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BACKGROUND Both M and N alleles encode antigens on Glycophorin A (GPA), a red blood cell (RBC) surface sialoglycoprotein. Interaction between RBC GPA and leukocyte surface lectins may downregulate their activation. The current study investigates if RBC autoantibodies against GPA, such as auto-anti-M/N, prime an activated phenotype in peripheral blood leukocytes. METHODS Leukocyte activation was assessed in whole blood from patients with auto-anti-GPA (anti-M/N) and compared to those with allo-anti-M/N and healthy subjects. Control samples from healthy subjects with no antibodies incubated in vitro with either anti-GPA or anti-Rh were analyzed for neutrophil and monocyte surface activation marker expression, reactive oxygen species (ROS) content, and formation of aggregates with RBCs. Samples incubated with an IgG1 isotype antibody served as controls. RESULTS Ex vivo, neutrophil CD66b and monocyte CD63 surface expression was increased in patients with auto-anti-M/N compared to those with allo anti-M/N (p = .1757; p = .0698) and to healthy subjects (p = .0186; p = .013). In vitro, neutrophil CD66b and monocyte CD63 surface expression was increased following incubation with anti-GPA compared to anti-Rh (p = .0003; p = .0328) and isotype control (p = .000; p = .0062). Intracellular ROS content increased in both neutrophils and monocytes incubated with anti-GPA compared to anti-Rh (p = .0012; p = .0693) and isotype control (p = .001; p = .0021). Percentage of neutrophil-RBC aggregates was decreased when incubated with anti-GPA compared to isotype control (p

Background In the setting of suspected septic transfusion reactions, bacterial culture of both the transfused patient and the residual blood component is recommended. Primary bacterial contamination can occur at the time of component collection. Clinically insignificant "secondary contamination" can occur during post-transfusion component discard, retrieval for culture, or manipulation of the bag at the time of culture sampling. Study design and methods This retrospective, multi-center study analyzes positive residual component culture results and companion patient blood cultures from 15 hospitals, 1 blood center, and all cultured transfusion reactions within the province of Quebec, Canada, over a 5-year period. Imputability was assigned as "definite" (concordant growth), "possible" (discordant growth or lack of growth in patient culture), or "unable to assess" (patient not cultured). Results There were 373 positive component cultures from 360 unique transfusion reactions, with 276 (76.7%) companion patient blood cultures performed, of which 10 (2.8%) yielded the pathogen detected in the positive component. Of these 10 definite pathogens, 7 (2 Staphylococcus aureus, 3 other staphylococci, and 1 Streptococcus pyogenes and 1 Bacillus sp.) were associated with platelet and 3 (Aeromonas veronii, Staphylococcus epidermidis, and Enterococcus faecalis) with RBC transfusions. RBC and plasma components comprised 70% of positive component cultures. Discussion The process of performing residual component culture is vulnerable to secondary contamination. The significance of microorganisms recovered from component culture cannot be interpreted in isolation. In the context of low prevalence of primary contamination of blood components, the positive predictive value of a positive component culture result is very low.

Background Blood usage and collections were impacted throughout 2020 both by the severity of the COVID‐19 pandemic as well as public health decisions affecting hospital operations. We sought to understand the longer‐term effects of the pandemic on blood usage via changes in case volume and clinical intensity as well as whether the blood needs of COVID‐19‐positive patients differed from other transfused patients. Study design and methods A single‐center retrospective study of blood use in 2020 as compared to 2014–2019 was conducted at a tertiary care center. Statistical analysis was performed in an R‐based workflow. p values are reported using two‐sided t‐tests for total hospital blood usage and using Mann–Whitney U tests for comparisons of patient blood usage. Results Mean monthly red cell usage in 2020 decreased by 11.2% (p = .003), plasma usage decreased by 23.8%, (p

AimsWhile the SARS-CoV-2 pandemic may be contained through vaccination, transfusion of convalescent plasma (CCP) from individuals who recovered from COVID-19 (CCP) is considered an alternative treatment. We investigate if CCP transfusion in patients with severe respiratory failure increases plasma titres of SARS-CoV-2 antibodies and improves clinical outcomes.MethodsPatients with COVID-19 (n=34) were consented for CCP transfusion and serial blood draws pretransfusion and post-transfusion. Plasma SARS-CoV-2 antireceptor binding domain (RBD) IgG and IgM titres were measured by ELISA serially, and compared with serial plasma titre levels from control patients (n=68). The primary outcome was survival at 30 days, and secondary outcomes were length of ventilator and/or extracorporeal membrane oxygenation (ECMO) support, length of stay (LOS) in the hospital and in the intensive care unit (ICU). Outcomes were compared with matched control patients (n=34). Kinetics of antibodies and clinical outcomes were compared using LOess regression and ORs, respectively.ResultsPrior to CCP transfusion, 74% of patients were anti-RBD seropositive for IgG (median 1:3200), and 81% were anti-RBD IgM seropositive (median 1:320), while 16% were seronegative. The kinetics of antibody titres in CCP recipients were similar to controls. CCP recipients presented with similar survival, duration on ventilatory and/or ECMO support, as well as ICU and hospital LOS compared with controls.ConclusionsCCP transfusion did not increase the kinetics of SARS-CoV2 antibodies and did not result in improved clinical outcomes in patients with COVID-19 with severe respiratory failure, suggesting that CCP may not be indicated in this category of patients.

The transfusion of blood products is a widely used practice but comes with the risk of transfusion-associated adverse events and fatalities. The primary aim of this study was to evaluate if strict adherence to transfusion guidelines would lead to a decrease in the rate of transfusion reactions that occurred when blood products were given outside of established indications. Hospital-wide educational programs and dedicated electronic transfusion order sets were used to encourage adherence to guidelines. A secondary aim of this study was to evaluate if a decrease in the incidence of transfusion reactions also lead to a decrease in associated healthcare costs.

Introduction Hypothermia at admission in trauma patients has been significantly associated with worse outcomes and increased blood usage. Previous studies have found variably significant associations between ambient temperatures and incidence of hypothermia in trauma patients. Methods The trauma quality improvement registry was queried for data on trauma patients admitted direct from the scene over a 5-year period. This database was matched to daily weather data taken from the nearest National Oceanic and Atmospheric Administration land-based climate monitoring center, and further combined with blood usage data from the laboratory information system. Results Multivariate logistic regression models predicted significant associations between ambient temperature and patient admission temperature for severely injured patients. No significant direct associations were predicted between ambient temperature and in-hospital mortality or blood usage. Models predicted a significant association between decreased admission temperature and increased likelihood of both blood transfusion and mortality for a severely injured subgroup. Conclusions Ambient temperature is a significant contributor to the rate of admission hypothermia in trauma patients. Most of the variability in admission temperatures for severely injured trauma patients remains unaccounted for by models using standard markers of anatomic and physiologic severity. Decreasing admission temperature is significantly associated with increased mortality and likelihood of blood transfusion for severely injured patients.

BACKGROUND Anemia is associated with poor outcome after major joint replacement surgery, but it is unclear whether sex and race modify its impact on outcome. We hypothesized that anemia would be associated with increased morbidity or mortality after knee arthroplasty surgery and that sex and race would be effect modifiers for this relationship. STUDY DESIGN AND METHODS We performed a retrospective cohort study of elective knee arthroplasty patients between 2013 and 2018 using data from the National Surgical Quality Improvement Program. Morbidity or mortality after surgery was compared between patients without anemia, with mild anemia, and with moderate to severe anemia. Multivariable logistic regression was used to determine adjusted odds for morbidity or mortality with anemia. Interaction terms were entered into the model to test for effect modification by sex and race. RESULTS 243 491 patients were included and 30 135 patients (12.4%) were anemic. Morbidity or mortality occurred in 3.7% of patients without anemia, 5.2% of patients with mild anemia, and 7.1% of patients with moderate to severe anemia (P

Background This study investigated the effect on mortality of transfusing ABO-incompatible plasma from all sources during trauma resuscitation. Methods Demographic, transfusion, and survival data were retrospectively extracted on civilian trauma patients. Patients were divided by receipt of any quantity of ABO-incompatible plasma from any blood product (incompatible group) or receipt of solely ABO-compatible plasma (compatible group). The primary outcome was 30-day mortality, while other outcomes included 6- and 24-hour mortality. Mixed-effects logistic regression was used to model the effect of various predictor variables, including receipt of incompatible plasma, on mortality outcomes. Results Nine hospitals contributed data on a total of 2618 trauma patients. There were 1282 patients in the incompatible group and 1336 patients in the compatible group. In both the unadjusted and adjusted models, the 6-hour, 24-hour, and 30-day mortality rates were not significantly different between these groups. The patients in the incompatible group were then divided into high volume (>342 mL) and low volume (≤342 mL) incompatible plasma recipients. In the adjusted model, the high-volume group had higher 24-hour mortality when the Trauma Injury Severity Score survival prediction was >50%. Mortality at 6 hours and 30 days was not higher in this model. The low-volume group did not have increased mortality at any of the time points in this adjusted model. Conclusion The transfusion of incompatible plasma in civilian trauma resuscitation does not lead to higher 30-day mortality. The finding of higher mortality in a select group of recipients in the secondary analysis warrants further study.

At the frontier of transfusion medicine and transplantation, the field of cellular therapy is emerging. Most novel cellular therapy products are produced under investigational protocols with no clear standardization across cell processing centers. Thus, the purpose of this study was to uncover any variations in manufacturing practices for similar cellular therapy products across different cell processing laboratories worldwide.An exploratory survey that was designed to identify variations in manufacturing practices in novel cellular therapy products was sent to cell processing laboratory directors worldwide. The questionnaire focused on the manufacturing life cycle of different cell therapies (i.e., collection, purification, in vitro expansion, freezing and storage, and thawing and washing), as well as the level of regulations followed to process each product type.The majority of the centers processed hematopoietic progenitor cells (HPCs) from peripheral blood (n = 18), bone marrow (n = 16) or cord blood (n = 19), making HPCs the most commonly processed cells. The next most commonly produced cellular therapies were lymphocytes (n = 19) followed by mesenchymal stromal cells (n = 14), dendritic cells (n = 9) and natural killer (NK) cells (n = 9). A minority of centers (5) processed pancreatic islet cells (n = 4), neural cells (n = 3) and induced-pluripotent stem cells (n = 3). Thirty-two laboratories processed products under an investigational status, for either phase I/II (n = 27) or phase III (n = 17) clinical trials. If purification methods were used, these varied for the type of product processed and by institution. Environmental monitoring methods also varied by product type and institution.This exploratory survey shows a wide variation in cellular therapy manufacturing practices across different cell processing laboratories. A better understanding of the effect of these variations on the quality of these cell-based therapies will be important to assess for further process evaluation and development.

Study objective The transfusion of older packed RBCs may be harmful in critically ill patients. We seek to determine the association between packed RBC age and mortality among trauma patients requiring massive packed RBC transfusion. Methods We analyzed data from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial. Subjects in the parent trial included critically injured adult patients admitted to 1 of 12 North American Level I trauma centers who received at least 1 unit of packed RBCs and were predicted to require massive blood transfusion. The primary exposure was volume of packed RBC units transfused during the first 24 hours of hospitalization, stratified by packed RBC age category: 0 to 7 days, 8 to 14 days, 15 to 21 days, and greater than or equal to 22 days. The primary outcome was 24-hour mortality. We evaluated the association between transfused volume of each packed RBC age category and 24-hour survival, using random-effects logistic regression, adjusting for total packed RBC volume, patient age, sex, race, mechanism of injury, Injury Severity Score, Revised Trauma Score, clinical site, and trial treatment group. Results The 678 patients included in the analysis received a total of 8,830 packed RBC units. One hundred patients (14.8%) died within the first 24 hours. On multivariable analysis, the number of packed RBCs greater than or equal to 22 days old was independently associated with increased 24-hour mortality (adjusted odds ratio [OR] 1.05 per packed RBC unit; 95% confidence interval [CI] 1.01 to 1.08): OR 0.97 for 0 to 7 days old (95% CI 0.88 to 1.08), OR 1.04 for 8 to 14 days old (95% CI 0.99 to 1.09), and OR 1.02 for 15 to 21 days old (95% CI 0.98 to 1.06). Results of sensitivity analyses were similar only among patients who received greater than or equal to 10 packed RBC units. Conclusion Increasing quantities of older packed RBCs are associated with increased likelihood of 24-hour mortality in trauma patients receiving massive packed RBC transfusion (≥10 units), but not in those who receive fewer than 10 units.

Background Culturing residual blood components after suspected septic transfusion reactions guides management of patients and cocomponents. Current practice, accuracy of provider vital sign assessment, and performance of the AABB culture criteria are unknown. A multicenter international study was undertaken to investigate these issues and develop improved culture criteria. Study design and methods Retrospective data for all transfusion reactions resulting in residual blood component culture in 2016 were collected from participating hospitals. The performance of the AABB culture criteria were assessed for detection of positive culture results. Modifications to the AABB criteria including 1) recommending culturing in the setting of isolated high fevers, 2) defining hypotension and tachycardia using objective parameters, and 3) incorporating antipyretic use were tested to determine if modifications improved performance. Modifications associated with improvement were incorporate into the BEST criteria. The AABB and the BEST criteria were then tested against a data set enriched for positive culture results to determine which criteria were superior. Results Data were collected from 20 centers encompassing 779,143 transfusions, 3,187 reported transfusion reactions, and 1,104 cultured components. There was marked variation in reaction reporting and culturing rates (0.0%-100.0%). Of 35 total positive component cultures, only one of 35 (2.9%) had concordant patient cultures; 12 of 34 (35.3%) did not have patient cultures performed. The BEST criteria had better sensitivity for detection of a positive culture result compared to the AABB criteria (74% vs. 41%), although specificity decreased (45% vs. 65%). Conclusion Compared to the AABB criteria, the BEST criteria have improved sensitivity for positive culture detection.

Pancreatic β-cells are a critical cell type in the pathology of diabetes. Models of genetic syndromes featuring diabetes can provide novel mechanistic insights into regulation of β-cells in the context of disease. We previously examined β-cell mass in models of two ciliopathies, Alström Syndrome (AS) and Bardet-Biedl Syndrome (BBS), which are similar in the presence of metabolic phenotypes, including obesity, but exhibit strikingly different rates of diabetes. Zebrafish models of these disorders show deficient β-cells with diabetes in AS models and an increased β-cells absent diabetes in BBS models, indicating β-cell generation or maintenance that correlates with disease prevalence. Using transcriptome analyses, differential expression of several exocrine pancreas proteases with directionality that was consistent with β-cell numbers were identified. Based on these lines of evidence, we hypothesized that pancreatic proteases directly impact β-cells. In the present study, we examined this possibility and found that pancreatic protease genes contribute to proper maintenance of normal β-cell numbers, proliferation in larval zebrafish, and regulation of AS and BBS β-cell phenotypes. Our data suggest that these proteins can be taken up directly by cultured β-cells and ex vivo murine islets, inducing proliferation in both. Endogenous uptake of pancreatic proteases by β-cells was confirmed in vivo using transgenic zebrafish and in intact murine pancreata. Taken together, these findings support a novel proliferative signaling role for exocrine pancreas proteases through interaction with endocrine β-cells., Summary: In this paper, we examine the role of exocrine pancreas protease genes in β-cell number using zebrafish and murine models, and identify a novel relationship between the two.

Background Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. Methods The Passive Immunity Trial for Our Nation (PassITON) is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the USA to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200–399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. Discussion This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. Trial registration ClinicalTrials.gov NCT04362176. Registered on 24 April 2020.

OBJECTIVESTo investigate if COVID-19 convalescent plasma (CCP) transfusion in patients with severe respiratory failure will increase plasma levels of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibody titers while improving survival and clinical outcomes.DESIGNObservational, retrospective, control study of anti-Receptor binding domain (RBD) of SARS-CoV-2 IgG and IgM titers from serial plasma samples drawn before and after CCP administration. Clinical improvement in CCP recipients is assessed and compared to COVID-19 control patients.SETTINGPatients hospitalized with severe COVID19, United States, between April 17 and July 19, 2020PARTICIPANTS34 patients hospitalized with severe or life threatening COVID-19 and who consented and received a CCP transfusion, 95 control patients with COVID-19 not transfused with CCP. 34 out the 95 control patients were matched for age, sex, and the level of respiratory support required. Patients less than 18 years old were excluded.MAIN OUTCOME MEASURESSerial trends of anti-RBD of SARS-CoV-2 IgG and IgM titers in CCP recipients are compared to those in control patients. The primary outcome is survival at 30 days, and the secondary outcomes are length of ventilatory and/or extracorporeal membrane oxygenation (ECMO) support, length of stay (LOS) in the hospital, and LOS in the ICU.RESULTSCCP transfusion occurred in 34 patients at a median of 12 days following COVID-19 symptom onset. Immediately prior to CCP transfusion, patients median anti-RBD SARS-CoV-2 IgG and IgM titers were 1:3200 (IQR, 1:50 to 1:9600) and 1:320 (IQR, 1:40 to 1:640) respectively. Following a Loess regression analysis, the kinetics and distribution of anti-RBD of SARS-CoV-2 IgG and IgM in plasma from CCP recipients were comparable to those from a control group of 68 patients who did not receive CCP. CCP recipients presented with similar survival, similar duration on ventilatory and/or ECMO support, as well as ICU and hospital LOS, compared to a matched control group of 34 patients.CONCLUSIONIn the present study, hospitalized COVID-19 patients with severe respiratory failure transfused with CCP presented with high titers of SARS-CoV-2 IgG antibodies before transfusion and did not show improved survival at 30 days.

BackgroundThere is an ongoing critical need to improve therapeutic strategies for COVID-19 pneumonia, particularly in the most severely affected patients. Adult mesenchymal stem cell (MSC) infusions have the potential to benefit critically ill patients with acute respiratory syndrome SARS-COV-2 infection, but clinical data supporting efficacy are lacking.MethodsWe conducted a case-control study of critically ill patients with laboratory-confirmed COVID-19, severe acute respiratory distress syndrome (ARDS). To evaluate clinical responsiveness in the most critically ill patient we examined outcomes in a sub-group of those requiring extracorporeal membrane oxygenation (ECMO) support. Patients (n=9) were administered with up to 3 infusions of intravenous (IV) MSCs and compared to a local ECMO control group (n=31). The primary outcome was safety, and the secondary outcomes were all-cause mortality (or rate of hospital discharge), cytokine levels, and viral clearance.FindingsMSC infusions (12 patients) were well tolerated and no side effects occurred. Of ECMO patients receiving MSC infusions, 2 out of 9 died (22.2%; 95%CI: 2.8%, 60.0%) compared with a mortality of 15 of 31 (48.4%; 95%CI: 30.2%, 66.9%; p = 0.25) in the ECMO control group. Isolated plasma exosomes containing the SARS-COV-2 Spike protein decreased after MSC infusions between day 14 or 21 after administration (p=0.003 and p=0.005, respectively) and was associated with a decrease in COVID-19 IgG Spike protein titer at same time points (p = 0.006 and p=0.007, respectively). Control ECMO patients receiving convalescent plasma did not clear COVID-19 IgG over the same time frame.InterpretationTogether these findings suggest that MSC IV infusion is well tolerated in patients with a broad range of severity including the most severe COVID-19 ARDS requiring ECMO. These data also raise the possibility that MSCs, in addition to exerting an immunomodulatory effect, contribute to viral clearance and strongly support the conduct of randomized placebo-controlled trial.

Background Culture-derived mesenchymal stromal cells (MSCs) exhibit variable characteristics when manufactured using different methods and different source materials. The purpose of this study was to assess the impact on MSC characteristics when different laboratories propagated MSCs from cultures initiated with BM aliquots derived from the same donor source material. Methods and methods Five aliquots from each of three different BM donors were distributed to five independent laboratories. Three laboratories plated whole BM and two laboratories a mononuclear BM cell fraction. Four laboratories cultured in media supplemented with fetal bovine serum (FBS) and one laboratory used human platelet lysate (hPL). Initial cell seeding densities (i.e., P0) ranged from 19.7 × 103/cm2-282 × 103/cm2 and for second seeding (i.e., P1) 0.05 × 103-5.1 × 103 cells/cm2. Post-thawed MSCs from each laboratory were analyzed for cell viability, immunophenotype, tri-lineage differentiation, fibroblast colony-forming units (CFU-F), gene expression, and immunosuppressive activity. Results Transit times from BM collection to receipt by laboratories located in the United States ranged from 16.0-30.0 h and from 41.5-71.5 h for a laboratory in Asia. Post-thaw culture derived MSCs rom BM #1, #2, and #3 exhibited viabilities that ranged from 74-92%, 61-96%, and 23-90%, respectively. CFU activity from BM #1, #2, and #3 per 200 MSCs plated averaged 45.1 ± 21.4, 49.3 ± 26.8 and 14.9 ± 13.3, respectively. No substantial differences were observed in immunophenotype, and immunosuppressive activities. Global gene expression profiles of MSCs revealed transcriptome differences due to different inter-laboratory methods and to donor source material with the center effects showing greater molecular differences than source material. Conclusion Functional and molecular differences exist among MSCs produced by different centers even when the same BM starting material is used to initiate cultures. These results indicated that manufacturing of MSCs by five independent centers contributed more to MSC variability than did the source material of the BM used in this study. Thus, emphasizing the importance of establishing worldwide standards to propagate MSCs for clinical use.

Background The COVID-19 pandemic caused downtrends in both blood collections and blood usage. Rapidly visualizing the impact of the pandemic and newly implemented hospital policies on usage could potentially inform blood ordering practices to help avoid wastage. Study design and methods Blood usage data were obtained from the laboratory information system. An R-based workflow was written in R Markdown for analysis and visualization. Reports were generated daily and shared with blood bank leadership. Selected reports were shared with institutional leadership, other departments, and collaborating blood suppliers. Results Mean daily transfusions dropped 42% from 3/9-13 to 3/16-20, with a significant decrease in usage of red cells, plasma, and cryoprecipitate. The greatest decline in use was seen in the general operating rooms, whereas outpatient transfusions remained steady. Weekly total blood usage decreased through the end of March into April and returned to normal levels in May. Conclusion During two 5-weekday periods of changing hospital policies, overall blood usage decreased by almost half. Visualization of usage by hospital location showed a large decrease in general operating room usage after cancellation of elective procedures. This data visualization has informed decisions to modify standing product orders during an initial period of decreased usage as well as return to normal orders in later months.

Background Whole blood (WB) is rapidly emerging as the treatment modality of choice for the initial resuscitation of civilian trauma patients across the United States. The reemergence of WB has been rapid and driven in part by recognition of the importance of early plasma transfusion in the resuscitation process. Study design and methods The study was designed as a critical analysis of the available literature on WB transfusion in civilian trauma patients. Studies were included if they reported on transfusion of cold-stored WB used in a civilian setting and measured safety, feasibility, or a direct clinical outcome. Results Examination of the available literature supports the feasibility and safety of WB used in treatment of civilian trauma patients. The evidence regarding clinical outcomes, particularly with direct comparison to equivalent doses of component therapy, is more limited. The literature is predominantly descriptive and retrospective in nature and limited by the heterogeneity of clinical WB protocols being used. Based on this limited data set, there are limited conclusions that can be used to definitely support or refute the clinical superiority of WB to component therapy. Conclusion Current literature supports the safety and feasibility of WB, but prospective randomized trials comparing WB to component therapy are needed to provide the definitive evidence on this topic.

BACKGROUND Growth in size and complexity of clinical hematopoietic progenitor cell (HPC) transplant programs necessitates parallel increases in cellular therapy laboratory (CTL) workload. Typically individually developed, HPC product processing is labor and time intensive. Variation in procedure type and numbers across CTLs complicates direct comparisons, and benchmark data are not readily available. STUDY DESIGN AND METHODS Studies were undertaken at seven CTLs. Transplant volume and staff numbers were determined. Staff recorded time performing tasks broken down into steps: paperwork, product acceptance, transport/infusion, processing, and cryopreservation. Times were added to obtain total times for 15 common CTL procedures. RESULTS Annual transplant volume ranged from 53.4 to 463.2, with products processed by a range of 2 to 10 dedicated CTL staff. Paperwork time constituted 23.7% to 62.3% total time; product processing time accounted for 1.8 (for National Marrow Donor Program product receipt) to 62.6% (for red blood cell reduction of allogeneic HPC products from bone marrow) of total processing time. Mean time for 15 procedures ranged from 1.27 to 8.28 hours (standard deviation range, 0.35-2.71 hr). Mean time for products from bone marrow versus peripheral blood was 6.6 ± 2.0 versus 5.5 ± 1.1 hours (p = 0.02). Cryopreservation (6.5 ± 1.6 vs. 4.4 ± 0.85 hr; p

The extra cellular matrix (ECM) is an important component of the pancreatic islet microenvironment that supports β-cell function and survival. During pancreatic islet isolation, the ECM disruption may cause β-cell primary nonfunction and apoptosis. Islet encapsulation with ECM proteins may enhance islet cell engraftment and prevent primary nonfunction. The present chapter highlights the importance of ECM protein components to be included in a pancreatic islet encapsulation platform for delivery in vivo. Each specific matrix component (e.g., fibronectin, laminin, and collagen IV) has a different type of interaction with the pancreatic β-cell via integrins on the β-cell surface. The role of various ECM proteins and their respective integrins are presented. Furthermore the latest developments in bioengineering of encapsulation methodologies that include these protein motifs are discussed.

Autoimmune hemolytic anemia (AIHA) is a group of rare but serious blood disorders in which the body attacks and destroys its own red blood cells. Although AIHA is defined as a singular pathologic entity caused by autoimmune-mediated erythrocyte destruction, it presents with extensive clinical heterogeneity that poses challenges to researchers and clinicians alike. Here, we break down AIHA into warm-, cold-, and mixed-type AIHA to describe the mechanism of autoantibody development in various AIHA etiologies and the corresponding determinants of red cell destruction. We also discuss the process of differentially diagnosing AIHA cases through clinical and laboratory evaluation and how to treat different AIHA pathologies. Finally, we conclude with suggestions for effective and proactive AIHA treatment and posit novel therapeutics and blood banking techniques that may become more integral for managing AIHA in the future.

Islet transplantation has emerged as a promising therapeutic option for the treatment of Type 1 diabetes. However, clinical success and efficacy are challenged by the loss of islet function during the peritransplantation period. This chapter highlights the application of silk protein-based matrices for improving islet encapsulation efficacy and transplantation outcomes to maintain a long-term graft function. The in vitro and in vivo results reveal that silk-based polymeric matrices (scaffolds/foams/hydrogels) provide a useful microenvironment for extrahepatic islet implantation to improve engraftment and long-term graft function. Silk-based strategies to eliminate or curtail the use of immunosuppressive drugs could be a promising therapy for the improvement of islet transplantation. Toward this goal, two approaches are discussed: (1) encapsulation of primary islets/islet-like clusters to prevent the infiltration of immune cells, and (2) the local release of biomolecules from biomaterial systems for vascularization and suppression/modulation of local immunity.

Background Viability testing is a common practice in laboratories. The goal of this study was to ascertain current laboratory practices internationally for performing viability testing for cryopreserved cord blood (CB) products and glean information about how to standardize the method to improve interlaboratory reproducibility. Study design and methods A survey to evaluate current laboratory practices for viability testing was designed and distributed internationally. The question topics included sampling and testing methods, responses to unexpected results, and the rating of the reliability of the CB quality tests, together with expectations for standardization. Results There were 32 respondents to the survey, of whom 28 responded to the more detailed questionnaire about viability methods. Overall, responses indicated that various stains were used among the laboratories, and when multiple sites used the same viability stain the methods differed. The majority of the respondents were in favor of standardizing the viability testing methods. A wide variety of preferences were communicated about how to standardize the method, but a majority did advocate the use of 7-aminoactinomycin D (7-AAD) with flow cytometry. Conclusions The survey results revealed a variety of tests and inconsistent interlaboratory practices for performing the viability assay. Flow cytometry with a 7-AAD dye was suggested as a first step toward standardization.

Kidney transplant patients are frequently anemic and at risk for red blood cell (RBC) transfusion. Previous studies suggest that pre-transplant RBC transfusion may improve kidney transplant outcomes; however, RBC transfusion is also associated with infection. The purpose of our study was to characterize the relationships between intraoperative RBC transfusion, delayed graft function (DGF), postoperative surgical site infection (SSI), and sepsis. Analysis was performed on a historical cohort of adult kidney transplant patients from a single medical center during a two-year period. Crude odds ratios for DGF, superficial and deep SSI, and sepsis were calculated for transfused patients and multivariate regression was used to control for potential confounders when significant relationships were identified. Four hundred forty-one patients had kidney transplant during the study period; 27.0% had RBC transfusion, 38.8% had DGF, 7.0% had superficial SSI, 7.9% had deep SSI, and 1.8% had sepsis. High dose RBC transfusion was associated with improved graft function, but this was negated after adjusting for confounders (OR = 0.86, 95% CI 0.26 to 2.88). There was no association between RBC transfusion and SSI. RBC transfusion was independently associated with sepsis (OR = 8.98, 95% CI 1.52 to 53.22), but the confidence interval was wide. Intraoperative RBC transfusion during kidney transplant is not associated with improved allograft function or incisional SSI, but is associated with postoperative sepsis. RBCs should not be liberally transfused during kidney transplant surgery to improve graft outcomes.

BACKGROUND Red blood cell (RBC) transfusion can be life-saving; however, the risks of RBC transfusion have been increasingly recognized, and current guidelines recommend restrictive transfusion in most patients. We hypothesized that RBC transfusions are decreasing in surgical patients. STUDY DESIGN AND METHODS A retrospective review of the National Surgical Quality Improvement Program database was performed from 2011 to 2015. Index cases in five surgical specialties were studied: neurosurgery, thoracic surgery, gynecologic surgery, orthopedic surgery, and vascular surgery. Patient characteristics, preoperative laboratory values, and surgery details were compared between years. The study's primary outcome was perioperative RBC transfusion, which was compared over the 5-year period for each specialty. Secondary outcomes were myocardial infarction and renal failure after surgery. In addition, trends in RBC transfusion between low-risk and high-risk patients and between emergency and elective surgery were examined. RESULTS RBC transfusion decreased in all surgical specialties except for thoracic and gynecologic surgery. RBC transfusion decreased substantially in orthopedic surgery, falling from 22.4% in 2011 to 6.3% in 2015 (p ≤ 0.0001). High-risk patients had greater reductions in the receipt of RBC transfusion than low-risk patients, and there were no increases in myocardial infarction or renal failure after surgery in any specialty. CONCLUSION RBC transfusion appears to be decreasing across multiple surgical specialties, with no apparent increase in myocardial infarctions or renal failure. This likely represents an important improvement in patient care. Continued efforts are needed to develop patient blood management programs and further reduce RBC transfusion.

Background. Platelet transfusion is a critical therapy for hematology-oncology patients at risk of transfusion-transmitted infection (TTI) and pulmonary injury. Amotosalen-UVA pathogen reduction (PR) treatment of apheresis platelet components (PC) in plasma or additive solution (INTERCEPT Blood System for Platelets, Cerus, Concord, CA) is FDA approved to reduce risk of TTI and transfusion associated graft vs. host disease (TA-GVHD). PRPC meet the FDA bacteria risk reduction guidance, and approximately 50% of U.S. PC are PRPC. Amotosalen-UVA PR replaces bacteria screening, gamma irradiation, and CMV serology. PR is performed within 24 hours of collection enabling early release of PRPC with 5-day storage. We tested the hypothesis that PRPC were not inferior to conventional PC(CPC) for the incidence of pulmonary injury. Methods. An open-label sequential cohort study in platelet transfusion dependent hematology-oncology patients was conducted under routine practice conditions in 15 clinical centers. Each site enrolled a CPC cohort followed by a PRPC cohort using 4 primary therapy strata matched ± 10%: chemotherapy without hematopoietic cell transplant (HCT), HCT with myeloablation, HCT with non-myeloablative conditioning, and HCT with reduced intensity conditioning (RIC). Patients were supported with the assigned PC type for up to 21 days with 7 days of surveillance after the last PC exposure. Patients participated in only one cohort. The primary endpoint was treatment emergent assisted mechanical ventilation (TEAMV) by intubation or tight mask with positive end expiration pressure (5cm H 2O) after initiation of study PC. All endpoint patients were adjudicated by a blinded pulmonary expert panel (PEP) for diagnosis of acute respiratory distress syndrome (ARDS) by the Berlin Criteria. Secondary endpoints included: time to initiation of TEAMV, clinically significant pulmonary adverse events (CSPAE, CTCAE ≥ Grade 2), transfusion reactions, and mortality. The incidence of TEAMV by non-inferiority (margin = 2.3%), and secondary endpoints were analyzed by modified intention to treat (mITT) and per protocol (PP). Sensitivity analyses with propensity score matching for key variables were conducted for the primary endpoint. The associations between PC and categorical variables were tested by stratified Cochran-Mantel-Haenszel and continuous variables by ANOVA for two-sided significance p = 0.05. results. A total of 2291 pediatric and adult patients (1068 PRPC and 1223 CPC) were enrolled in the respective cohorts with transfusion of 5,277 PRPC and 5,491 CPC. PC assignment compliance and study completion were > 94%. For the mITT data set, the cumulative incidence of TEAMV was lower for the PRPC cohort (log rank p = 0.039) than the CPC cohort (2.9% versus 4.6%, HR = 0.633: 95% CI 0.408-0.982). PRPC by mITT were non-inferior to CPC for the incidence of TEAMV due to all indications, and for TEAMV with pulmonary dysfunction (PD) by PEP (Table). PP analyses were consistent with mITT. Relative risk (RR) of TEAMV showed significantly (p Figure 1 Figure 1. Disclosures Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Nooka: Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Adaptive technologies: Consultancy; GlaxoSmithKline: Consultancy, Other: Travel expenses; Karyopharm Therapeutics: Consultancy. Uhl: UpToDate: Patents & Royalties; Abbott: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau. Spinella: Secure Transfusion Services: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cerus Corporation: Consultancy, Research Funding. Liu: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Benjamin: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Corash: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company.

Objectives Inconclusive RBC antibody identification (ABID) may delay RBC crossmatch. An increased number of inconclusive ABID was observed, and an algorithm was developed to improve ABID efficiency. Methods RBC antibody screen (AS) and ABID were initially performed using solid-phase RBC adherence assay (SPRCA) and manual tube method. A retrospective analysis of AS and ABID results was performed pre- and postalgorithm implementation. Results The number of inconclusive ABID results decreased from 26 to six per month pre- and postimplementation, respectively. SPRCA became the primary AS method, and manual tube became the gold standard for ABID. SPRCA was used for ABID upon reference specialist secondary review and allowed identification of 30 specific RBC antibodies, for which no patients developed signs or symptoms of a hemolytic transfusion reaction. Conclusions RBC reference workflow using SPRCA and manual tube methods for AS and ABID decreases "inconclusive" ABID without adverse events.

BACKGROUND Allergic transfusion reactions are drawbacks to the benefits of transfusion. Classically, allergic transfusion reactions depend on histamine release from mast cells or basophils, but other leukocyte subsets may also be important. Thus, we propose to better define the exact leukocyte subsets involved in allergic transfusion reactions. STUDY DESIGN AND METHODS The overall objective of the current study was to compare the activation of specific peripheral blood leukocyte subsets (monocytes, neutrophils, eosinophils, and basophils) in a cohort of 13 patients who received chronic transfusions and had a history of allergic transfusion reactions compared with a control group of patients who received chronic transfusions and had no history of allergic transfusion reactions. Leukocyte subsets were analyzed by flow cytometry at baseline and after red blood cell transfusion, and cytokine levels in platelet-free plasma collected at the same time points were measured by Luminex assay. RESULTS Flow cytometry and cytokine profiles before and after transfusion did not differ significantly between patients who did and did not have a history of allergic transfusion reactions (p > 0.05). However, post-transfusion samples from both groups showed a decrease in CD63 expression in basophils, monocytes, and eosinophils and a decrease in CD45 expression in all leukocyte subsets compared with pretransfusion samples. Interleukin 10 levels increased after transfusion in the group with a history of allergic transfusion reactions (p = 0.0469), and RANTES (regulated upon activation, normal T-cell expressed and secreted) was significantly decreased post-transfusion in all patients (p = 0.0122). CONCLUSION None of the leukocyte subsets from patients who had a history of allergic transfusion reactions significantly increased in activation either before or after transfusion. All leukocyte subsets from patients who did and did not have a history of allergic transfusion reactions decreased in their activation profile upon transfusion challenge.

The complement is a key player of the innate immune response. It provides defense mechanisms that are not specific, but very efficient at neutralizing any invader, accounting for 4% of the proteins in the peripheral blood. Nevertheless, there is a dark side to the complement system, as it may activate its machinery against healthy cells such as peripheral blood red blood cells and platelets resulting in undesired hemolysis and thrombocytopenia, respectively. Understanding and identifying the role of complement in these settings allow physicians to adjust their diagnostic and therapeutic modalities accordingly. The role of complement in the pathophysiology and management of autoimmune hemolytic anemia and of alloimmune-mediated thrombocytopenia is under investigation and discussed.

The clinical link between loss of β-cell mass and diabetes susceptibility provides a promising avenue of research for novel therapeutics targeting the proliferative axis. To identify potential new pathways involved we utilized two zebrafish genetic models Alström Syndrome (AS) and Bardet-Biedl Syndrome (BBS) that exhibit strikingly different diabetes rates, ∼75% in AS and ∼4% in BBS. We have previously shown β-cell loss in AS and increase in BBS, corresponding to their diabetes rates. RNA-Sequencing of these models identified several exocrine pancreas proteases that were differentially expressed between AS and BBS. Thus, we hypothesized that the exocrine pancreas proteases affect endocrine pancreas function. To test our hypothesis, we overexpressed each enzyme in transgenic zebrafish embryos in which β-cells can be visualized. In control animals, overexpression of exocrine pancreas proteases significantly increased the β-cell number. Overexpression rescued the loss of β-cells observed in animals depleted of alms1. We found ctrb1 overexpression led to increased β-cell proliferation in transgenic larvae and rescued the AS model reduction in proliferation. To test for endogenous protease uptake, we generated a transgenic GFP-tagged CTRB1 and found that 10% of β-cells were GFP+, suggesting a direct interaction between the exocrine and endocrine pancreas. We also found that the inactive, zymogen, form of these enzymes are taken up by β-cells in vitro and induce proliferation in cultured MIN6 β-cells and freshly isolated ex vivo islet cultures, suggesting this effect is conserved in mammalian systems. These data support an important role for exocrine pancreatic enzymes in the modulation of β-cells in diabetes. Disclosure T.L. Hostelley: None. J. Dunleavey: None. E.J. Larkin: None. A.J. Jones: None. D.L. Boyes: None. M.J. Fontaine: None. N.A. Zaghloul: None. Funding National Institutes of Health (F31DK115179-01A1, T32DK098107, R01DK102001, R25GM055036)

Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx. Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) ≥ 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality. We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis.We analyzed a subset of patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial who survived at least 72 hours after hospital admission, and we determined elevated Synd-1 levels (≥ 40 ng/mL) 4 hours after hospital arrival. Sepsis was defined a priori as meeting systemic inflammatory response criteria and having a known or suspected infection. Univariate analysis was performed to identify variables associated with elevated Synd-1 levels and sepsis. Significant variables at a value of p0.2 in the univariate analysis were chosen by purposeful selection and analyzed in a mixed effects multivariate logistic regression model to account for the 12 different study sites.We included 512 patients. Of these, 402 (79%) had elevated Synd-1 levels, and 180 (35%) developed sepsis. Median Synd-1 levels at 4 hours after admission were 70 ng/dL (interquartile range [IQR] 36 to 157 ng/dL) in patients who did not develop sepsis, and 165 ng/dL [IQR 67 to 336 ng/dL] in those who did (p0.001). Adjusting for treatment arm and site, multivariable analyses revealed that elevated Synd-1 status, Injury Severity Score (ISS), and total blood transfused were significantly associated with an increased likelihood of developing sepsis.Elevated Synd-1 levels 4 hours after admission in severely injured adult trauma patients who survived the initial 72 hours after hospital admission are associated with subsequent sepsis.

BACKGROUND Plasma volume reduction (PVR) may reduce the risk of hemolysis associated with transfusion of plateletpheresis blood products (PLTs) containing ABO-incompatible plasma. But PVR may delay PLT issue. In collaboration with our blood donor center we evaluated an automated screen of PLT for high-titer ABO antibody and to apply PVR to high-titer PLTs. STUDY DESIGN AND METHODS At the donor center, plasma from PLT donors was tested using an automated microplate system (PK7300, Beckman). PK settings were set for a detection cutoff equivalent to 1 in 256 using a manual tube method. The donors associated with high-titer PLTs were characterized by sex and age. In the transfusion service, the number of PVR procedures was evaluated before and after implementation of the high-titer screen. RESULTS During validation, 157 of 1008 PLT units (15%) were positive by the automated method versus 121 (12%) by manual method. After implementation, 2112 of 15,240 PLT units were high-titer, with higher frequency in donations from females versus males (18% vs. 12%, p

BACKGROUND The Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial was a randomized clinical trial comparing survival after transfusion of two different blood component ratios for emergency resuscitation of traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of request. STUDY DESIGN AND METHODS At the 12 Level 1 trauma centers participating in PROPPR, blood components transfused and delivery times were tabulated, with a focus on universal donor (UD) plasma management. The adequacy of site plans was assessed by comparing the bedside blood availability times to study goals and the new American College of Surgeons guidelines. RESULTS Eleven of 12 sites were able to consistently deliver 6 units of thawed UD plasma to their trauma-receiving unit within 10 minutes and 12 units in 20 minutes. Three sites used blood group A plasma instead of AB for massive transfusion without complications. Approximately 4700 units of plasma were given to the 680 patients enrolled in the trial. No site experienced shortages of AB plasma that limited enrollment. Two of 12 sites reported wastage of thawed AB plasma approaching 25% of AB plasma prepared. CONCLUSION Delivering UD plasma to massively hemorrhaging patients was accomplished consistently and rapidly and without excessive wastage in high-volume trauma centers. The American College of Surgeons Trauma Quality Improvement Program guidelines for massive transfusion protocol UD plasma availability are practicable in large academic trauma centers. Use of group A plasma in trauma resuscitation needs further study.

Blood group incompatibility remains a significant barrier to kidney transplantation. Approximately, one-third of donors are blood group incompatible with their intended recipient. Options for these donor-recipient pairs include blood group incompatible transplantation or kidney paired donation. However, the optimal protocol for blood group incompatible transplantation is unknown. Protocols differ in techniques to remove ABO antibodies, titer targets, and immunosuppression regimens. In addition, the mechanisms of graft accommodation to blood group antigens remain poorly understood. We describe a blood group incompatible protocol using pretransplant therapeutic plasma exchange (TPE), high-dose intravenous immunoglobulin, and rituximab in addition to prednisone, mycophenolate mofetil, and tacrolimus. In this protocol, we do not exclude patients based on a high initial titer and do not implement post-transplant TPE. All 16 patients who underwent this protocol received a living donor transplant with 100% patient and graft survival, and no reported episodes of antibody-mediated rejection to date with a median follow-up of 2.6 years (range 0.75-4.7 years). We conclude that blood group incompatible transplantation can be achieved without post-transplant TPE.

The success of pancreatic islet (PI) transplantation is challenged by PI functional damage during the peritransplantation period. A silk-based encapsulation platform including mesenchymal stromal cells (MSCs) was evaluated for islet cell delivery in vivo. Islet equivalents (IEQs) were transplanted into the epididymal fat pads of mice with streptozotocin-induced diabetes. Three PI combinations were tested: (A) co-encapsulated in silk with MSCs; (b) encapsulated in silk alone; or (c) pelleted. Blood glucose levels were monitored and intraperitoneal glucose tolerance test (IPGTT) was performed upon return to euglycaemia. Grafts were removed for histology and cytokine content analysis. Mice with PI grafts in silk showed a prompt return to euglycaemia. IPGTT was significantly improved with PI in silk with MSCs, compared to PI in silk alone or pelleted. Both Th1 and Th2 cytokines were increased in PI grafts in silk, but Th1 cytokines were decreased significantly with PI and MSC co-encapsulation. Histological analysis showed osteogenesis and chondrogenesis in the silk grafts containing MSCs. Future studies will evaluate MSC stability and function in vivo and improve silk biocompatibility for applications in islet transplantation. Copyright © 2015 John Wiley & Sons, Ltd.

BACKGROUND Transfusion-transmitted babesiosis (TTB) has been rapidly increasing in incidence since the beginning of the 21st century. Asymptomatic individuals with Babesia infection are able to donate blood in the United States because of the lack of specific blood donation testing. Blood products collected in Babesia-endemic areas are distributed nationally; thus, clinicians in nonendemic states may fail to include babesiosis in the differential diagnosis of a patient who had a recent transfusion history and a fever of unknown origin. STUDY DESIGN AND METHODS We report the details of two cases of clinical transfusion-transmitted babesiosis and one asymptomatic infection identified in red blood cell recipients in two nonendemic states (South Carolina and Maryland), which, when combined with three recent additional cases in nonendemic states, totals six recipient infections in three nonendemic states. RESULTS Delayed diagnosis of transfusion-transmitted babesiosis places patients at risk for increased morbidity and mortality and may result in clinical mismanagement or unnecessary treatments. A peripheral blood smear should be reviewed in any patient with a recent transfusion and a fever of unknown origin. Prompt communication of the diagnosis among physicians is key to ensuring that patients with transfusion-transmitted babesiosis are treated expeditiously, and a transfusion service investigation is necessary to identify additional recipients from the same donor. CONCLUSION TTB is appearing in traditionally nonendemic states because of blood product distribution patterns. Clinicians should include TTB on the differential diagnosis in any patient presenting who had a recent transfusion history and a fever of unknown origin, regardless of where the transfusion took place.

Background Clinical studies have demonstrated that the early and empiric use of plasma improves survival after hemorrhagic shock. We have demonstrated in rodent models of hemorrhagic shock that resuscitation with plasma is protective to the lungs compared with lactated Ringer's solution. As our long-term objective is to determine the molecular mechanisms that modulate plasma's protective effects in injured bleeding patients, we have used human plasma in a mouse model of hemorrhagic shock. The goal of the current experiments is to determine if there are significant adverse effects on lung injury when using human versus mouse plasma in an established murine model of hemorrhagic shock and laparotomy. Methods Mice underwent laparotomy and 90 minutes of hemorrhagic shock to a mean arterial pressure (MAP) of 35 ± 5 mm Hg followed by resuscitation at 1× shed blood using either mouse fresh frozen plasma (FFP), human FFP, or human lyophilized plasma. Mean arterial pressure was recorded during shock and for the first 30 minutes of resuscitation. After 3 hours, animals were killed, and lungs collected for analysis. Results There was a significant increase in early MAP when mouse FFP was used to resuscitate animals compared with human FFP or human lyophilized plasma. However, despite these differences, analysis of the mouse lungs revealed no significant differences in pulmonary histopathology, lung permeability, or lung edema between all three plasma groups. Analysis of neutrophil infiltration in the lungs revealed that mouse FFP decreased neutrophil influx as measured by neutrophil staining; however, myeloperoxidase immunostaining revealed no significant differences in between groups. Conclusion The study of human plasma in a mouse model of hemorrhagic shock is feasible but does reveal some differences compared with mouse plasma-based resuscitation in physiologic measures such as MAP postresuscitation. Measures of end organ function such as lung injury appear to be comparable in this acute model of hemorrhagic shock and resuscitation.

BACKGROUND Red blood cell transfusion related to select surgical procedures accounts for approximately 2.8 million transfusions in the United States yearly and occurs commonly after hip fracture surgeries. Randomized controlled trials have demonstrated lack of clinical benefit with higher versus lower transfusion thresholds in postoperative hip fracture repair patients with cardiac disease or risk factors for cardiac disease. The economic implications of a higher versus lower hemoglobin (Hb) threshold have not yet been investigated. STUDY DESIGN AND METHODS A decision tree analysis was constructed to estimate differences in healthcare costs and charges between a Hb transfusion threshold strategy of 8 g/dL versus 10 g/dL from the perspective of both Centers for Medicare and Medicaid Services (CMS) as well as hospitals. Secondary outcome measures included differences in transfusion-related adverse events. RESULTS Among the 133,697 Medicare beneficiaries undergoing hip fracture repair in 2012, we estimated that 45,457 patients would be anemic and at risk for transfusion. CMS would save an estimated $11.3 million to $24.3 million in payments, while hospitals would reduce charges by an estimated $52.7 million to $93.6 million if the restrictive transfusion strategy were to be implemented nationally. Additionally, rates of transfusion-associated circulatory overload, transfusion-related acute lung injury, acute transfusion reactions, length of stay, and mortality would be reduced. CONCLUSIONS This model suggests that the uniform adoption of a restrictive transfusion strategy among patients with cardiac disease and risk factors for cardiac disease undergoing hip fracture repair would result in significant reductions in clinically important outcomes with significant cost savings.

Islet cell transplantation has therapeutic potential to cure type 1 diabetes (T1D), which is characterized by autoimmune-mediated destruction of insulin-producing β cells. However, current success rates are limited by long-term decline in islet graft function resulting partially from poor revascularization and immune destruction. Mesenchymal stem cells (MSCs) have the potential to enhance islet transplantation and prevent disease progression by a multifaceted approach. MSCs have been shown to be effective at inhibiting inflammatory-mediated immune responses and at promoting tissue regeneration. The immunomodulatory and tissue repairing properties of MSCs may benefit β cell regeneration in the context of T1D. This review will elucidate how MSCs can minimize β cell damage by providing survival signals and simultaneously modulate the immune response by inhibiting activation, and proliferation of several immune cell types. In addition, MSCs can enhance islet graft revascularization, maintaining long-term β cell viability and function.

BACKGROUND: Recent studies show that transfusing older blood may lead to increased mortality. This raises the issue of whether transfusing fresher blood can be achieved without jeopardizing blood availability. STUDY DESIGN AND METHODS: We propose a simple family of policies that is defined by a single threshold: rather than transfusing the oldest available blood that is younger than 42 days, we transfuse the oldest blood that is younger than the threshold, and if there is no blood younger than the threshold then we transfuse the youngest blood that is older than the threshold. To assess this policy, we build a simulation model using data from Stanford University Medical Center. We focus on the tradeoff between the mean age of transfused blood and the fraction of transfused blood that is imported. RESULTS: For hospitals in which the local supply is greater than demand, our policy with a threshold of 14 days leads to a decrease of 10 to 20 days in the mean age of transfused blood while increasing the fraction of imported blood to less than 0.005 (i.e., 0.5%). If the health benefits from transfusing fresher blood can be confirmed by randomized clinical trials, then conservative assumptions suggest that this policy could reduce the annual number of transfused patients who die within 1 year by 20,000. CONCLUSION: The proposed allocation policy with a threshold of 14 days could allow many US hospitals to significantly reduce the age of transfused blood, thereby possibly reducing morbidity and mortality, while having a negligible impact on supply chain operations. T he allocation of available red blood cells (RBCs) for transfusion to patients is a difficult problem: compatibility between donor and recipient must be maintained, and the age and quantity of available RBCs need to be accounted for. More specifically, while there is a tendency to use older available blood to prevent outdating, stored RBCs undergo biochemical changes that impact RBC function, and the age of transfused blood has been reported to be associated with an increased risk of infection, postoperative complications, and/or short-term and long-term mortality.

BACKGROUND Immune refractoriness to platelet (PLT) transfusion is primarily due to HLA antibody. Patients at our institution are identified as refractory due to HLA by a Luminex-based immunoglobulin (Ig)G-single-antigen-bead (SAB) assay, but in highly sensitized patients, antigen-negative compatible donors cannot be found due to the high sensitivity of the IgG-SAB method. We developed an assay that detects only HLA antibodies binding the first complement component (C1q). We hypothesized that the C1q-SAB method might be more relevant than the IgG-SAB method because the antibodies identified may activate the complement cascade causing PLT destruction. STUDY DESIGN AND METHODS Thirteen highly sensitized refractory patients received 177 PLT units incompatible by the IgG-SAB method. They were retrospectively retested by the C1q-SAB method. Calculated percent reactive antibody (CPRA) and HLA antibody specificities were compared between the two methods and corrected count increment (CCI) values were analyzed. Additionally the impact of ABO compatibility on CCI responses was evaluated. RESULTS The mean CPRA value was significantly lower by C1q-SAB (60%) than by IgG-SAB (94%; p < 0.05). Patients showed significantly better CCI (10.6 × 10(9) ± 0.8 × 10(9) /L) with C1q-compatible (n = 134) than with C1q-incompatible PLTs (n = 43) (2.5 × 10(9) ± 0.9 × 10(9) /L/m(2) ; p < 0.0001). ABO compatibility did not significantly impact the CCI values (p < 0.0001). Our results show that 75% of PLT units previously considered incompatible were actually compatible. CONCLUSION For highly refractory patients to PLT transfusion, the C1q-based SAB binding assay may be a better method for identifying clinically relevant HLA antibodies and selecting PLT units that will result in acceptable CCI.

BACKGROUND: Laboratory-based quality improvement (QI) initiatives can improve clinical outcomes and patient safety. STUDY DESIGN AND METHODS: We present three cases of QI that impact processes from the transfusion service (TS) laboratory to the patient's bedside. RESULTS: Case 1 was event discovery reporting (EDR). We were able to reduce our biologic product deviation reports from 41 (17%) of 238 EDRs to only 19 (7%) of 272 (p

BACKGROUND: Evolving concerns about storage lesions for red blood cells (RBCs) have led to ongoing trials evaluating the benefits of transfusing fresher blood to acutely ill patients. STUDY DESIGN AND METHODS: We evaluated several RBC maximum shelf lives (MSLs) and their impact on RBC availability and outdate rate. First, we determined the mean age of the RBC units in our inventory by analyzing the data set of 18,987 nonirradiated RBC units transfused at our institution from April 2008 to March 2009. Second, we determined the feasibility of issuing RBC units of a designated age to patients using the same data set. We defined six scenarios where RBC units have different MSLs: Scenarios 1, 2, 3, 4, and 5 used a MSL of 7, 14, 21, 28, and 35 days, respectively. Scenario 6 used a combination of different MSLs depending on the category of patients. RESULTS: RBC units spent on average 8.6 days on the shelf with a mean age of 10.2 days at delivery and 18.8 days at issue for transfusion. Using the original 18,987 data points, we observed a shortfall in the availability of RBC units, decreased by 51, 20, 10, 4, 1, and 0% and an increase in the outdate rate to 3.2, 2.2, 1.0, 0.6, 0.4, and 4.5% for Scenarios 1, 2, 3, 4, 5, and 6, respectively, compared to baseline. CONCLUSION: Changing the MSL for RBC units would require novel approaches to RBC inventory management to meet hospital demands with acceptable outdate rates.

BACKGROUND: Our goal is to minimize unnecessary cytomegalovirus (CMV)-seronegative blood transfusion to preserve the CMV-seronegative blood inventory for patients who are identified as CMV seronegative. STUDY DESIGN AND METHODS: We implemented a CMV antibody reflex testing protocol for patients who require CMV-compatible blood but in whom a CMV serostatus is unknown (coded as CMVT in our computer system). A solid-phase red blood cell (RBC) adherence antibody detection system was validated to detect CMV antibodies in plasma samples (received for ABO/Rh type and RBC antibody screen) with acceptable sensitivity and specificity. We evaluated the impact of this CMV antibody reflex testing on the management of RBC and platelet (PLT) inventory for patients requiring CMV-compatible blood. RESULTS: Over a 16-month period, implementation of CMV antibody reflex testing identified 361 (34%) of 1063 previously CMV-untested patients who required CMV-compatible blood and who were CMV seronegative. We observed a 75% decrease in the number of CMVT patients in our data base from 190 per month before implementation to 57 at 16 months postimplementation. Consequently we reevaluated the percentage in our blood inventory of CMV-seronegative units required while potentially saving 1234 CMV-seronegative blood products (835 RBCs and 399 PLTs) each month. CONCLUSION: A strategy of performing CMV antibody reflex testing in the transfusion service allows more effective blood inventory management and control in maintaining a CMV-seronegative blood inventory dedicated for patients who truly require it.

Background The decision to use red blood cell transfusion and/or blood products (fresh frozen plasma, platelets, cryoprecipitate) to manage obstetric hemorrhage or treat postpartum anemia is often made empirically by physicians. We performed a retrospective study to review transfusion outcomes in pregnant and postpartum patients at a large obstetric center. Methods A retrospective, observational study was performed of obstetric in-patients who received red blood cell transfusion and/or blood products over a one-year period. Data abstracted included transfusion data, pre-transfusion hemoglobin (Hb) and lowest recorded (nadir) Hb, and maternal and neonatal outcomes. Results During the study period, 74 patients received transfusion therapy (1.4%). Pre-transfusion and nadir Hb values were 7.6g/dL and 7.0g/dL respectively. Median [IQR] total red blood cells transfused were 2 units [2-3], with 41 (55%) patients receiving 1-2 units. Based on chart review, no specific indications for transfusion were identified in 25 patients (34%), and 13 patients (18%) had undetected postpartum anemia (Hb values Conclusion More formal assessment and documentation of the etiologic factors associated with transfusion management in pregnant patients is advised. In addition, the identification and management of undetected postpartum anemia is underappreciated.