A genome-wide association study of alloimmunization in the TOPMed OMG-SCD cohort identifies a locus on chromosome 12.

BACKGROUND: Red cell alloimmunization after exposure to donor red cells is a very common complication of transfusion for patients with sickle cell disease (SCD), resulting frequently in accelerated donor red blood cell destruction. Patients show substantial differences in their predisposition to alloimmunization, and genetic variability is one proposed component. Although several genetic association studies have been conducted for alloimmunization, the results have been inconsistent, and the genetic determinants of alloimmunization remain largely unknown. STUDY DESIGN AND METHODS: We performed a genome-wide association study (GWAS) in 236 African American (AA) SCD patients from the Outcome Modifying Genes in Sickle Cell Disease (OMG-SCD) cohort, which is part of Trans-Omics for Precision Medicine (TOPMed), with whole-genome sequencing data available. We also performed sensitivity analyses adjusting for different sets of covariates and applied different sample grouping strategies based on the number of alloantibodies patients developed. RESULTS: We identified one genome-wide significant locus on chr12 (p = 3.1e-9) with no evidence of genomic inflation (lambda = 1.003). Further leveraging QTL evidence from GTEx whole blood and/or Jackson Heart Study PBMC RNA-Seq data, we identified a number of potential genes, such as ARHGAP9, STAT6, and ATP23, that may be driving the association signal. We also discovered some suggestive loci using different analysis strategies. DISCUSSION: We call for the community to collect additional alloantibody information within SCD cohorts to further the understanding of the genetic basis of alloimmunization in order to improve transfusion outcomes.

Epidemiological and clinical features, therapeutic strategies and outcomes in patients with hyperhaemolysis: A systematic review.

Hyperhaemolysis syndrome (HHS), a severe form of delayed haemolytic transfusion reaction most commonly described in patients with sickle cell disease (SCD), involves destruction of both donor and recipient red blood cells (RBCs). As the epidemiology and underlying pathophysiology have yet to be definitively elucidated, recognition can be challenging. We systematically reviewed PubMed and EMBASE to identify all cases of post-transfusion hyperhaemolysis and characterized the epidemiological, clinical and immunohaematological characteristics and treatments of HHS. We identified 51 patients (33 females and 18 males), including 31 patients with SCD (HbSS, HbSC and HbS/ß-thalassaemia). The median haemoglobin nadir (3.9 g/dL) occurred a median of 10 days post-transfusion. 32.6% and 45.7% of patients had a negative indirect anti-globulin test and a negative direct anti-globulin test, respectively. The most common therapies included corticosteroids and intravenous immune globulin. 66.0% of patients received ≥1 supportive transfusion, which was associated with a longer median hospital stay/time to recovery (23 days vs. 15 days; p = 0.015) compared to no supportive transfusion. These findings illustrate that HHS that often results in marked anaemia 10 days post-transfusion is not restricted to patients with haemoglobinopathies, and additional transfused RBCs may be associated with a longer time-to-recovery.

How do we build a comprehensive Vein-to-Vein (V2V) database for conduct of observational studies in transfusion medicine? Demonstrated with the Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric V2V database protocol.

BACKGROUND: The Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P) is the fourth iteration of the National Heart, Lung, and Blood Institute's REDS program and includes a focus on pediatric populations. The REDS-IV-P Vein-to-Vein (V2V) database encompasses linked information from blood donors, blood components, and patients to facilitate studies in transfusion medicine. STUDY DESIGN AND METHODS: The V2V database is an Observational Medical Outcomes Partnership Common Data Model database. The study period is April 1, 2019 through December 31, 2023. Data from all donors and donations at participating blood centers, all blood components derived from the donations, and all inpatient visits and selected outpatient visits at participating hospitals are included. The database captures all information within patient data domains not restricting data to a preselected subset of medical records. RESULTS: The V2V database contains data from 7 blood centers and 22 hospitals. We project the database will have over 2 billion pieces of information from 1.3 million patients with 20.6 million healthcare encounters. The database will include data on approximately 1 million transfused units and 2.3 million donors with approximately 6.8 million donation visits. CONCLUSION: The REDS-IV-P V2V database is a comprehensive database with data from millions of blood donors, blood components, and patients. A diverse set of data from the encounters are included in the database such that emerging questions can likely be addressed. The Observational Medical Outcomes Partnership Common Data Model is an efficient, flexible, and increasingly used common data model. The final de-identified database will be publicly available.

Hypoxic storage of donor red cells preserves deformability after exposure to plasma from adults with sickle cell disease.

BACKGROUND: Red cell (RBC) transfusions are beneficial for patients with sickle cell disease (SCD), but ex vivo studies suggest that inflamed plasma from patients with SCD during crises may damage these RBCs, diminishing their potential efficacy. The hypoxic storage of RBCs may improve transfusion efficacy by minimizing the storage lesion. We tested the hypotheses that (1) The donor RBCs exposed to the plasma of patients in crisis would have lower deformability and higher hemolysis than those exposed to non-crisis plasma, and (2) hypoxic storage, compared to standard storage, of donor RBCs could preserve deformability and reduce hemolysis. STUDY DESIGN AND METHODS: 18 SCD plasma samples from patients who had severe acute-phase symptoms (A-plasma; n = 9) or were at a steady-state (S = plasma; n = 9) were incubated with 16 RBC samples from eight units that were stored either under conventional(CRBC) or hypoxic(HRBC) conditions. Hemolysis and microcapillary deformability assays of these RBCs were analyzed using linear mixed-effect models after each sample was incubated in patient plasma overnight at 37°C RESULTS: Relative deformability was 0.036 higher (p < 0.0001) in HRBC pairs compared to CRBC pairs regardless of plasma type. Mean donor RBC hemolysis was 0.33% higher after incubation with A-plasma compared to S-plasma either with HRBC or CRBC (p = 0.04). HRBCs incubated with steady-state patient plasma demonstrated the highest deformability and lowest hemolysis. CONCLUSION: Hypoxic storage significantly influenced RBC deformability. Patient condition significantly influenced post-incubation hemolysis. Together, HRBCs in steady-state plasma maximized donor red cell ex vivo function and survival.

In hospitalized patients undergoing therapeutic plasma exchange, major bleeding prevalence depends on the bleeding definition: An analysis of The Recipient Epidemiology and Donor Evaluation Study-III.

BACKGROUND: Major bleeding in patients undergoing therapeutic plasma exchange (TPE) has been studied in large databases; but without standardizing bleeding definitions. Therefore, we used standardized definitions to evaluate major bleeding in hospitalized patients undergoing TPE using public use data files from the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III). STUDY DESIGN AND METHODS: In a retrospective cross-sectional analysis, we identified TPE-treated adults in a first inpatient encounter. We evaluated major bleeding prevalence using (1) International Classification of Diseases (ICD) or Current Procedural Terminology (CPT) codes, (2) packed red blood cell (PRBC) transfusion, or (3) hemoglobin (Hgb) decline. Patients with major bleeding prior to their first TPE were excluded from the analysis. RESULTS: Among 779 patients undergoing TPE, major bleeding by at least one of the three bleeding definitions occurred in 135 patients (17.3%). For each of the ICD/CPT, PRBC, and Hgb definitions, the prevalence of major bleeding was 2.8% (n = 31), 7.4% (n = 81), and 5.4% (n = 59), respectively. Only 3.7% of bleeds (5/135) were captured by all three definitions and 19.3% (26/135) exclusively by any two pairwise definitions. The addition of PRBC transfusion and Hgb decline to ICD/CPT code definitions increased bleeding prevalence threefold. CONCLUSION: Among hospitalized adults undergoing TPE in the REDS-III study, the prevalence of major bleeding was 17.3%. The addition of PRBC and Hgb decline to ICD codes increased bleeding prevalence threefold. Future studies are needed to develop validated models that identify patients at risk for major bleeding during TPE.

Blood conservation strategies at United States hospitals during the COVID-19 pandemic: Findings from a multi-institutional analysis - International Society of Blood Transfusion survey.

BACKGROUND: Due to the coronavirus disease 2019 (COVID-19) pandemic, the transfusion medicine community has experienced unprecedented blood supply shortages since March 2020. As such, numerous changes to everyday practice have occurred with a specific emphasis on blood conservation. We sought to determine the strategies used to mitigate blood shortages and promote blood conservation during the pandemic. METHODS: An anonymous, 37-question survey was developed using Research Electronic Data Capture and distributed via e-mail to transfusion medicine specialists across the US obtained via publicly available databases. RESULTS: Amongst surveyed [41.1% response rate (51/124 institutions)], 98.0% experienced a product shortage, with the greatest number reporting red blood cell (RBC) shortages (92.0%). This led to 35.3% of institutions altering the composition and/or number of blood product suppliers, including a 100% increase in the number of institutions acquiring blood from organizations that connect hospital transfusion services with blood collection centers (e.g., Blood Buy) compared to before March 2020. Prospective triaging of blood products was the most common blood conservation strategy (68.1%), though 35.4% altered their RBC exchange or transfusion program for patients receiving chronic RBC transfusion/exchange. As a result of these changes, 78.6% of institutions reported that these changes resulted in a reduction in blood product usage, and 38.1% reported a decrease in product wastage. CONCLUSIONS: Most hospitals experienced the effects of the supply shortage, and many of them implemented blood conserving measures. Conservation strategies were associated with decreased blood utilization and waste, and future studies could evaluate whether these changes persist.

Variation in Neonatal Transfusion Practice.

OBJECTIVE: To estimate the incidence of blood product transfusion, including red blood cells, platelets, and plasma, and characterize pretransfusion hematologic values for infants during their initial hospitalization after birth. STUDY DESIGN: Retrospective cohort study using data from 7 geographically diverse US academic and community hospitals that participated in the National Heart Lung and Blood Institute Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) from 2013 to 2016. Pretransfusion hematologic values were evaluated closest to each transfusion and no more than 24 hours beforehand. RESULTS: Data from 60 243 infants were evaluated. The incidence of any transfusion differed by gestational age (P < .0001), with 80% (95% CI 76%-84%) transfused at <27 weeks of gestation (n = 329) and 0.5% (95% CI 0.5%-0.6%) transfused at ≥37 weeks of gestation (n = 53 919). The median pretransfusion hemoglobin was 11.2 g/dL (10th-90th percentile 8.8-14.1) for the entire cohort, ranging from 10.5 g/dL (8.8-12.3) for infants born extremely preterm at <27 weeks of gestation to 13.0 g/dL (10.5-15.5) for infants born at term. The median pretransfusion platelet count (×109/L) was 71 (10th-90th percentile 26-135) for the entire cohort, and was >45 for all gestational age groups examined. The median pretransfusion international normalized ratio for the entire cohort was 1.7 (10th-90th percentile 1.2-2.8). CONCLUSIONS: There is wide variability in pretransfusion hemoglobin, platelet count, and international normalized ratio values for neonatal transfusions. Our findings suggest that a large proportion of neonatal transfusions in the US are administered at thresholds greater than supported by the best-available evidence and highlight an opportunity for improved patient blood management.

Human leukocyte antigen (HLA)-incompatible mean fluorescence intensity-selected platelet products have corrected count increments similar to HLA antigen-matched platelets.

BACKGROUND: Donor specific antibody sum mean fluorescence intensity (MFI) values have been successfully used in transplant medicine to assess risk for organ rejection. However, little is known regarding whether MFI values could be similarly used to aid in platelet product selection. We have developed a novel protocol where MFI values are used to offer human leukocyte antigen (HLA)-incompatible platelet products when HLA antigen-matched products are not available. We aimed to evaluate the efficacy of this protocol. METHODS: We performed a 4-year retrospective chart review for all patients who received at least one MFI-selected platelet product. A corrected count increment (CCI) was calculated for each transfusion event. A mixed effects model was used to investigate the association between CCIs for MFI-selected, HLA antigen matched, and random donor platelet transfusions. A random effects expectation-maximization regression tree was used to define the extent to which other patient variables, such as age, sex, and diagnosis impacted the CCI for each platelet transfusion. RESULTS: Twenty highly HLA alloimmunized patients received a total of 591 platelets. MFI-selected platelet (low MFI) transfusions had a significantly higher median CCI 0-6 hour post-transfusion (13,559, interquartile range [IQR]: 8275-18,736) compared to random donor platelets (2121, IQR: 0-10,368, p < 0.0001). There was no significant difference in median CCI between HLA antigen matched and MFI selected platelet transfusions (p = 0.2). Mixed effects and regression modeling revealed that MFI-selected platelet products had a significantly higher CCI than non-matched platelets, even when accounting for other significant patient variables. CONCLUSION: MFI-selected HLA-incompatible platelet products could provide a comparable alternative to traditional HLA antigen-matched platelet products.

Hospital transfusion service operations during the SARS-CoV-2 pandemic: Lessons learned from the AABB hospital survey in preparation for the next infectious disease outbreak.

BACKGROUND: The SARS-CoV-2 pandemic disrupted hospital operations, affected the blood supply, and challenged the health care system to develop new therapeutic options, including convalescent plasma (CCP). The aim of this study is to describe and analyze blood supply fluctuations and the use of convalescent plasma in 2020. METHODS: AABB distributed a weekly and biweekly questionnaire through email to hospital-based members (HBM). RESULTS: The survey was sent to 887 HBM with 479 unique respondents, most of the hospitals served pediatric and adult patients, and all states of the country participated, except Idaho and Vermont. Fifty four percent of HBM reported increased wastage in the early phase of the pandemic (May), which decreased to 4% by the end of June and throughout the rest of the year. The majority of HBM reported receiving alerts from their blood suppliers reporting blood shortages throughout the year. During March and April, only 12% of HBM were performing elective surgical procedures. The top reasons to delay procedures were: bed availability (28%); COVID-19 caseload (23%; and blood availability (19%). By mid-April, 42% HBM had transfused CCP and reported >24 h delay in getting the units; the vast majority obtained CCP using the Expanded Access Protocol, and later, the Emergency Use Authorization. HBM consistently prioritized the most severe patients to receive CCP, but the proportion of severely ill recipients fell from 52% to 37% between May and October, with an increase from 5% to 21% of HBM providing CCP transfusion early in the course of the disease. DISCUSSION: Blood utilization and availability fluctuated during the pandemic. The fluctuations appeared to be related to the number of COVID-19 in the community. The use and regulatory landscape of CCP rapidly evolved over the first 8 months of the pandemic.

Transfusion practices for pediatric oncology and hematopoietic stem cell transplantation patients: Data from the National Heart Lung and Blood Institute Recipient Epidemiology and Donor Evaluation Study-III (REDS-III).

BACKGROUND: To evaluate transfusion practices in pediatric oncology and hematopoietic stem cell transplant (HSCT) patients. STUDY DESIGN AND METHODS: This is a multicenter retrospective study of children with oncologic diagnoses treated from 2013 to 2016 at hospitals participating in the National Heart Lung and Blood Institute Recipient Epidemiology and Donor Evaluation Study-III. Transfusion practices were evaluated by diagnosis codes and pre-transfusion laboratory values. RESULTS: A total of 4766 inpatient encounters of oncology and HSCT patients were evaluated, with 39.3% (95% confidence interval [CI]: 37.9%-40.7%) involving a transfusion. Red blood cells (RBCs) were the most commonly transfused component (32.4%; 95% CI: 31.1%-33.8%), followed by platelets (22.7%; 95% CI: 21.5%-23.9%). Patients in the 1 to <6 years of range were most likely to be transfused and HSCT, acute myeloid leukemia, and aplastic anemia were the diagnoses most often associated with transfusion. The median hemoglobin (Hb) prior to RBC transfusion was 7.5 g/dl (10-90th percentile: 6.4-8.8 g/dl), with 45.7% of transfusions being given at 7 to <8 g/dl. The median platelet count prior to platelet transfusion was 20 × 109 /L (10-90th percentile: 8-51 × 109 /L), and 37.9% of transfusions were given at platelet count of >20-50 × 109 /L. The median international normalized ratio (INR) prior to plasma transfusion was 1.7 (10-90th percentile: 1.3-2.7), and 36.3% of plasma transfusions were given at an INR between 1.4 and 1.7. DISCUSSION: Transfusion of blood components is common in hospitalized pediatric oncology/HSCT patients. Relatively high pre-transfusion Hb and platelet values and relatively low INR values prior to transfusion across the studied diagnoses highlight the need for additional studies in this population.

Transfusion practices in a large cohort of hospitalized children.

BACKGROUND: While previous studies have described the use of blood components in subsets of children, such as the critically ill, little is known about transfusion practices in hospitalized children across all departments and diagnostic categories. We sought to describe the utilization of red blood cell, platelet, plasma, and cryoprecipitate transfusions across hospital settings and diagnostic categories in a large cohort of hospitalized children. STUDY DESIGN AND METHODS: The public datasets from 11 US academic and community hospitals that participated in the National Heart Lung and Blood Institute Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) were accessed. All nonbirth inpatient encounters of children 0-18 years of age from 2013 to 2016 were included. RESULTS: 61,770 inpatient encounters from 41,943 unique patients were analyzed. Nine percent of encounters involved the transfusion of at least one blood component. RBC transfusions were most common (7.5%), followed by platelets (3.9%), plasma (2.5%), and cryoprecipitate (0.9%). Children undergoing cardiopulmonary bypass were most likely to be transfused. For the entire cohort, the median (interquartile range) pretransfusion laboratory values were as follows: hemoglobin, 7.9 g/dl (7.1-10.4 g/dl); platelet count, 27 × 109 cells/L (14-54 × 109 cells/L); and international normalized ratio was 1.6 (1.4-2.0). Recipient age differences were observed in the frequency of RBC irradiation (95% in infants, 67% in children, p < .001) and storage duration of RBC transfusions (median storage duration of 12 [8-17] days in infants and 20 [12-29] days in children, p < .001). CONCLUSION: Based on a cohort of patients from 2013 to 2016, the transfusion of blood components is relatively common in the care of hospitalized children. The frequency of transfusion across all pediatric hospital settings, especially in children undergoing cardiopulmonary bypass, highlights the opportunities for the development of institutional transfusion guidelines and patient blood management initiatives.

Chronic Pain Does Not Impact Baseline Circulating Cytokine Levels in Adults with Sickle Cell Disease.

Chronic pain affects 50% of adults with sickle cell disease (SCD). Although inflammation is thought to contribute to the pathogenesis of chronic pain, no studies have examined the differences in circulating cytokines between patients with SCD with and without chronic pain. We performed an observational cohort study using blood and urine samples from adults with SCD with and without chronic pain at their usual state of health. We tested the hypothesis that, compared to those without chronic pain, those with chronic pain would have significantly higher baseline circulating proinflammatory cytokines. A total of 61 adults with SCD, 40 with chronic pain and 21 without chronic pain were tested. When SCD patients with chronic pain were compared to those without chronic pain, no significant differences in cytokine levels were noted. The variables most associated with the diagnosis of chronic pain in this population were opioid dose and subject age.

Transfusion Practices in Pediatric Cardiac Surgery Requiring Cardiopulmonary Bypass: A Secondary Analysis of a Clinical Database.

OBJECTIVES: To describe blood component usage in transfused children with congenital heart disease undergoing cardiopulmonary bypass surgery across perioperative settings and diagnostic categories. DESIGN: Datasets from U.S. hospitals participating in the National Heart, Lung, and Blood Institute Recipient Epidemiology and Donor Evaluation Study-III were analyzed. SETTING: Inpatient admissions from three U.S. hospitals from 2013 to 2016. PATIENTS: Transfused children with congenital heart disease undergoing single ventricular, biventricular surgery, extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eight hundred eighty-two transfused patients were included. Most of the 185 children with single ventricular surgery received multiple blood products: 81% RBCs, 79% platelets, 86% plasma, and 56% cryoprecipitate. In the 678 patients undergoing biventricular surgery, 85% were transfused plasma, 75% platelets, 74% RBCs, and 48% cryoprecipitate. All 19 patients on extracorporeal membrane oxygenation were transfused RBCs, plasma, and cryoprecipitate, and 18 were transfused platelets. Intraoperatively, patients commonly received all three components, while postoperative transfusions were predominantly single blood components. Pretransfusion hemoglobin values were normal/low-normal for age for all phases of care for single ventricular surgery (median hemoglobin 13.2-13.5 g/dL). Pretransfusion hemoglobin values for biventricular surgeries were higher intraoperatively compared with other timing (12.2 g/dL vs 11.2 preoperative and postoperative; p < 0.0001). Plasma transfusions for all patients were associated with a near normal international normalized ratio: single ventricular surgeries median international normalized ratio was 1.3 postoperative versus 1.8 intraoperative and biventricular surgeries median international normalized ratio was 1.1 intraoperative versus 1.7 postoperative. Intraoperative platelet transfusions with biventricular surgeries had higher median platelet count compared with postoperative pretransfusion platelet count (244 × 109/L intraoperative vs 69 × 109/L postoperative). CONCLUSIONS: Children with congenital heart disease undergoing cardiopulmonary bypass surgery are transfused many blood components both intraoperatively and postoperatively. Multiple blood components are transfused intraoperatively at seemingly normal/low-normal pretransfusion values. Pediatric evidence guiding blood component transfusion in this population at high risk of bleeding and with limited physiologic reserve is needed to advance safe and effective blood conservation practices.

Red cell exchange for patients with sickle cell disease: an international survey of current practices.

INTRODUCTION: Red cell exchange (RCE) therapy is increasingly used to treat patients with acute or chronic manifestations of sickle cell disease (SCD). However, little is known regarding the most safe and effective practice parameters associated with this particular therapy. METHODS: A SCD subcommittee of members of the American Society for Apheresis (ASFA) developed a 122-question survey and administered it via email to other ASFA members. The survey inquired about clinical indications for treatment, practice patterns, and transfusion policies for RCE when used for patients with SCD. RESULTS: Ninety-nine distinct institutions completed the survey. Twenty-one (21%) were from outside of the US. Twenty-two (22%) provided chronic transfusion therapy to >10 patients, and both adult (25%) and pediatric-focused services (20%) were represented. Common acute indications for RCE included acute chest syndrome, acute ischemic stroke, and pre-surgical prophylaxis. Common chronic indications included primary stroke prophylaxis, secondary stroke prophylaxis, and recurrent acute chest syndrome. Respondents most commonly set a post-RCE treatment target of 30% for the hematocrit and hemoglobin S levels, regardless of the therapeutic indication. Units for RCE were phenotypically matched in 95% of cases. About 40% of respondents reported using isovolemic hemodilution. CONCLUSIONS: This survey solicited the current practice variations in RCE from a diverse range of practice sites. Many sites reported similar practice patterns and challenges but some variations emerged. To our knowledge, this survey represents the largest and most in-depth investigation of the use of RCE for patients with SCD, and could inform future studies in the field.

The evanescence and persistence of RBC alloantibodies in blood donors.

BACKGROUND: Blood donors represent a healthy population, whose red blood cell (RBC) alloantibody persistence or evanescence kinetics may differ from those of immunocompromised patients. A better understanding of the biologic factors impacting antibody persistence is warranted, as the presence of alloantibodies may impact donor health and the fate of the donated blood product. METHODS: Donor/donation data collected from four US blood centers from 2012 to 2016 as part of the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) were analyzed. Clinically significant antibodies from blood donors with more than one donation who underwent at least one follow-up antibody screen after the initial antibody identification were included. Of 632,378 blood donors, 481 (128 males and 353 females) fit inclusion criteria. RESULTS: Antibody screens detected 562 alloantibodies, with 368 of 562 (65%) of antibodies being persistently detected and with 194 of 562 (35%) becoming evanescent. Factors associated with antibody persistence included antibody specificity, detection at the first donation, reported history of transfusion, and detection of multiple antibodies concurrently. Anti-D, C, and Fya were most likely to persist, while anti-M, Jka , and S were most frequently evanescent. CONCLUSIONS: These data provide insight into variables impacting the duration of antibody detection, and they may also influence blood donor center policies regarding donor recruitment/acceptance.

Early and sustained improvement in fatigue-related quality of life following red blood cell transfusion in outpatients.

PURPOSE: Outpatients with hematologic disease often receive red cell transfusion to treat anemia and fatigue. The effect of transfusion on fatigue-related quality of life and how well this effect is sustained has not been quantified. The study aim was to describe the early and sustained impact over 4 weeks of red cells on patient-reported fatigue in outpatients age ≥ 50 receiving transfusion as routine clinical care. METHODS: FACIT-Fatigue scale scores were measured pre-transfusion and at visits targeting 3, 7, and 28 days post-transfusion. Group-based trajectory modeling of patient fatigue scores by study day was used to identify the number of distinct trajectories (Groups), then longitudinal mixed effects modeling of fatigue scores was used to estimate group-specific mean improvements early after transfusion and between days 3 and 28 post-transfusion. RESULTS: Four distinct fatigue score trajectory groups were identified and were found to be correlated with baseline fatigue scores (means 12, 26, 34, and 47 points). In the three groups with the lowest fatigue trajectories (indicating greater fatigue), improvements in fatigue early after transfusion achieved the established minimum clinically important difference (≥ 3 points, Group p = 0.0039). In all trajectory groups, mean fatigue levels did not change significantly between 3 and 28 days (± 1 point, Group p = 0.60). CONCLUSION: Patient-reported fatigue varies widely among older adult outpatients with hematologic disorders. Nonetheless, trajectory modeling suggests that most anemic patients can expect a noticeable improvement in fatigue in the first few days after transfusion that generally is sustained up to 4 weeks.

The controversial role of red cell transfusions for sickle cell pain.

PURPOSE OF REVIEW: Red cell transfusions are one of the most common and important therapies used for patients with sickle cell disease (SCD). For prevention of strokes, there is abundant evidence that transfusions are efficacious, whereas for other indications, such as prevention of pain, there are less data. Nonetheless, with few therapeutic options, the use of transfusion for prevention of acute pain has increased in children and adults with SCD without a clear understanding of its benefits. RECENT FINDINGS: Although it makes conceptual sense that red cell transfusions would prevent pain that arises from vaso-occlusion, we now know that the mechanism of pain is more complex than vaso-occlusion alone. Recent taxonomies recognize a chronic pain syndrome that is both common in adults with SCD and affects the presentation of acute pain. It is not known if acute pain on the background of chronic pain responds differently to sickle cell therapies, such as hydroxyurea and blood transfusion. SUMMARY: In this review, we will examine the studies that have investigated whether red cell transfusions are efficacious for preventing pain. In the absence of high-quality data that specifically addresses this question, we will outline our approach, which might soon change with new drugs and curative therapies on the horizon.

Mechanisms of alloimmunization in sickle cell disease.

PURPOSE OF REVIEW: Red blood cell (RBC) transfusion is an important treatment for some complications of sickle cell disease (SCD). On the contrary, transfusion may lead to alloimmunization to RBC antigens, with such alloantibodies putting patients at risk for acute or delayed hemolysis, and increasing the difficulty of finding compatible RBCs. Patients with SCD are more susceptible to developing RBC alloantibodies than other multiply transfused patient populations, for reasons that are not completely understood. In this review, we summarize the available data about risk factors and underlying mechanisms associated with RBC alloimmunization in SCD. RECENT FINDINGS: Although RBC antigen matching between blood donors and transfusion recipients can decrease alloimmunization, complete matching at all loci is not feasible. Patients with SCD show evidence of increased inflammation at baseline and in times of illness. Resultant changes to the innate and adaptive immune systems presumably influence the development of RBC alloantibodies as well as RBC autoantibodies. SUMMARY: The inflammation and immune dysregulation associated with SCD may be therapeutic targets for preventing the formation of antibodies and/or for mitigating the dangers of existing RBC alloantibodies. As long as RBC transfusion therapy remains an important treatment for SCD, the quest to improve its safety profile will continue.

Red blood cell alloimmunization is associated with lower expression of FcγR1 on monocyte subsets in patients with sickle cell disease.

BACKGROUND: Despite the clinical significance of red blood cell (RBC) alloantibodies, there are currently no laboratory tests available to predict which patients may be at risk of antibody formation after transfusion exposure. Given their phagocytic and inflammatory functions, we hypothesized that differences in circulating monocytes may play a role in alloimmunization. STUDY DESIGN AND METHODS: Forty-two adults with sickle cell disease (SCD) were recruited, with data extracted from the electronic medical record and peripheral blood analyzed by flow cytometry for total monocytes, monocyte subsets (CD14 high/CD16 low+ classical monocytes, CD14 high/CD16 high+ intermediate monocytes, and CD14 intermediate/CD16 high+ non-classical/inflammatory monocytes), and FcγR1 (CD64) expression. Thirteen "non-responder" patients (non-alloimmunized patients with documented RBC transfusion at the study institution) were compared to 20 alloimmunized "responder" patients, who had a total of 44 RBC alloantibodies identified. RESULTS: There were no significant differences in the percentages of total monocytes, monocyte subsets, or measured cytokines between non-responders and responders. However, non-responders had higher CD64 expression on classical monocytes (MFI mean 3424 ± standard deviation 1141) compared to responders (MFI mean 2285 ± 1501), p = 0.029, and on intermediate monocytes (MFI mean 3720 ± 1191) compared to responders (MFI mean 2497 ± 1640), p = 0.033. CONCLUSIONS: Monocytes and the inflammatory milieu increasingly are being appreciated to play a role in some complications of SCD. The differences in FcγR1 expression on monocyte subsets noted between responders and non-responders, which cannot be directly explained by the serum cytokines evaluated, warrant further investigation.