Fewer severe infections with tranexamic acid in patients with hematologic malignancies.

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.

Another piece of the hemolytic disease of the fetus and newborn puzzle after RhD-positive transfusion in trauma resuscitation: the proportion of pregnant women who produce high titer anti-D.

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%.

Therapeutic plasma exchange is feasible and tolerable in severely injured patients with trauma-induced coagulopathy.

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.

Prophylactic Platelet Transfusion: Is There Evidence of Benefit, Harm, or No Effect?

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.

Low Titer Group O Whole Blood In Injured Children Requiring Massive Transfusion.

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.

Prophylactic tranexamic acid in patients with hematologic malignancy: a placebo-controlled, randomized clinical trial.

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.

CD4+ T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1-Dependent.

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.

Prehospital low titer group O whole blood is feasible and safe: Results of a prospective randomized pilot trial.

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.

Plasma trial: Pilot randomized clinical trial to determine safety and efficacy of plasma transfusions.

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.

How well do platelets prevent bleeding?

Prophylactic platelet transfusions are used to reduce the risk of spontaneous bleeding in patients with treatment- or disease-related severe thrombocytopenia. A prophylactic platelet-transfusion threshold of <10 × 103/µL has been shown to be safe in stable hematology/oncology patients. A higher threshold and/or larger or more frequent platelet doses may be appropriate for patients with clinical features associated with an increased risk of bleeding such as high fevers, sepsis, disseminated intravascular coagulation, anticoagulation therapy, or splenomegaly. Unique factors in the outpatient setting may support the use of a higher platelet-transfusion threshold and/or dose of platelets. A prophylactic platelet-transfusion strategy has been shown to be associated with a lower risk of bleeding compared with no prophylaxis in adult patients receiving chemotherapy but not for autologous transplant recipients. Despite the use of prophylactic platelet transfusions, a high incidence (50% to 70%) of spontaneous bleeding remains. Using a higher threshold or larger doses of platelets does not change this risk. New approaches to reduce the risk of spontaneous bleeding, including antifibrinolytic therapy, are currently under study.

Whole Blood is Superior to Component Transfusion for Injured Children: A Propensity Matched Analysis.

OBJECTIVE: To compare a propensity-matched cohort of injured children receiving conventional blood component transfusion to injured children receiving low-titer group O negative whole blood. SUMMARY OF BACKGROUND DATA: Transfusion of whole blood in pediatric trauma patients is feasible and safe. Effectiveness has not been evaluated. METHODS: Injured children ≥1 years old can receive up to 40 mL/kg of cold-stored, uncrossmatched whole blood during initial hemostatic resuscitation. Whole blood recipients (2016-2019) were compared to a propensity-matched cohort who received at least 1 uncrossmatched red blood cell unit in the trauma bay (2013-2016). Cohorts were matched for age, hypotension, traumatic brain injury, injury mechanism, and need for emergent surgery. Outcomes included time to resolution of base deficit, product volumes transfused, and INR after resuscitation. RESULTS: Twenty-eight children who received whole blood were matched to 28 children who received components. The whole blood group had faster time to resolution of base deficit [median (IQR) 2 (1-2.5) hours vs 6 (2-24) hours, respectively; P < 0.001]. The post-transfusion INR was decreased in whole blood vs component cohort [median (IQR) 1.4 (1.3-1.5) vs 1.6 (1.4-2.2); P = 0.01]. Lower plasma volumes [median (IQR) = 5 (0-15) mL/kg vs 11 (5-35) mL/kg; P = 0.04] and lower platelet volumes [median (IQR) = 0 (0-2) vs 3 (0-8); P = 0.03] were administered to the whole blood group versus component group. Other clinical variables (in-hospital death, hospital length of stay, intensive care unit length of stay, and ventilator days) did not differ between groups. CONCLUSIONS: Compared to component transfusion, whole blood transfusion results in faster resolution of shock, lower post-transfusion INR, and decreased component product transfusion. Larger cohorts are required to support these findings.

Association of donor age, body mass index, hemoglobin, and smoking status with in-hospital mortality and length of stay among red blood cell-transfused recipients.

BACKGROUND: Recent publications have reported conflicting findings regarding associations of blood donor demographics and mortality of transfused patients. We hypothesized that the analysis of additional donor characteristics and consideration of alternative outcomes might provide insight into these disparate results. STUDY DESIGN AND METHODS: We analyzed data from a retrospective cohort of transfused patients from the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III). We used stratified Cox regression models to estimate associations between blood donor characteristics and hospital mortality and posttransfusion length of stay among patients transfused red blood cell (RBC) units. Donor characteristics evaluated included age, body mass index, hemoglobin levels, and smoking status. The statistical analyses were adjusted for recipient factors, including total number of transfusions. RESULTS: We studied 93,726 patients in 130,381 hospitalizations during which 428,461 RBC units were transfused. There were no associations between blood donor characteristics and hospital mortality. Receipt of RBC units from donors less than 20 years of age was associated with a shorter hospital length of stay (hazard ratio for discharge per transfused unit, 1.03; 95% confidence interval, 1.02-1.04; p < 0.001) but not for other donor characteristics. CONCLUSION: We found no evidence of associations between blood donor factors and in-hospital mortality. Our finding of shorter hospital length of stay in patients transfused RBCs from younger donors is intriguing but requires confirmation. Future collaborations are needed to develop a framework of appropriate methodologic approaches to be used in linked analyses across large cohorts.

Transfusion-Associated Circulatory Overload and Transfusion-Related Acute Lung Injury: Etiology and Prevention.

Transfusion-related acute lung injury and transfusion-associated circulatory overload are characterized by acute pulmonary edema within 6 hours of blood transfusion. Despite recognition as the leading causes of transfusion-related mortality, they remain difficult to study due to underrecognition and nonspecific diagnostic criteria. Recent study has shown that inflammatory cytokines and cardiopulmonary biomarker may be useful in differentiating pulmonary transfusion reactions and furthering our understanding of their pathogenesis. It is clear that donor / component mitigation and patient blood management strategies have decreased the incidence of pulmonary transfusion reactions. Additional clinical and translational research focused on identifying at-risk transfusion recipients is needed to further prevent these frequently severe cardiopulmonary events.

Cold-stored whole blood platelet function is preserved in injured children with hemorrhagic shock.

BACKGROUND: Recent data demonstrate the safety of uncrossmatched cold-stored whole blood (WB) transfusion in pediatric trauma patients. The hemostatic capabilities of platelets within the cold-stored WB unit have been demonstrated via in vitro studies and animal models. However, platelet function has not been evaluated in pediatric recipients of cold-stored WB transfusions. METHODS: Injured children, 2 years or older and 10 kg or greater with hemorrhagic shock received up to 30 mL/kg of cold-stored, low titer (<50) anti-A and -B, leukoreduced, group O- WB during their initial resuscitation. Patients were included if (1) they received WB and no conventional platelets, and (2) platelet count and thromboelastography maximum amplitude were measured both before and after transfusion. These data and relevant clinical outcomes (mortality, intensive care unit length of stay [LOS], hospital LOS and ventilator days) were compared to a historical cohort of pediatric trauma patients who received uncrossmatched red blood cells (RBC) and conventional room temperature platelets. RESULTS: Twenty-two children were included in the study; 14 in the component cohort versus 8 in the WB cohort. Neither posttransfusion platelet count (129 × 109/L vs. 135 × 109/L) nor function (thromboelastography maximum amplitude, 59.5 mm vs. 60.2 mm) differed significantly between children receiving cold-stored platelets within the WB unit versus children who received conventional warm platelets. Median (interquartile range) weight-adjusted platelet transfusion volume in the historical cohort was 4.6 (2.5-7.7) mL/kg vs. 2.4 (1.3-4.0) mL/kg in the WB cohort (p = 0.03). There was no difference between groups in age, race, mechanism of injury, Injury Severity Score, vital signs, and severe traumatic brain injury (TBI). Outcomes, including mortality, intensive care unit LOS, hospital LOS, and ventilator days, were not significantly different between groups. CONCLUSION: No difference was seen in posttransfusion platelet number or function in severely injured children receiving cold-stored WB platelets as compared to those receiving conventional room temperature-stored platelets. Larger cohorts are required to confirm these findings. LEVEL OF EVIDENCE: Therapeutic, level IV.

Clinical trials evaluating red blood cell transfusion thresholds: An updated systematic review and with additional focus on patients with cardiovascular disease.

BACKGROUND: Several new trials evaluating transfusion strategies in patients with cardiovascular disease have recently been published, increasing the number of enrolled patients by over 30%. The objective was to evaluate transfusion thresholds in patients with cardiovascular disease. METHODS: We conducted an updated systematic review of randomized trials that compared patients assigned to maintain a lower (restrictive transfusion strategy) or higher (liberal transfusion strategy) hemoglobin concentration. We focused on new trial data in patients with cardiovascular disease. The primary outcome was 30-day mortality. Specific subgroups were patients undergoing cardiac surgery and with acute myocardial infarction. RESULTS: A total of 37 trials that enrolled 19,049 patients were appraised. In cardiac surgery, mortality at 30days was comparable between groups (risk ratio 0.99; 95% confidence interval 0.74-1.33). In 2 small trials (n=154) in patients with myocardial infarction, the point estimate for the mortality risk ratio was 3.88 (95% CI, 0.83-18.13) favoring the liberal strategy. Overall, from 26 trials enrolling 15,681 patients, 30-day mortality was not different between restrictive and liberal transfusion strategies (risk ratio 1.0, 95% CI, 0.86-1.16). Overall and in the cardiovascular disease subgroup, there were no significant differences observed across a range of secondary outcomes. CONCLUSIONS: New trials in patients undergoing cardiac surgery establish that a restrictive transfusion strategy of 7 to 8g/dL is safe and decreased red cell use by 24%. Further research is needed to define the optimal transfusion threshold in patients with acute myocardial infarction.

Risk factors for red blood cell alloimmunization in the Recipient Epidemiology and Donor Evaluation Study (REDS-III) database.

Despite the significance of red blood cell (RBC) alloimmunization, the lack of standardized registries in the US has prevented the completion of large studies. Data from 3·5 years of the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) recipient database, containing information from 12 hospitals, were studied. A RBC alloantibody responder had an antibody identified at any point during the study, and a non-responder had a negative antibody screen at least 15 days post-RBC transfusion. Demographics, blood type, ICD9/10 codes, and other potential correlates were evaluated. Of 319 177 (2·07%) screened patients, 6597 had a total of 8892 clinically significant RBC alloantibodies identified, with 75% being in the Rh or Kell families. Alloimmunization was more common in females (2·38%) than males (1·68%), and in RhD negative (2·82%) than RhD positive (1·94%) patients. Age, sex, RhD status and race were associated with being a responder, and certain diagnoses (including sickle cell disease or trait, systemic lupus erythematosus, rheumatoid arthritis and myelodysplastic syndrome) were more common among responders than non-responders. Data collected in this multi-centre recipient database provide the largest RBC alloimmunized patient cohort studied in the US, with previously known demographic and disease associations of responder status confirmed, and new associations identified.

Contemporary Risk Factors and Outcomes of Transfusion-Associated Circulatory Overload.

OBJECTIVES: Transfusion-associated circulatory overload is characterized by hydrostatic pulmonary edema following blood transfusion. Restrictive transfusion practice may affect the occurrence and severity of transfusion-associated circulatory overload in critically ill patients. We sought to examine contemporary risk factors and outcomes for transfusion-associated circulatory overload. DESIGN: Case-control study. SETTING: Four tertiary care hospitals. PATIENTS: We prospectively enrolled 200 patients with transfusion-associated circulatory overload identified by active surveillance and 405 controls matched by transfusion intensity. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 20,845 transfused patients who received 128,263 blood components from May 2015 until July 2016, transfusion-associated circulatory overload incidence was one case per 100 transfused patients. In addition to cardiovascular comorbidities, multivariable analysis identified the following independent predictors of transfusion-associated circulatory overload: acute kidney injury, emergency surgery, pretransfusion diuretic use, and plasma transfusion-the latter especially in females. Compared with matched controls, transfusion-associated circulatory overload cases were more likely to require mechanical ventilation (71% vs 49%; p < 0.001), experienced longer intensive care and hospital lengths of stay following transfusion, and had higher mortality (21% vs 11%; p = 0.02) even after adjustment for other potentially confounding variables. CONCLUSIONS: Despite restrictive transfusion practice, transfusion-associated circulatory overload remains a frequent complication of transfusion and is an independent risk factor for in-hospital morbidity and mortality. In addition to cardiovascular and renal risk factors, plasma transfusion was associated with transfusion-associated circulatory overload after controlling for other covariates. Additional research is needed to examine the benefit of reduced erythrocyte or plasma exposure in patients at high risk for transfusion-associated circulatory overload.

Should All Massively Transfused Patients Be Treated Equally? An Analysis of Massive Transfusion Ratios in the Nontrauma Setting.

OBJECTIVES: Although balanced resuscitation has become integrated into massive transfusion practice, there is a paucity of evidence supporting the delivery of high ratios of plasma and platelet to RBCs in the nontrauma setting. This study investigated the administration of blood component ratios in the massively transfused nontrauma demographic. DESIGN: Retrospective analysis of a prospective, observational cohort of massively bleeding patients. SETTING: Surgical and critically ill patients at a tertiary medical center between 2011 and 2015. PATIENTS: Massively transfused nontrauma patients. INTERVENTIONS: Patients receiving plasma, platelet, and RBC transfusions were categorized into high and low ratio groups and analyzed for differences in characteristics and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 30-day mortality. Secondary outcomes included 48-hour mortality, hospital length of stay, ICU length of stay, and ventilator-free days. Among 601 massively transfused nontrauma patients, cardiothoracic surgery and gastrointestinal or hepato-pancreatico-biliary bleeds were the most common indications for massive transfusion. Higher fresh frozen plasma ratios (> 1:2) were not associated with increased 30-day mortality. A high platelets-to-packed RBCs ratio (> 1:2) was associated with decreased 48-hour mortality (10.5% vs 19.3%; p = 0.032), but not 30-day mortality. Fresh frozen plasma-to-packed RBCs and platelets-to-packed RBCs ratios were not associated with 30-day mortality hazard ratios after controlling for baseline characteristics and disease severity. CONCLUSIONS: The benefits of higher ratios of fresh frozen plasma-to-packed RBCs and platelets-to-packed RBCs described in trials of trauma patients were not observed in this analysis of a nontrauma, massively transfused population. These data suggest that greater than 1:2 ratio transfusion in the setting of massive hemorrhage may not be appropriate for all patients, and that further research to guide appropriate resuscitation strategies in nontrauma patients is warranted.

Massive Transfusion in Cardiac Surgery: The Impact of Blood Component Ratios on Clinical Outcomes and Survival.

BACKGROUND: Cardiac surgery is the most common setting for massive transfusion in medically advanced countries. Studies of massive transfusion after injury suggest that the ratios of administered plasma and platelets (PLT) to red blood cells (RBCs) affect mortality. Data from the Red Cell Storage Duration Study (RECESS), a large randomized trial of the effect of RBC storage duration in patients undergoing complex cardiac surgery, were analyzed retrospectively to investigate the association between blood component ratios used in massively transfused patients and subsequent clinical outcomes. METHODS: Massive transfusion was defined as those who had ≥6 RBC units or ≥8 total blood components. For plasma, high ratio was defined as ≥1 plasma unit:1 RBC unit. For PLT transfusion, high ratio was defined as ≥0.2 PLT doses:1 RBC unit; PLT dose was defined as 1 apheresis PLT or 5 whole blood PLT equivalents. The clinical outcomes analyzed were mortality and the change in the Multiple Organ Dysfunction Score (ΔMODS) comparing the preoperative score with the highest composite score through the earliest of death, discharge, or day 7. Outcomes were compared between patients transfused with high and low ratios. Linear and Cox regression were used to explore relationships between predictors and continuous outcomes and time to event outcomes. RESULTS: A total of 324 subjects met the definition of massive transfusion. In those receiving high plasma:RBC ratio, the mean (SE) 7- and 28-day ΔMODS was 1.24 (0.45) and 1.26 (0.56) points lower, (P = .007 and P = .024), respectively, than in patients receiving lower ratios. In patients receiving high PLT:RBC ratio, the mean (SE) 7- and 28-day ΔMODS were 1.55 (0.53) and 1.49 (0.65) points lower (P = .004 and P = .022), respectively. Subjects who received low-ratio plasma:RBC transfusion had excess 7-day mortality compared with those who received high ratio (7.2% vs 1.7%, respectively, P = .0318), which remained significant at 28 days (P = .035). The ratio of PLT:RBCs was not associated with differences in mortality. CONCLUSIONS: This analysis found that in complex cardiac surgery patients who received massive transfusion, there was an association between the composition of blood products used and clinical outcomes. Specifically, there was less organ dysfunction in those who received high-ratio transfusions (plasma:RBCs and PLT:RBCs), and lower mortality in those who received high-ratio plasma:RBC transfusions.

Aged Human Stored Red Blood Cell Supernatant Inhibits Macrophage Phagocytosis in an HMGB1 Dependent Manner After Trauma in a Murine Model.

Red blood cell transfusions in the setting of trauma are a double-edged sword, as it is a necessary component for life-sustaining treatment in massive hemorrhagic shock, but also associated with increased risk for nosocomial infections and immune suppression. The mechanisms surrounding this immune suppression are unclear. Using supernatant from human packed red blood cell (RBC), we demonstrate that clearance of Escherichia coli by macrophages is inhibited both in vitro and in vivo using a murine model of trauma and hemorrhagic shock. We further explore the mechanism of this inhibition by demonstrating that human-stored RBCs contain soluble high-mobility group box 1 protein (HMGB1) that increases throughout storage. HMGB1 derived from the supernatant of human-stored RBCs was shown to inhibit bacterial clearance, as neutralizing antibodies to HMGB1 restored the ability of macrophages to clear bacteria. These findings demonstrate that extracellular HMGB1 within stored RBCs could be one factor leading to immune suppression following transfusion in the trauma setting.