Hazard regression models were generated to adjust for potential confounders., Results: Cryoprecipitate was transfused to 33.9% (152/449) of children during LTH. The median (Interquartile range) time to cryoprecipitate administration was 108 (47-212) minutes. Children in the cryoprecipitate group were younger, more often female, with higher BMI and pre-LTH PRISM score and lower platelet counts. After adjusting for PRISM score, bleeding etiology, age, sex, RBC volume, platelet volume, antifibrinolytic use and cardiac arrest, cryoprecipitate administration was independently associated with lower 6-h mortality, Hazard Ratio (95% CI), 0.41 (0.19-0.89), (p = 0.02) and 24-h mortality, Hazard Ratio (95% CI), 0.46 (0.24-0.89), (p = 0.02)., Conclusion: Cryoprecipitate transfusion to children with LTH was associated with reduced early mortality. A prospective randomized trial is needed to determine if cryoprecipitate can improve outcomes in children with LTH., (© 2023 AABB.)

Background: State of the Science (SoS) meetings are used to define and highlight important unanswered scientific questions. The National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, and the Office of the Assistant Secretary for Health (OASH), Department of Health and Human Services held a virtual SoS in transfusion medicine (TM) symposium., Study Design and Methods: In advance of the symposium, six multidisciplinary working groups (WG) convened to define research priorities in the areas of: blood donors and the supply, optimizing transfusion outcomes for recipients, emerging infections, mechanistic aspects of components and transfusion, new computational methods in transfusion science, and impact of health disparities on donors and recipients. The overall objective was to identify key basic, translational, and clinical research questions that will help to increase and diversify the volunteer donor pool, ensure safe and effective transfusion strategies for recipients, and identify which blood products from which donors best meet the clinical needs of specific recipient populations., Results: On August 29-30, 2022, over 400 researchers, clinicians, industry experts, government officials, community members, and patient advocates discussed the research priorities presented by each WG. Dialogue focused on the five highest priority research areas identified by each WG and included the rationale, proposed methodological approaches, feasibility, and barriers for success., Discussion: This report summarizes the key ideas and research priorities identified during the NHLBI/OASH SoS in TM symposium. The report highlights major gaps in our current knowledge and provides a road map for TM research., (© 2023 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Due to platelet availability limitations, platelet units ABO mismatched to recipients are often transfused. However, since platelets express ABO antigens and are collected in plasma which may contain ABO isohemagglutinins, it remains controversial as to whether ABO non-identical platelet transfusions could potentially pose harm and/or have reduced efficacy., Study Design and Methods: The large 4-year publicly available Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) database was used to investigate patient outcomes associated with ABO non-identical platelet transfusions. Outcomes included mortality, sepsis, and subsequent platelet transfusion requirements., Results: Following adjustment for possible confounding factors, no statistically significant association between ABO non-identical platelet transfusion and increased risk of mortality was observed in the overall cohort of 21,176 recipients. However, when analyzed by diagnostic category and recipient ABO group, associations with increased mortality for major mismatched transfusions were noted in two of eight subpopulations. Hematology/Oncology blood group A and B recipients (but not group O) showed a Hazard Ratio (HR) of 1.29 (95%CI: 1.03-1.62) and intracerebral hemorrhage group O recipients (but not groups A and B) showed a HR of 1.75 (95%CI: 1.10-2.80). Major mismatched transfusions were associated with increased odds of receiving additional platelet transfusion each post-transfusion day (through day 5) regardless of the recipient blood group., Discussion: We suggest that prospective studies are needed to determine if specific patient populations would benefit from receiving ABO identical platelet units. Our findings indicate that ABO-identical platelet products minimize patient exposure to additional platelet doses., (© 2023 AABB.)

Introduction: The impact of blood storage on red blood cell (RBC) alloimmunization remains controversial, with some studies suggesting enhancement of RBC-induced alloantibody production and others failing to observe any impact of storage on alloantibody formation. Since evaluation of storage on RBC alloimmunization in patients has examined antibody formation against a broad range of alloantigens, it remains possible that different clinical outcomes reflect a variable impact of storage on alloimmunization to specific antigens., Methods: RBCs expressing two distinct model antigens, HEL-OVA-Duffy (HOD) and KEL, separately or together (HOD × KEL), were stored for 0, 8, or 14 days, followed by detection of antigen levels prior to transfusion. Transfused donor RBC survival was assessed within 24 h of transfusion, while IgM and IgG antibody production were assessed 5 and 14 days after transfusion., Results: Stored HOD or KEL RBCs retained similar HEL or KEL antigen levels, respectively, as fresh RBCs, but did exhibit enhanced RBC clearance with increased storage age. Storage enhanced IgG antibody formation against HOD, while the oppositive outcome occurred following transfusion of stored KEL RBCs. The distinct impact of storage on HOD or KEL alloimmunization did not appear to reflect intrinsic differences between HOD or KEL RBCs, as transfusion of stored HOD × KEL RBCs resulted in increased IgG anti-HOD antibody development and reduced IgG anti-KEL antibody formation., Conclusions: These data demonstrate a dichotomous impact of storage on immunization to distinct RBC antigens, offering a possible explanation for inconsistent clinical experience and the need for additional studies on the relationship between RBC storage and alloimmunization., (© 2023 AABB.)

Background: The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD)., Methods: A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization., Results: Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD., Conclusions: We find no support for an increased risk of BPD with iron supplementation., Trial Registration Number: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT: Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Children are at increased risk from transfusion-related medical errors. Clinical decision support (CDS) can enhance pediatric providers' decision-making regarding transfusion practices including indications, volume, rate, and special processing instructions. Our objective was to use CDS in a pediatric health system to reduce:blood product-related safety events from ordering errors;special processing ordering errors for patients with T-cell dysfunction, sickle cell disease (SCD), or thalassemia;transfusions administered faster than 5 mL/kg/h., Materials and Methods: In this single-center before and after quality improvement study, we evaluated how user-centered design of pediatric blood product orders influenced pediatric transfusion practices and outcomes. Safety events were identified through active and passive surveillance. Other clinically relevant outcomes were identified through electronic health record queries., Results: Blood product-related safety events from ordering errors did not change significantly from the baseline period (6 events, 0.4 per month, from 1/1/2018-3/27/2019) to the intervention period (1 event, 0.1 per month, from 3/28/2019-12/31/2019; rate ratio: 0.27 [0.01-2.25]). Packed red blood cell (PRBC) and platelet orders for patients with T-cell dysfunction that did not specify irradiation decreased significantly from 488/12,359 (3.9%) to 204/6,711 (3.0%, risk ratio: 0.77 [0.66-0.90]). PRBC orders for patients with SCD or thalassemia that did not specify phenotypically similar units fell from 386/2,876 (13.4%) to 57/1,755 (3.2%, risk ratio: 0.24 [0.18-0.32]). Transfusions administered faster than 5 mL/kg/h decreased from 4,112/14,641 (28.1%) to 2,125/9,263 (22.9%, risk ratio: 0.82 [0.78-0.85])., Discussion: User-centered design of CDS for pediatric blood product orders significantly reduced special processing ordering errors and inappropriate transfusion rates. Larger studies are needed to evaluate the impact on safety events.

Abstract: Transfusion of blood products to a hemorrhaging pediatric trauma patient requires seamless partnership and communication between trauma, emergency department, critical care, and transfusion team members. To avoid confusion and delays, understanding of blood banking principles and mutually agreed upon procedures and policies must be regularly updated as knowledge evolves. Because pediatric patients require specialized considerations distinct from those in adults, this brief review covers transfusion principles, policies, and procedures specific to the resuscitation of pediatric trauma patients., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Hemorrhagic shock in pediatric trauma patients remains a challenging yet preventable cause of death. There is little high-quality evidence available to guide specific aspects of hemorrhage control and specific resuscitation practices in this population. We sought to generate clinical recommendations, expert consensus, and good practice statements to aid providers in care for these difficult patients.The Pediatric Traumatic Hemorrhagic Shock Consensus Conference process included systematic reviews related to six subtopics and one consensus meeting. A panel of 16 consensus multidisciplinary committee members evaluated the literature related to 6 specific topics: (1) blood products and fluid resuscitation for hemostatic resuscitation, (2) utilization of prehospital blood products, (3) use of hemostatic adjuncts, (4) tourniquet use, (5) prehospital airway and blood pressure management, and (6) conventional coagulation tests or thromboelastography-guided resuscitation. A total of 21 recommendations are detailed in this article: 2 clinical recommendations, 14 expert consensus statements, and 5 good practice statements. The statement, the panel's voting outcome, and the rationale for each statement intend to give pediatric trauma providers the latest evidence and guidance to care for pediatric trauma patients experiencing hemorrhagic shock. With a broad multidisciplinary representation, the Pediatric Traumatic Hemorrhagic Shock Consensus Conference systematically evaluated the literature and developed clinical recommendations, expert consensus, and good practice statements concerning topics in traumatically injured pediatric patients with hemorrhagic shock., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: In paediatric trauma patients, there are limited prospective data regarding blood components and mortality, with some literature suggesting decreased mortality with high ratios of plasma and platelets to red blood cells (RBCs) in massive transfusions; however, most paediatric massive transfusions occur for non-traumatic aetiologies and few studies assess blood product ratios in these children. This study's objective was to evaluate whether high blood product ratios or low deficits conferred a survival benefit in children with non-traumatic life-threatening bleeding., Materials and Methods: This is a secondary analysis of the five-year, multicentre, prospective, observational massive transfusion epidemiology and outcomes in children study of children with life-threatening bleeding from US, Canadian and Italian medical centres. Primary interventions were plasma:RBC and platelets:RBC (high ratio ≥1:2 ml/kg) and plasma and platelet deficits. The primary outcome was mortality at 6 h, 24 h and 28 days. Multivariate logistic regression models were used to determine independent associations with mortality., Results: A total of 222 children were included from 24 medical centres: 145 children (median [interquartile range] age 2.1 years [0.3-11.8]) with operative bleeding and 77 (8.0 years [1.2-14.7]) with medical bleeding. In adjusted analyses, neither blood product ratios nor deficits were associated with mortality at 6 h, 24 h or 28 days., Conclusion: This paper addresses a lack of prospective data in children regarding optimal empiric massive transfusion strategies in non-traumatic massive haemorrhage and in finding no decrease in mortality with high plasma or platelet to RBC ratios or lower deficits supports an exploratory analysis for mortality., (© 2022 International Society of Blood Transfusion.)

Enzymes catalyze biochemical reactions and play critical roles in human health and disease. Enzyme variants and deficiencies can lead to variable expression of glycans, which can affect physiology, influence predilection for disease, and/or directly contribute to disease pathogenesis. Although certain well-characterized enzyme deficiencies result in overt disease, some of the most common enzyme deficiencies in humans form the basis of blood groups. These carbohydrate blood groups impact fundamental areas of clinical medicine, including the risk of infection and severity of infectious disease, bleeding risk, transfusion medicine, and tissue/organ transplantation. In this review, we examine the enzymes responsible for carbohydrate-based blood group antigen biosynthesis and their expression within the human population. We also consider the evolutionary selective pressures, e.g. malaria, that may account for the variation in carbohydrate structures and the implications of this biology for human disease., Competing Interests: The authors declare no competing interests., (© 2022.)

Background: A paucity of data exists about the current practice of fetal red blood cell (RBC) transfusion in the United States (US). This investigation describes intrauterine transfusion (IUT) RBC product selection and processing practices at different US institutions., Methods: A transfusion medicine and maternal-fetal medicine (MFM) team designed a survey to interrogate and characterize RBCs utilized for IUT. This survey was distributed to seventy US institutions with fetal treatment centers (October 2020-April 2021) identified through the NAFTNet (North American Fetal Therapy Network)., Results: Thirty-seven institutions responded (response rate 53%, 37/70), but five were excluded for not performing IUTs. Most (84%; 27/32) performed 1-24 IUTs annually; two performed >50 IUTs/year. Group O, Rh(D) negative RBC units were always used by 66% (21/32), and 75% (24/32) provided hemoconcentrated RBCs by washing (17/24) or dry packing (6/24). Overall, 66% (21/32) targeted a hematocrit ≥75%. Fifty percent provided both leukocyte-reduced and CMV-negative RBC units. Irradiation of RBC units was performed within 6 h of issue at 63% (20/32) of sites. Most (81%, 26/32) used RBC units at <7 days of age after collection, 56% (18/32) always provided washed RBC units, while 19% (6/32) issued washed RBC only if fresh units are unavailable. Implicated maternal RBC alloantibodies were matched for 78% (25/32) of the time. The transfused volume was universally determined by the MFMs., Discussion: Heterogeneity and lack of standardization exist in RBC product selection and special processing steps for IUTs in the US. Hence, the establishment of a consensus to standardize IUT protocols is needed., (© 2022 AABB.)

Background: Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and severely reduced or absent ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) activity, with varying degrees of organ dysfunction. As TTP is rare in pediatrics, most of the medical and scientific literature has largely reported on adult patients. As a result, limited data exist regarding the clinical features, comorbidities, treatment response, and long-term outcomes in pediatric patients with immune-mediated TTP., Methods: A single-center retrospective cohort study was conducted of all children and adolescents presenting to Children's Healthcare of Atlanta, Atlanta, Georgia, between the years 2001 and 2021 with immune-mediated TTP (iTTP). Clinical features, treatments, and outcomes, including long-term neurocognitive function, were analyzed., Results: Eighteen individuals were identified, six of whom had a total of 10 relapses, amounting to 28 episodes overall. Thirty-eight percent of the patients experienced exacerbations but, ultimately, 85% achieved a clinical response and clinical remission. Only one in-hospital death occurred (mortality rate 5.5%). Seventy-three percent of analyzed patients demonstrated long-term neurocognitive abnormalities, including cognitive delay, learning difficulties, and severe depression., Conclusions: Children and adolescents recovering from iTTP are at high risk for neurocognitive deficits from initial and possibly ongoing microvascular disease. Due to risk for long-term neurological deficits, we recommend neuropsychological testing in addition to monitoring of other organ functions in all children with TTP, as well as long-term surveillance of ADAMTS13 activity during remission to detect and promptly treat early relapse., (© 2022 Wiley Periodicals LLC.)

Introduction: Current in-hospital burden and healthcare utilization patterns for persons with haemophilia (PWH) A and B, including both children (ages < 18 years) and adults (ages ≥ 18 years), in the United States (US) are lacking., Aim: To evaluate healthcare utilization, the prevalence of comorbidities, and mortality in hospitalized paediatric and adult PWH using a contemporary nationally representative cohort., Methods: Hospitalizations of PWH either as the primary reason for admission (principal diagnosis) or one of all listed diagnoses were identified using ICD-10 codes from the 2017 Nationwide Inpatient Sample (NIS), the largest publicly available all-payer inpatient discharge database in the US. Sampling weights were applied to generate nationally representative estimates., Results: The contemporary cohort included 10,555 hospitalizations (paediatrics, 18.3%; adults, 81.7%) among PWH as one-of-all listed diagnoses (n = 1465 as principal diagnosis). Median age (interquartile range) was 46 (24-66) years overall; adults, 54 (35-70) years and paediatric, 4 (1-11). The most common comorbidities in adults were hypertension (33.4%), hyperlipidaemia (23.6%), and diabetes (21.1%). In children, hemarthrosis (11.4%), contusions (9.6%), and central line infections (9.3%) were the most common. The overall mortality rate was 2.3%. Median hospital charges per haemophilia admission were $52,616 ($24,303-$135,814) compared to $26,841 ($12,969-$54,568) for all-cause admissions in NIS., Conclusion: Bleeding and catheter-related infections are the significant reasons for paediatric haemophilia admissions. Adult haemophilia admissions tend to be associated with age-related comorbidities. Costs for haemophilia-related hospitalizations are higher than the national average for all-cause hospitalizations., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Adaptive immunity can target a nearly infinite range of antigens, yet it is tempered by tolerogenic mechanisms that limit autoimmunity. Such immunological tolerance, however, creates a gap in adaptive immunity against microbes decorated with self-like antigens as a form of molecular mimicry. Our results demonstrate that the innate immune lectin galectin-7 (Gal-7) binds a variety of distinct microbes, all of which share features of blood group-like antigens. Gal-7 binding to each blood group expressing microbe, including strains of Escherichia coli , Klebsiella pneumoniae , Providencia alcalifaciens, and Streptococcus pneumoniae , results in loss of microbial viability. Although Gal-7 also binds red blood cells (RBCs), this interaction does not alter RBC membrane integrity. These results demonstrate that Gal-7 recognizes a diverse range of microbes, each of which use molecular mimicry while failing to induce host cell injury, and thus may provide an innate form of immunity against molecular mimicry., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Humoral immunity to factor VIII (FVIII) represents a significant challenge for the treatment of patients with hemophilia A. Current paradigms indicate that neutralizing antibodies against FVIII (inhibitors) occur through a classical CD4 T cell, germinal center (GC) dependent process. However, clinical observations suggest that the nature of the immune response to FVIII may differ between patients. While some patients produce persistent low or high inhibitor titers, others generate a transient response. Moreover, FVIII reactive memory B cells are only detectable in some patients with sustained inhibitor titers. The determinants regulating the type of immune response a patient develops, let alone how the immune response differs in these patients remains incompletely understood. One hypothesis is that polymorphisms within immunoregulatory genes alter the underlying immune response to FVIII, and thereby the inhibitor response. Consistent with this, studies report that inhibitor titers to FVIII differ in animals with the same F8 pathogenic variant but completely distinct backgrounds; though, how these genetic disparities affect the immune response to FVIII remains to be investigated. Given this, we sought to mechanistically dissect how genetics impact the underlying immune response to FVIII. In particular, as the risk of producing inhibitors is weakly associated with differences in HLA, we hypothesized that genetic factors other than HLA influence the immune response to FVIII and downstream inhibitor formation. Our data demonstrate that FVIII deficient mice encoding the same MHC and F8 variant produce disparate inhibitor titers, and that the type of inhibitor response formed associates with the ability to generate GCs. Interestingly, the formation of antibodies through a GC or non-GC pathway does not appear to be due to differences in CD4 T cell immunity, as the CD4 T cell response to an immunodominant epitope in FVIII was similar in these mice. These results indicate that genetics can impact the process by which inhibitors develop and may in part explain the apparent propensity of patients to form distinct inhibitor responses. Moreover, these data highlight an underappreciated immunological pathway of humoral immunity to FVIII and lay the groundwork for identification of biomarkers for the development of approaches to tolerize against FVIII., Competing Interests: SM serves on the advisory board for Genentech, Sanofi Genzyme, Takeda, Biomarin, and CSL Behring. SM consults for Pfizer and Spark, as well as receives research funding from Octapharma, Genentech. RJ is the CEO and part-owner of Biconcavity Inc, as well as owns stock in BioMarin Pharmaceutical Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Patel, Lundgren, Baldwin, Cox, Parker, Healey, Jajosky, Zerra, Josephson, Doering, Stowell and Meeks.)

Background: Alloimmunization can be a significant barrier to red blood cell (RBC) transfusion. While alloantigen matching protocols hold promise in reducing alloantibody formation, transfusion-dependent patients can still experience RBC alloimmunization and associated complications even when matching protocols are employed. As a result, complementary strategies capable of actively preventing alloantibody formation following alloantigen exposure are warranted., Study Design and Methods: We examined whether pharmacological removal of macrophages using clodronate may provide an additional strategy to actively inhibit RBC alloimmunization using two preclinical models of RBC alloimmunization. To accomplish this, mice were treated with clodronate, followed by transfusion of RBCs expressing the HOD (HEL, OVA, and Duffy) or KEL antigens. On days 5 and 14 post transfusion, anti-HOD or anti-KEL IgM and IgG antibodies were evaluated., Results: Low dose clodronate effectively eliminated key marginal zone macrophage populations from the marginal sinus. Prior treatment with clodronate, but not empty liposomes, also significantly inhibited IgM and IgG anti-HOD alloantibody formation following transfusion of HOD RBCs. Similar exposure to clodronate inhibited IgM and IgG antibody formation following KEL RBC transfusion., Conclusions: Clodronate can inhibit anti-HOD and anti-KEL antibody formation following RBC transfusion in preclinical models. These results suggest that clodronate may provide an alternative approach to actively inhibit or prevent the development of alloantibodies following RBC transfusion, although future studies will certainly be needed to fully explore this possibility., (© 2022 AABB.)

Background: The Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P) is a new iteration of prior National Heart, Lung, and Blood Institute (NHLBI) REDS programs that focus on improving transfusion recipient outcomes across the lifespan as well as the safety and availability of the blood supply., Study Design and Methods: The US program includes blood centers and hospitals (22 including 6 free-standing Children's hospitals) in four geographic regions. The Brazilian program has 5 participating hemocenters. A Center for Transfusion Laboratory Studies (CTLS) and a Data Coordinating Center (DCC) support synergistic studies and activities over the 7-year REDS-IV-P program., Results: The US is building a centralized, vein-to-vein (V2V) database, linking information collected from blood donors, their donations, the resulting manufactured components, and data extracts from hospital electronic medical records of transfused and non-transfused patients. Simultaneously, the Brazilian program is building a donor, donation, and component database. The databases will serve as the backbone for retrospective and prospective observational studies in transfusion epidemiology, transfusion recipient outcomes, blood component quality, and emerging blood safety issues. Special focus will be on preterm infants, patients with sickle cell disease, thalassemia or cancer, and the effect of donor biologic variability and component manufacturing on recipient outcomes. A rapid response capability to emerging safety threats has resulted in timely studies related to Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2)., Conclusions: The REDS-IV-P program endeavors to improve donor-recipient-linked research with a focus on children and special populations while also maintaining the flexibility to address emerging blood safety issues., (© 2022 AABB.)