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Background Blood conservation strategies have been shown to be effective in decreasing red blood cell (RBC) utilization in specific patient groups. However, few data exist describing the extent of RBC transfusion reduction or their impact on transfusion practice and mortality in a diverse inpatient population.

BACKGROUND: The use of plasma frozen within 24 hours after phlebotomy (FP24) is likely to increase as male donors become the predominant source of plasma products. This study was performed to investigate the levels of clotting factors in thawed plasma (TP) prepared from FP24 during 5 days of storage at 1 to 6 degrees C. STUDY DESIGN AND METHODS: Five units of A, B, and O and 3 units of AB FP24 were obtained from the local blood provider. They were thawed and maintained at 1 to 6 degrees C for a total of 5 days. Within 6 hours of thawing and every 24 hours thereafter for 5 days, each unit was assayed for the following clotting factors: Factor (F)II, FV, FVII, FVIII, F IX, FXI, FXII, antithrombin (AT), protein C (PC), and protein S (PS). ADAMTS-13 was assayed on Days 2, 4, and 5. Time is expressed as mean hours or days (standard deviation). RESULTS: On average the units were frozen 21.3 (3.8) hours after phlebotomy and had been frozen for a mean of 30.1 (32.3) days before thawing. The activities of all procoagulant factors including FVIII, along with AT, PC, and ADAMTS-13, were well maintained in their normal range during the 5-day storage. The activity of PS was slightly below the normal range by Day 5. CONCLUSIONS: The activity of all factors assayed, except for PS, were within their normal range during the 5-day storage period. These results show comparable factor assay levels in TP prepared from fresh-frozen plasma and FP24. [ABSTRACT FROM AUTHOR]

Background: Despite prophylactic platelet transfusions, hypoproliferative thrombocytopenia is associated with bleeding; historical risk factors include hematocrit (HCT) ≤ 25%, activated partial thromboplastin time ≥ 30 s, international normalized ratio ≥ 1.2, and platelets ≤ 5000/μL., Methods: We performed a post hoc analysis of bleeding outcomes and risk factors in participants with hematologic malignancy and hypoproliferative thrombocytopenia enrolled in the American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (A-TREAT) and randomized to receive either tranexamic acid (TXA) or placebo., Results: World Health Organization (WHO) grade 2+ bleeding occurred in 46% of 330 participants, with no difference between the TXA (44%) and placebo (47%) groups (p = 0.66). Overall, the most common sites of bleeding were oronasal (18%), skin (17%), gastrointestinal (11%), and genitourinary (11%). Among participants of childbearing potential, 28% experienced vaginal bleeding. Platelets ≤5000/μL and HCT < 21% (after adjusting for severe thrombocytopenia) were independently associated with increased bleeding risk (HR 3.78, 95% CI 2.16-6.61; HR 2.67, 95% CI 1.35-5.27, respectively). Allogeneic stem cell transplant was associated with nonsignificant increased risk of bleeding versus chemotherapy alone (HR 1.34, 95% CI 0.94-1.91)., Discussion: The overall rate of WHO grade 2+ bleeding was similar to previous reports, albeit with lower rates of gastrointestinal bleeding. Vaginal bleeding was common in participants of childbearing potential. Platelets ≤5000/μL remained a risk factor for bleeding. Regardless of platelet count, bleeding risk increased with HCT < 21%, suggesting a red blood cell transfusion threshold above 21% should be considered to mitigate bleeding. More investigation is needed on strategies to reduce bleeding in this population., (© 2024 The Author(s). Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

COVID-19 convalescent plasma (CCP) was one of the first therapies to receive emergency use authorization for management of COVID-19. We assessed the effectiveness of CCP in a propensity-matched analysis, and whether the presence of antibodies in the recipient at the time of treatment or the titer of antibodies in the administered CCP influenced clinical effectiveness. In an inpatient population within a single large health system, a total of 290 CCP patients were matched to 290 controls. While CCP increased titers of anti-SARS-CoV-2 RBD IgG titers post-CCP (p = <0.0001), no differences in 30-day survival were observed between CCP patients and controls in univariate and multivariate analyses. Survival at 30 days was numerically lower in recipients who were seronegative prior to CCP administration, compared to those with low titer and high titer anti-SARS-CoV-2 RBD IgG, respectively, but did not reach statistical significance (56% vs 82% vs 75%, p = 0.16). Patients who received 2 units of high-titer CCP had numerically better survival versus those who received fewer high-titer units, but this was not statistically significant (p = 0.08). CCP did not improve 30-day survival compared to propensity matched controls. Together these data support that CCP therapy provides limited benefit to hospitalized patients with SARS-CoV-2 infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Iasella et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Granulocyte transfusions for patients with prolonged neutropenia and severe infections has been a controversial practice. Previous studies suggest a benefit of high-dose granulocyte transfusions (≥0.6 × 10 9 /kg), although, until recently, the consistent production of high-dose units has been challenging. Here, we present our experience and results utilizing high-dose granulocyte transfusions at a large, tertiary academic medical center for the treatment of infections in adult, neutropenic patients., Study Design/methods: A retrospective chart review (2018-2021) was conducted for all patients who received high-dose granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. Gathered parameters included patient demographics, clinical history, infection status, dose, clinical outcomes, pre- and post-absolute neutrophil count (ANC), and transfusion times including time between granulocyte collection, administration, and posttransfusion ANC count. Gathered parameters were summarized using descriptive statistics, outcomes were assessed utilizing Kaplan-Meier curves/log-rank/regression testing., Results: Totally 28 adult, neutropenic patients refractory to antimicrobial agents and/or G-CSF received a total of 173 granulocyte concentrates. Median ANC increased from 0.7 × 10 9 /L pre-transfusion to 1.6 × 10 9 /L posttransfusion. The mean granulocyte yield was 77.4 × 10 9 resulting in an average dose per kilogram of 0.90 × 10 9  ± 0.30 × 10 9 granulocytes. Composite day 42 survival and microbial response was 42.9% (n = 12/28) without significant adverse reactions., Discussion: Here, we demonstrate the successful and safe implementation of high-dose granulocyte transfusions for neutropenic patients. Given the rapid and consistent production, distribution, and improved granulocyte quality, further investigations to determine the clinical efficacy of G-CSF primed granulocyte transfusions is now possible., (© 2024 AABB.)

Background: Donor genetic variation is associated with red blood cell (RBC) storage integrity and post-transfusion recovery. Our previous large-scale genome-wide association study demonstrated that the African G6PD deficient A- variant (rs1050828, Val68Met) is associated with higher oxidative hemolysis after cold storage. Despite a high prevalence of X-linked G6PD mutation in African American population (>10%), blood donors are not routinely screened for G6PD status and its importance in transfusion medicine is relatively understudied., Study Design and Methods: To further evaluate the functional effects of the G6PD A- mutation, we created a novel mouse model carrying this genetic variant using CRISPR-Cas9. We hypothesize that this humanized G6PD A- variant is associated with reduced G6PD activity with a consequent effect on RBC hemolytic propensity and post-transfusion recovery., Results: G6PD A- RBCs had reduced G6PD protein with ~5% residual enzymatic activity. Significantly increased in vitro hemolysis induced by oxidative stressors was observed in fresh and stored G6PD A- RBCs, along with a lower GSH:GSSG ratio. However, no differences were observed in storage hemolysis, osmotic fragility, mechanical fragility, reticulocytes, and post-transfusion recovery. Interestingly, a 14% reduction of 24-h survival following irradiation was observed in G6PD A- RBCs compared to WT RBCs. Metabolomic assessment of stored G6PD A- RBCs revealed an impaired pentose phosphate pathway (PPP) with increased glycolytic flux, decreasing cellular antioxidant capacity., Discussion: This novel mouse model of the common G6PD A- variant has impaired antioxidant capacity like humans and low G6PD activity may reduce survival of transfused RBCs when irradiation is performed., (© 2024 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Background: Tranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding in a multitude of clinical settings from postpartum hemorrhage to trauma. TXA may have clinical effects unrelated to bleeding; plasminogen, the target of TXA, alters immune responses, and TXA appears to decrease the risk of infection in patients undergoing cardiac surgery, as well as joint arthroplasty., Objectives: To address whether TXA alters rates of infection and inflammatory outcomes in patients with hematologic malignancies., Methods: We performed a post hoc analysis of outcomes of patients randomized to receive either TXA or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (Clinicaltrials.gov identifier: NCT02578901)., Results: TXA did not change the overall rate of infections, but the rate of severe infections (Common Toxicology Criteria for Adverse Events grade 3+) was lower in patients who received TXA compared with the placebo group. Patients who experienced grade 3+ infections had higher rates of World Health Organization grade 2+ bleeding and red blood cell transfusion requirements than patients who did not experience a grade 3+ infection, irrespective of treatment group. TXA did not impact other inflammatory outcomes such as mucositis, rash, or graft vs host disease., Conclusion: Patients with hematologic malignancies who received TXA had less severe infections than those who received placebo with no difference in overall rate of infection or other inflammatory outcomes. Further investigation is needed on the impact of TXA on infections in this population., (© 2024 The Author(s).)

Background: After the transfusion of RhD-positive red blood cell (RBC)-containing products to an RhD-negative woman of childbearing potential (WCP) during trauma resuscitation, there are several events that must occur for that WCP to have a future pregnancy affected by hemolytic disease of the fetus and newborn (HDFN). This study identified and quantitated the frequency of a novel event in the sequence from RhD-positive transfusion during trauma resuscitation to an HDFN outcome, that is, the development of a high titer anti-D among women who were D-alloimmunized., Methods: The transfusion service records at one maternity hospital were searched to locate all anti-D titers that had been performed on pregnant women between 1996 and 2022. The highest titer score during each pregnancy was recorded for this study. The critical titer threshold at this institution was ≥16. Passive anti-D caused by Rh immunoglobulin were excluded from analysis., Results: There were 97 pregnancies in 85 patients who had an immune-stimulated anti-D; in 60 of 97 (62%) pregnancies, the highest titer score was ≥16. There were 12 patients who had titers performed in two pregnancies during the study period; the correlation between the maximum titer in each pregnancy was not statistically significant (Spearman rank correlation r=0.42, p=0.17)., Conclusion: In this single center study, 62% of D-alloimmunized pregnant women had a high titer antibody. When considering all of the events that must occur for HDFN to happen, the rate of perinatal mortality was calculated to be 0.04% and the rate of perinatal death or serious adverse event from HDFN was 0.24%., Competing Interests: Competing interests: PS consults for Hemanext, Cerus, CSL Behring, is on the scientific advisory board for Haima and Octapharma and is a co-founder and chief medical officer for Kalocyte. DJT is on the scientific advisory board for Fresenius Kabi. MHY is on the scientific advisory board for Hemanext and has given paid lectures for Terumo BCT, Grifols. SPE and CL do not have any conflicts of interest to disclose., (© 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.)

Objectives: Trauma-induced coagulopathy (TIC) occurs in a subset of severely injured trauma patients. Despite having achieved surgical hemostasis, these individuals can have persistent bleeding, clotting, or both in conjunction with deranged coagulation parameters and typically require transfusion support with plasma, platelets, and/or cryoprecipitate. Due to the multifactorial nature of TIC, targeted interventions usually do not have significant clinical benefits. Therapeutic plasma exchange (TPE) is a non-specific modality of removing and replacing a patient's plasma in a euvolemic manner that can temporarily normalize coagulation parameters and remove deleterious substances, and may be beneficial in such patients with TIC., Methods: In a prospective case series, TPE was performed in severely injured trauma patients diagnosed with TIC and transfusion requirement. These individuals all underwent a series of at least 3 TPE procedures performed once daily with plasma as the exclusive replacement fluid. Demographic, injury, laboratory, TPE, and outcome data were collected and analyzed., Results: In total, 7 patients received 23 TPE procedures. All patients had marked improvements in routine coagulation parameters, platelet counts, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activities, inflammatory markers including interleukin-6 concentrations, and organ system injuries after completion of their TPE treatments. All-cause mortality rates at 1 day, 7 days, and 30 days were 0%, 0%, and 43%, respectively, and all patients for whom TPE was initiated within 24 hours after injury survived to the 30-day timepoint. Surgical, critical care, and apheresis nursing personnel who were surveyed were universally positive about the utilization of TPE in this patient population. These procedures were tolerated well with the most common adverse event being laboratory-diagnosed hypocalcemia., Conclusion: TPE is feasible and tolerable in severely injured trauma patients with TIC. However, many questions remain regarding the application of TPE for these critically ill patients including identification of the optimal injured population, ideal time of treatment initiation, appropriate treatment intensity, and concurrent use of adjunctive treatments., Level of Evidence: Level V., Competing Interests: Competing interests: JSR is a consultant and advisor for Sanofi SA. He has received honoraria from Sanofi SA. MDN is the Chief Medical Officer of Haima Therapeutics. He receives research funding from the NIH, Department of Defense, and DARPA. He has received research funding from Haemonetics, Alexion, and Instrumentation Laboratories. He has received honoraria from Haemonetics and Takeda., (© 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: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level., Methods: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days., Results: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49)., Conclusions: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: The introduction of low titer group O whole blood (LTOWB) that contains potentially ABO-incompatible plasma and the increasing use of group A plasma, due to shortages of AB plasma, in trauma patients whose ABO group is unknown could put the recipients of incompatible plasma at risk of increased morbidity and mortality. This study evaluated civilian trauma patient outcomes following receipt of incompatible plasma., Methods: One trauma center's patient contributions to three multicenter studies of different trauma resuscitation strategies was analyzed; these patients were separated into two groups based on receipt of only compatible plasma versus receipt of any quantity of incompatible plasma. Multivariate analysis was performed to determine if receipt of incompatible plasma was associated with 24-hour or 30-day mortality., Results: There were 347 patients eligible for this secondary analysis with 167 recipients of only compatible plasma and 180 recipients of incompatible plasma. The two groups were well matched demographically and on both prehospital and hospital arrival vital signs. The median (IQR) volume of incompatible plasma received by these patients was 684 ml (342, 1229). There was not a significant difference between the groups in 24-hour and 30-day mortality, nor in in-hospital or intensive care unit lengths of stay. In the Cox proportional-hazards regression model for both 24-hour and 30-day survival, receipt of incompatible plasma was not independently predictive of either mortality endpoint., Conclusion: Receipt of incompatible plasma was not independently associated with increased mortality in trauma patients. Prospective studies are needed to confirm these findings.

The use of blood products to resuscitate injured and massively bleeding patients in the prehospital and early in-hospital phase of the resuscitation is increasing. Using group O red blood cells (RBC) and low titer group O whole blood (LTOWB) avoids an immediate hemolytic reaction from recipient's naturally occurring anti-A and - B, but choosing the RhD type for these products is more nuanced and requires the balancing of product availability and survival benefit against the risk of D-alloimmunization, especially in females of childbearing potential (FCP) due to the possible future occurrence of hemolytic disease of the fetus and newborn (HDFN). Recent models have estimated the risk of fetal/neonatal death from HDFN resulting from D-alloimmunization of an FCP during her trauma resuscitation at between 0-6.5% depending on her age at the time of the transfusion and other societal factors including trauma mortality, her age when she becomes pregnant, frequency of different RHD genotypes in the population, and the probability that the woman will have children with different fathers; this is counterbalanced by an approximately 24% risk of death from hemorrhagic shock. This review will discuss the different models of HDFN outcomes following RhD-positive transfusion as well as the results of recent surveys where the public was asked about their preferences for urgent transfusion in light of the risks of fetal/neonatal adverse events.

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.)

Background: The use of low-titer group O whole blood is increasing. To reduce wastage, unused units can be converted to packed red blood cells. Supernatant is currently discarded post-conversion; however, it could be a valuable transfusable product. The aim of this study was to evaluate supernatant prepared from late-storage low-titer group O whole blood being converted to red blood cells, hypothesizing it will have higher hemostatic activity compared to fresh never-frozen liquid plasma., Methods: Low-titer group O whole blood supernatant (n = 12) prepared on storage day 15 was tested on days 15, 21, and 26 and liquid plasma (n = 12) on 3, 15, 21, and 26. Same-day assays included cell counts, rotational thromboelastometry, and thrombin generation. Centrifuged plasma from units was banked for microparticle characterization, conventional coagulation, clot structure, hemoglobin, and additional thrombin generation assays., Results: Low-titer group O whole blood supernatant contained more residual platelets and microparticles compared to liquid plasma. At day 15, low-titer group O whole blood supernatant elicited a faster intrinsic clotting time compared to liquid plasma (257 ± 41 vs. 299 ± 36 s, P = 0.044), and increased clot firmness (49 ± 9 vs. 28 ± 5 mm, P < 0.0001). Low-titer group O whole blood supernatant showed more significant thrombin generation compared to liquid plasma (day 15 endogenous thrombin potential 1,071 ± 315 vs. 285 ± 221 nM·min, P < 0.0001). Flow cytometry demonstrated low-titer group O whole blood supernatant contained significantly more phosphatidylserine and CD41+ microparticles. However, thrombin generation in isolated plasma suggested residual platelets in low-titer group O whole blood supernatant were a greater contributor than microparticles. Additionally, low-titer group O whole blood supernatant and liquid plasma showed no difference in clot structure, despite higher CD61+ microparticle presence., Conclusions: Plasma supernatant produced from late-storage low-titer group O whole blood shows comparable, if not enhanced, in vitro hemostatic efficacy to liquid plasma., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

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.)

Objective: The safety of Low Titer Group O Whole Blood (LTOWB) transfusion has not been well-studied in small children., Methods: This is a single-center retrospective cohort study of pediatric recipients of RhD-LTOWB (June 2016-October 2022) who weigh less than 20 kilograms. Biochemical markers of hemolysis (lactate dehydrogenase, total bilirubin, haptoglobin, and reticulocyte count) and renal function (creatinine and potassium) were recorded on the day of LTOWB transfusion and post-transfusion days 1 and 2. Group O and non-Group O recipients were compared., Results: Twenty-one children were included. Their median (interquartile range [IQR]) weight was 12 kg (12-18) with minimum 2.8 kg, and median (IQR) age was 3 years (1.75-5.00) with minimum 0.08 years (29 days old). The most common indication for transfusion was trauma (17/21; 81%). The median (IQR) volume of LTOWB transfused was 30 mL/kg (20-42). There were 9 non-group O and 12 group O recipients. There were no statistically significant differences in the median concentrations of any of the biochemical markers of hemolysis or the renal function markers between the non-group O and the group O recipients at any of the three time points (p > 0.05 for all comparisons). There were also no statistically significant differences in demographic parameters or clinical outcomes including 28-day mortality, length of stay, ventilator days, and venous thromboembolism between the groups. No transfusion reactions were reported in either group., Conclusion: These data suggest LTOWB use is safe in children weighing less than 20 kg. Further multi-center studies and larger cohorts are needed to confirm these results., (© 2023 AABB.)

Background: The D-alloimmunization rate in trauma patients does not appear to depend on the number of RhD-positive units transfused. The effect of the timing and pattern of RhD-positive transfusions has not been evaluated., Methods: RhD-negative trauma patients who were transfused with RhD-positive red blood cells (RBC) or low titer group O whole blood (collectively called RBCs) on at least two separate calendar days and who had antibody detection tests performed at least 14 days after the second RhD-positive RBC transfusion without receiving RhIg were included in the analysis. Patients whose anti-D was detected within 14 days of the index RhD-positive RBC transfusion were excluded. Patient demographics and the dates of RhD-positive RBC transfusions and results of antibody detection tests performed after the index transfusion were collected on eligible patients., Results: There were 44/61 (72.1%) patients in whom anti-D was not detected (non-alloimmunized) and 17/61 (27.9%) in whom anti-D was detected (alloimmunized). The patients had similar demographics with trends towards higher median admission heart rates and lower median admission Glasgow Coma Scale values in the alloimmunized group. Both groups received statistically identical median quantities of RhD-positive RBCs (non-alloimmunized 5 vs. alloimmunized 4 units, p = .53), however, the alloimmunized group received all their RhD-positive RBCs over a significantly shorter period of time compared to the non-alloimmunized (median 4 vs. 15 days, respectively, p = .01)., Conclusion: Receipt of all RhD-positive RBCs over a shorter period of time was associated with higher D-alloimmunization rates. These results need to be confirmed in larger studies., (© 2023 AABB.)

Objective: The aim of this study was to assess the survival impact of low-titer group O whole blood (LTOWB) in injured pediatric patients who require massive transfusion., Summary Background Data: Limited data are available regarding the effectiveness of LTOWB in pediatric trauma., Methods: A prospective observational study of children requiring massive transfusion after injury at UPMC Children's Hospital of Pittsburgh, an urban academic pediatric Level 1 trauma center. Injured children ages 1 to 17 years who received a total of >40 mL/kg of LTOWB and/or conventional components over the 24 hours after admission were included. Patient characteristics, blood product utilization and clinical outcomes were analyzed using Kaplan-Meier survival curves, log rank tests and Cox proportional hazards regression analyses. The primary outcome was 28-day survival., Results: Of patients analyzed, 27 of 80 (33%) received LTOWB as part of their hemostatic resuscitation. The LTOWB group was comparable to the component therapy group on baseline demographic and physiologic parameters except older age, higher body weight, and lower red blood cell and plasma transfusion volumes. After adjusting for age, total blood product volume transfused in 24 hours, admission base deficit, international normalized ratio (INR), and injury severity score (ISS), children who received LTOWB as part of their resuscitation had significantly improved survival at both 72 hours and 28 days post-trauma [adjusted odds ratio (AOR) 0.23, P = 0.009 and AOR 0.41, P = 0.02, respectively]; 6-hour survival was not statistically significant (AOR = 0.51, P = 0.30). Survivors at 28 days in the LTOWB group had reduced hospital LOS, ICU LOS, and ventilator days compared to the CT group., Conclusion: Administration of LTOWB during the hemostatic resuscitation of injured children requiring massive transfusion was independently associated with improved 72-hour and 28-day survival., Competing Interests: The following conflicts of interest are relevant to this study: M.H.Y. has given paid lectures and received travel reimbursement from Terumo BCT, the manufacturer of the PLT-sparing leukoreduction filter used in the preparation of the LTOWB units. The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The American Trial Using Tranexamic Acid (TXA) in Thrombocytopenia (A-TREAT, NCT02578901) demonstrated no superiority of TXA over placebo in preventing World Health Organization (WHO) grade 2 or higher bleeding in patients with severe thrombocytopenia requiring supportive platelet transfusion following myeloablative therapy for hematologic disorders. In this ancillary study, we sought to determine whether this clinical outcome could be explained on the basis of correlative assays of fibrinolysis. Plasma was collected from A-TREAT participants (n = 115) before the initiation of study drug (baseline) and when TXA was at steady-state trough concentration (follow-up). Global fibrinolysis was measured by 3 assays: euglobulin clot lysis time (ECLT), plasmin generation (PG), and tissue-type plasminogen activator (tPA)-challenged clot lysis time (tPA-CLT). TXA was quantified in follow-up samples by tandem mass spectrometry. Baseline samples did not demonstrate fibrinolytic activation by ECLT or tPA-CLT. Furthermore, neither ECLT nor levels of plasminogen activator inhibitor-1, tPA, plasminogen, alpha2-antiplasmin, or plasmin-antiplasmin complexes were associated with a greater risk of WHO grade 2+ bleeding. TXA trough concentrations were highly variable (range, 0.7-10 μg/mL) and did not correlate with bleeding severity, despite the fact that plasma TXA levels correlated strongly with pharmacodynamic assessments by PG (Spearman r, -0.78) and tPA-CLT (r, 0.74). We conclude that (1) no evidence of fibrinolytic activation was observed in these patients with thrombocytopenia, (2) trough TXA concentrations varied significantly between patients receiving the same dosing schedule, and (3) tPA-CLT and PG correlated well with TXA drug levels., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Accumulating evidence from clinical trials suggests that a lower (restrictive) hemoglobin threshold (<8 g/dL) for red blood cell (RBC) transfusion, compared with a higher (liberal) threshold (≥10 g/dL) is safe. However, in anemic patients with acute myocardial infarction (MI), maintaining a higher hemoglobin level may increase oxygen delivery to vulnerable myocardium resulting in improved clinical outcomes. Conversely, RBC transfusion may result in increased blood viscosity, vascular inflammation, and reduction in available nitric oxide resulting in worse clinical outcomes. We hypothesize that a liberal transfusion strategy would improve clinical outcomes as compared to a more restrictive strategy., Methods: We will enroll 3500 patients with acute MI (type 1, 2, 4b or 4c) as defined by the Third Universal Definition of MI and a hemoglobin <10 g/dL at 144 centers in the United States, Canada, France, Brazil, New Zealand, and Australia. We randomly assign trial participants to a liberal or restrictive transfusion strategy. Participants assigned to the liberal strategy receive transfusion of RBCs sufficient to raise their hemoglobin to at least 10 g/dL. Participants assigned to the restrictive strategy are permitted to receive transfusion of RBCs if the hemoglobin falls below 8 g/dL or for persistent angina despite medical therapy. We will contact each participant at 30 days to assess clinical outcomes and at 180 days to ascertain vital status. The primary end point is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary end points include all-cause mortality at 30 days, recurrent adjudicated MI, and the composite outcome of all-cause mortality, nonfatal recurrent MI, ischemia driven unscheduled coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or readmission to the hospital for ischemic cardiac diagnosis within 30 days. The trial will assess multiple tertiary end points., Conclusions: The MINT trial will inform RBC transfusion practice in patients with acute MI., Competing Interests: Disclosures JLC: DSMB member for Cerus Corporation project. MMB: DSMB member for Cerus Corporation project. JDA: Research funding MicroPort, Boston Scientific. Advisory Boards Philips, Medtronic. Consulting Abbott, Shockwave, Penumbra, Recor. SGG: Research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (eg, advisory boards) from: Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, Valeo Pharma; and salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, TIMI Study Group (Brigham Health). AMG: None. MHB: None. Philippe Gabriel Steg: has received research grants from Bayer, Merck, Sanofi, Servier; has been a speaker or consultant for Amarin, Amgen, AstraZeneca, Bayer, Bristol-Myers-Squibb, Janssen, Lexicon, Merck, Novartis, Novo-Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, Servier. He is a Senior Associate Editor for Circulation. APD: Consultant Velakor Biotherapeutics Inc. RDL: Grants from Bristol-Myers Squibb, GlaxoSmithKline plc., Medtronic, Pfizer, Bayer, Sanofi; consulting fees from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Novo Nordisk, GlaxoSmithKline plc., Medtronic, Merck, Pfizer, Portola, Sanofi; and honoraria for lectures from Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, Novo Nordisk, and Bayer. PCH: DSMB member of Cerus Corporation project., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Ex vivo labeling with 51 chromium represents the standard method to determine red blood cell (RBC) survival after transfusion. Limitations and safety concerns spurred the development of alternative methods, including biotinylated red blood cells (BioRBC)., Study Design and Methods: Autologous units of whole blood were divided equally into two bags and stored under standard blood bank conditions at 2 to 6°C (N = 4 healthy adult volunteers). One bag was biotinylated (15 μg/ml) on storage days 5 to 7 (fresh) and the other was biotinylated (3 μg/ml) on days 35 to 42 (aged). The proportion of circulating BioRBC was measured serially, and cell-surface biotin was quantified with reference to molecules of equivalent soluble fluorochrome. Clearance kinetics were modeled by RBC age distribution at infusion (Gaussian vs. uniform) and decay over time (constant vs. exponential)., Results: Data were consistent with biphasic exponential clearance of cells of uniform age. Our best estimate of BioRBC clearance (half-life [T 1/2 ]) was 49.7 ± 1.2 days initially, followed by more rapid clearance 82 days after transfusion (T 1/2  = 15.6 ± 0.6 days). As BioRBC aged in vivo, molecules of equivalent soluble fluorochrome declined with a T 1/2 of 122 ± 9 days, suggesting gradual biotin cleavage. There were no significant differences between the clearance of fresh and aged BioRBC., Conclusion: Similar clearance kinetics of fresh and aged BioRBC may be due to the extensive washing required during biotinylation. Survival kinetics consistent with cells with uniform rather than Gaussian or other non-uniform age distributions suggest that washing, and potentially RBC culling, may extend the storage life of RBC products., (© 2022 AABB.)

Evidence of the effectiveness of prophylactic use of tranexamic acid (TXA) in thrombocytopenia is lacking. To determine whether TXA safely reduces bleeding incidence in patients undergoing treatment for hematologic malignancies, a randomized, double-blind clinical trial was conducted from June 2016 through June 2020. Of 3120 screened adults, 356 patients were eligible and enrolled, and 337 patients (mean age, 53.9; 141 [41.8%] women), randomized to 1300 mg TXA orally or 1000 mg TXA through IV (n = 168) vs placebo (n = 169) thrice daily for maximum 30 days. Three hundred thirty patients were activated when their platelet counts fell below 30 000 per µL; 279 (83%) had complete outcome ascertainment. World Health Organization (WHO) grade ≥2 bleeding was observed in the 30 days following activation in 50.3% (73/145) and 54.2% (78/144) of patients in the TXA and placebo groups, with an adjusted odds ratio of 0.83 (95% confidence interval [CI], 0.50-1.34; P = .44). There was no statistically significant difference in the mean number of platelet transfusions (mean difference, 0.1; 95% CI, -1.9 to 2.0), mean days alive without grade ≥2 bleeding (mean difference, 0.8; 95% CI, -0.4 to 2.0), thrombotic events (6/163 [3.7%] TXA, 9/163 [5.5%] placebo), or deaths due to serious bleeding. Most common adverse events were: diarrhea (116/164 [70.7%] TXA and 114/163 [69.9%] placebo); febrile neutropenia (111/164 [67.7%] TXA, 105/163 [64.4%] placebo); fatigue (106/164 [64.6%] TXA, 109/163 [66.9%] placebo); and nausea (104/164 [63.4%] TXA, 97/163 [59.5%] placebo). Among patients with hematologic malignancy undergoing chemotherapy or hematopoietic stem cell transplantation, prophylactic treatment with TXA compared with placebo did not significantly reduce the risk of WHO grade ≥2 bleeding., (© 2022 by The American Society of Hematology.)

Background: The serological safety of transfusing low titer group O whole blood (LTOWB) with an anti-A and anti-B titer of <100 was evaluated in group O and non-group O trauma recipients., Methods: Civilian adult trauma patients who received ≥4 units of leukoreduced LTOWB during their initial resuscitation and who survived for >24 h after admission at two level 1 trauma centers were included in this retrospective study. Lactate dehydrogenase (LDH), total bilirubin, haptoglobin, potassium, creatinine were evaluated on the day of LTOWB transfusion (day 0) and on the next 3 days., Results: There were 77 injured recipients evaluated: 39 non-group O and 38 group O. The median (IQR) number of transfused LTOWB units was 4 (4-6) and 4 (4-5), respectively, and the maximum number of units was 8 and 11, respectively. The non-group O patients received a median (IQR) volume of 1710 ml (1368-2070) of ABO-incompatible plasma. Comparing non-group O to group O recipients, there were no significant differences in the median haptoglobin, LDH, or creatinine concentrations at any time point. The median concentration of total bilirubin was significantly higher amongst the non-group O recipients on days 1 and 2, while on day 0 the median potassium concentration was significantly higher amongst the group O recipients. All median elevated values were within the laboratory's normal range. Amongst the non-group O recipients there were no reported transfusion reactions., Conclusion: Receiving at least four LTOWB units (anti-A&B titer <100) was not associated with biochemical/clinical evidence of hemolysis in adult trauma patients., (© 2022 AABB.)

Rationale: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. Objectives: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. Methods: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. Measurements and Main Results: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4 + lymphopenia predominated, with lower CD4 + /CD8 + ratios in severe COVID-19 compared with patients with mild disease ( P  < 0.0001). In severe disease, immunodominant CD4 + T-cell responses to Spike-1 (S1) produced increased in vitro TNF-α (tumor necrosis factor-α) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4 + TNF-α + T-cell responses inversely correlated with absolute CD4 + counts from patients with severe COVID-19 ( n  = 76; R  = -0.797; P  < 0.0001). In vitro TNF-α blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4 + T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 ( P  < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFκB signaling in S1-stimulated CD4 + cells with infliximab treatment. We also evaluated BAL and lung explant CD4 + T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-α compared with peripheral blood mononuclear cells. Conclusions: Together, our findings show CD4 + dysfunction in severe COVID-19 is TNF-α/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-α blockade may be beneficial in severe COVID-19.

Introduction: Low titer group O whole blood (LTOWB) resuscitation is increasingly common in both military and civilian settings. Data regarding the safety and efficacy of prehospital LTOWB remain limited., Methods: We performed a single-center, prospective, cluster randomized, prehospital through in-hospital whole blood pilot trial for injured air medical patients. We compared standard prehospital air medical care including red cell transfusion and crystalloids followed by in-hospital component transfusion to prehospital and in-hospital LTOWB resuscitation. Prehospital vital signs were used as inclusion criteria (systolic blood pressure ≤90 mm Hg and heart rate ≥108 beats per minute or systolic blood pressure ≤70 mm Hg for patients at risk of hemorrhage). Primary outcome was feasibility. Secondary outcomes included 28-day and 24-hour mortality, multiple organ failure, nosocomial infection, 24-hour transfusion requirements, and arrival coagulation parameters., Results: Between November 2018 and October 2020, 86 injured patients were cluster randomized by helicopter base. The trial has halted early at 77% enrollment. Overall, 28-day mortality for the cohort was 26%. Injured patients randomized to prehospital LTOWB (n = 40) relative to standard care (n = 46) were similar in demographics and injury characteristics. Intent-to-treat Kaplan-Meier survival analysis demonstrated no statistical mortality benefit at 28 days (25.0% vs. 26.1%, p = 0.85). Patients randomized to prehospital LTOWB relative to standard care had lower red cell transfusion requirements at 24 hours (p < 0.01) and a lower incidence of abnormal thromboelastographic measurements. No transfusion reactions during the prehospital or in-hospital phase of care were documented., Conclusion: Prehospital through in-hospital LTOWB resuscitation is safe and may be associated with hemostatic benefits. A large-scale clinical trial is feasible with protocol adjustment and would allow the effects of prehospital LTOWB on survival and other pertinent clinical outcomes to be appropriately characterized., Level of Evidence: Therapeutic/Care Management, Level II., (Copyright © 2022 American Association for the Surgery of Trauma.)

Background: Genetic variants have been found to influence red blood cell (RBC) susceptibility to hemolytic stress and affect transfusion outcomes and the severity of blood diseases. Males have a higher susceptibility to hemolysis than females, but little is known about the genetic mechanism contributing to the difference., Results: To investigate the sex differences in RBC susceptibility to hemolysis, we conducted a sex-stratified genome-wide association study and a genome-wide gene-by-sex interaction scan in a multi-ethnic dataset with 12,231 blood donors who have in vitro osmotic hemolysis measurements during routine blood storage. The estimated SNP-based heritability for osmotic hemolysis was found to be significantly higher in males than in females (0.46 vs. 0.41). We identified SNPs associated with sex-specific susceptibility to osmotic hemolysis in five loci (SPTA1, KCNA6, SLC4A1, SUMO1P1, and PAX8) that impact RBC function and hemolysis., Conclusion: Our study established a best practice to identify sex-specific genetic modifiers for sexually dimorphic traits in datasets with mixed ancestries, providing evidence of different genetic regulations of RBC susceptibility to hemolysis between sexes. These and other variants may help explain observed sex differences in the severity of hemolytic diseases, such as sickle cell and malaria, as well as the viability of red cell storage and recovery., (© 2022. The Author(s).)

There has been renewed interest in the use of low titer group O whole blood (LTOWB) for the resuscitation of civilian casualties. LTOWB offers several advantages over conventional components such as providing balanced resuscitation in one bag that contains less additive/preservative solution than an equivalent volume of conventional components, is easier and faster to transfuse than multiple components, avoids blood product ratio confusion, contains cold stored platelets, and reduces donor exposures. The resurgence in its use in the resuscitation of civilian trauma patients has led to the publication of an increasing number of studies on its use, primarily amongst adult recipients but also in pediatric patients. These studies have indicated that hemolysis does not occur amongst adult and pediatric non-group O recipients of a modest quantity of LTOWB. The published studies to date on mortality have shown conflicting results with some demonstrating a reduction following LTOWB transfusion while most others have not shown a reduction; there have not been any studies to date that have found significantly increased overall mortality amongst LTOWB recipients. Similarly, when other clinical outcomes, such as venous thromboembolism, sepsis, hospital or intensive care unit lengths of stay are evaluated, LTOWB recipients have not demonstrated worse outcomes compared to conventional component recipients. While definitive proof of the trends in these morbidity and mortality outcomes awaits confirmation in randomized controlled trials, the evidence to date indicates the safety of transfusing LTOWB to injured civilians.

Background: Early administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19., Methods: In this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression. In addition, all the patients presented to the emergency department within 7 days after symptom onset and were in stable condition for outpatient management. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included the worst severity of illness on an 8-category ordinal scale, hospital-free days within 30 days after randomization, and death from any cause., Results: A total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, -6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups., Conclusions: The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression. (SIREN-C3PO ClinicalTrials.gov number, NCT04355767.)., (Copyright © 2021 Massachusetts Medical Society.)

Importance: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive., Objective: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19., Design, Setting, and Participants: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021., Interventions: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916)., Main Outcomes and Measures: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events., Results: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group., Conclusions and Relevance: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Background: Laboratory results can be affected by sample to sample carryover. Carryover of different analytes occurring in automated clinical chemistry, immunology, hematology, and molecular laboratories is well described. However, carryover in a transfusion service laboratory is not reported in medical literature., Materials and Methods: Immunohematology testing results, demographic data, and clinical data were reviewed on three patients retrospectively from 2015 to 2019., Results: Type and screen samples tested on automated gel platform from two D+ patients were affected by anti-D carryover from a patient sample with a very high-titer anti-D. Additional immunohematology and molecular testing confirmed that anti-D in samples of two D+ patients was due to carryover., Conclusion: A case of anti-D carryover caused false detection of anti-D in two D+ patients. Carryover can have implications for patient management. Transfusion laboratory staff need to be aware of it and investigate any unexpected results further., (© 2021 AABB.)

Background: Low titer group O whole blood (LTOWB) is used as the initial resuscitative fluid in an increasing number of pediatric trauma and massive bleeding transfusion protocols. There is little data on adverse events following its transfusion in pediatric trauma patients., Study Design and Methods: Blood bank records were queried for pediatric recipients of at least one unit of red blood cells (RBCs) (component group) or LTOWB (LTOWB group) within 24 h of admission between May 2013 and August 2020. Subjects with early death (<72 h) were excluded. Propensity-score matching of LTOWB and component groups was performed. Adverse events were recorded, including transfusion reaction, thromboembolism, acute kidney injury, sepsis, and organ failure based on PELOD-2 score, along with hospital and ICU length of stay (LOS) and ventilator days., Results: Thirty-six LTOWB recipients were matched to 36 conventional component recipients. Subjects were 52% male, with blunt injury mechanism (82%), median (IQR) injury severity score = 27 (21-35), and 26% in-hospital mortality. The groups were well matched in terms of demographics and injury characteristics. There were no clinically or statistically significant differences in adverse outcomes including reported transfusion reaction, organ failure, acute kidney injury, sepsis/bacteremia, and venous thromboembolism. Hospital LOS, ventilator days, mortality, and functional disability at discharge were also not significantly different. The LTOWB group had significantly shorter ICU LOS compared to the component group., Conclusion: LTOWB transfusion did not increase the risk of adverse events in children. However, larger studies are required to confirm these results., (© 2021 AABB.)

Background: A risk assessment model for predicting the risk of haemolytic disease of the fetus and newborn (HDFN) in future pregnancies following the transfusion of Rh(D)-positive red blood cell (RBC)-containing products to females of childbearing potential (FCP) was developed, accounting for the age that the FCP is transfused in various countries., Methods: The HDFN risk prediction model included the following inputs: risk of FCP death in trauma, Rh(D) alloimmunization rate following Rh(D)-positive RBC transfusion, expected number of live births following resuscitation, probability of carrying an Rh(D)-positive fetus, the probability of HDFN in an Rh(D)-positive fetus carried by an alloimmunized mother. The model was implemented in Microsoft R Open, and one million FCPs of each age between 18 and 49 years old were simulated. Published data from eight countries, including the United States, were utilized to generate country-specific HDFN risk estimates., Results: The risk predictions showed similar characteristics for each country in that the overall risk of having a pregnancy affected by HDFN was higher if the FCP was younger when she received her Rh(D)-positive transfusion than if she was older. In the United States, the overall risk of HDFN if the FCP was transfused at age 18 was 3·4% (mild: 1·20%, moderate: 0·45%; severe: 1·15%; IUFD: 0·57%); the risk was approximately 0% if the FCP was 43 years or older at the time of transfusion., Conclusion: This model can be used to predict HDFN outcomes when establishing transfusion policies as it relates to the administration of Rh(D)-positive products for massively bleeding FCPs., (© 2021 International Society of Blood Transfusion.)

Introduction: Early transfusion reduces mortality in bleeding patients. In this setting, RhD-positive blood products might be transfused. This study determined the association between the RhD-alloimmunization rate and the number of RhD-positive products transfused., Methods: RhD-negative patients between 13 and 50 years who were transfused with ≥1 RhD-positive red blood cell (RBC) or whole blood units between January 1, 2000 and December 31, 2019 in a healthcare network were identified. Study patients had to have had at least one antibody detection test performed ≥14 days after the index RhD-positive transfusion and not receive RhIg. Patients were stratified into groups that received 1, 2, 3-5, 6-10, 11-20, and >20 RhD-positive transfusions and the RhD-alloimmunization rate was determined for each group., Results: There were 335 patients included; 52/335 (15.5%) were females. Overall, there were 117/335 (34.9%, CI: 29.8%-40.3%) recipients who became RhD-alloimmunized. There was no significant dosage effect in the RhD-alloimmunization rates as the exposure to RhD-positive units increased from one RhD-positive unit to more than 20 RhD-positive units (p = .270 for non-parametric trend test). In an exploratory analysis, patients who received 100% of their RhD-positive transfusions within 72 h of the index transfusion had a significantly higher rate of RhD-alloimmunization compared to those who were transfused over a longer period of time (42.3% vs. 21.4%, respectively; p = .001)., Conclusion: These results suggest that there may not be an increased RhD-alloimmunization risk with transfusing multiple RhD-positive units after one RhD-positive unit has been transfused. These findings need confirmation in larger studies., (© 2021 AABB.)

Background: Low-titer Group O Whole Blood (LTOWB) is used with increasing frequency in adult and pediatric trauma and massive bleeding transfusion protocols. There is a risk of acute hemolytic reactions in non-group O recipients due to the passive transfusion of anti-A and anti-B in the LTOWB. This study investigated the hemolysis risk among pediatric recipients of LTOWB., Study Design and Methods: Blood bank records were queried for pediatric recipients of LTOWB between June 2016 and August 2020 and merged with clinical data. The primary outcome was laboratory evidence of hemolysis as manifested by changes in lactate dehydrogenase (LDH), haptoglobin, total bilirubin, reticulocyte count, potassium, and creatinine. Per protocol, these values were collected on hospital days 0-2 for recipients of LTOWB. Transfusion reactions were reported to the hospital's blood bank., Results: Forty-seven children received LTOWB transfusion between 2016 and 2020; 21 were group O and 26 were non-group O. The groups were comparable in terms of the total volume of transfused blood products, demographics, and clinical outcomes. The most common indication for LTOWB transfusion was hemorrhagic shock due to trauma. There were no clinically or statistically significant differences in baseline, post-transfusion day 1, or post-transfusion day 2 hemolysis markers between the group O and non-group O LTOWB recipients. There were no adverse events or transfusion reactions reported., Discussion: Use of up to 40 ml/kg of LTOWB appears to be serologically safe for children in hemorrhagic shock., (© 2021 AABB.)

Background: Plasma is frequently administered to patients with prolonged INR prior to invasive procedures. However, there is limited evidence evaluating efficacy and safety., Study Design and Methods: We performed a pilot trial in hospitalized patients with INR between 1.5 and 2.5 undergoing procedures conducted outside the operating room. We excluded patients undergoing procedures proximal to the central nervous system, platelet counts <40,000/μl, or congenital or acquired coagulation disorders unresponsive to plasma. We randomly allocated patients stratified by hospital and history of cirrhosis to receive plasma transfusion (10-15 cc/kg) or no transfusion. The primary outcome was change in hemoglobin concentration within 2 days of procedure., Results: We enrolled 57 patients, mean age 56.0, 34 (59.6%) with cirrhosis, and mean INR 1.92 (SD = 0.27). In the intention to treat analysis, there were 10 of 27 (38.5%) participants in the plasma arm with a post procedure INR <1.5 and one of 30 (3.6%) in the no treatment arm (p < .01). The mean INR after receiving plasma transfusion was -0.24 (SD 0.26) lower than baseline. The change from pre-procedure hemoglobin level to lowest level within 2 days was -0.6 (SD = 1.0) in the plasma transfusion arm and -0.4 (SD = 0.6) in the no transfusion arm (p = .29). Adverse outcomes were uncommon., Discussion: We found no differences in change in hemoglobin concentration in those treated with plasma compared to no treatment. The change in INR was small and corrected to less than 1.5 in minority of patients. Large trials are required to establish if plasma is safe and efficacious., (© 2021 AABB.)

Introduction: Low-titer group O whole blood (LTOWB) is being increasingly transfused to injured patients. This study evaluated a range of clinical outcomes to determine if receipt of LTOWB predisposed recipients to worse outcomes compared to recipients of conventional component therapy (CCT)., Methods: A retrospective analysis of trauma patients who received at least 3 units of LTOWB (LTOWB group) versus those that received at least 3 units of RBCs, 1 unit of plasma and 1 unit of platelets but no LTOWB (CCT group) during the first 24 h of their admission was performed. Causal treatment effects were explored using propensity score matching (PSM) and coarsened exact matching (CEM). Important clinical outcomes were evaluated., Results: There were 165 CCT and 155 LTOWB recipients eligible for matching. PSM and CEM reduced covariate imbalances between the CCT and LTOWB groups, with the exception that males remained over-represented in the LTOWB group due to the hospital's former resuscitation policy of not administering RhD-positive LTOWB to females <50. In both of the matched analyses, the LTOWB group received a median of 4 LTOWB units. There were no significant differences in 6-, 24-h mortality or 30-day mortality between groups, nor were there differences in the frequency of other clinical outcomes such as acute kidney injury, sepsis, venous/arterial thromboembolism; delta MODS was lower for the LTOWB recipients in the exact match group., Conclusion: In both matched analyses, administration of a median of four LTOWB units did not result in a different frequency of major clinical outcomes including mortality., (© 2021 AABB.)