Red Blood Cell Requirements Research Articles

Alloimmunization in patients with sickle cell disease and underrecognition of accompanying delayed hemolytic transfusion reactions.

Patients with sickle cell disease (SCD) often require red blood cell (RBC) transfusions but alloimmunization remains a significant complication. Alloantibodies can lead to delayed hemolytic transfusion reactions (DHTRs) days to weeks after a RBC transfusion, but may be underrecognized in patients with chronic hemolysis. This retrospective study aimed to determine the incidence and severity of DHTRs associated with new antibody detection in a cohort of 624 patients with SCD who received transfusion with C-, E-, and K-matched RBCs from primarily African American donors over a 14-year period. We identified potential DHTRs by the change in hemoglobin (Hb) and %HbS at baseline, before transfusion, and up to 30 days after the transfusion that preceded new antibody identification. Laboratory evidence of a DHTR was associated with 54 of 178 evaluable antibodies at first detection (30%), among which less than half were recognized by the patient or provider at the time of the event. A DHTR was associated with 26% of Rh antibodies identified in patients receiving serologic Rh-matched RBCs, and 38% of non-Rh antibodies. Twenty-one of the 54 DHTRs (39%) were associated with a Hb decline greater than 1 g/dL lower than pretransfusion values. Among these 21 severe DHTRs, Rh specificities were identified in 10 of 12 DHTRs in chronically transfused patients, while non-Rh specificities were associated with seven of nine DHTRs in episodically transfused patients. High clinical suspicion and monitoring for DHTRs is warranted, as they may be more common in patients with SCD than previously appreciated.

The fraction of CD117/c-KIT-expressing erythroid precursors predicts ESA response in low-risk myelodysplastic syndromes.

Compelling evidence has emerged for the relevance of flow cytometry (FC) in the diagnostic work-up of myelodysplastic syndromes (MDS) but due to technical issues, the erythroid lineage has been under investigated, specifically in the therapeutic context. Using the "no red cell lysis" method developed to set up the RED-score, we specifically quantified the fraction of CD117/c-KIT-expressing erythroid precursors in a cohort of 144 MDS patients and studied the correlation with response to erythropoiesis-stimulating agents (ESA) in a sub cohort of 63 low-risk MDS patients. We confirmed the previously reported increase in CD117/c-KIT-expressing erythroid precursors in a subset of MDS patients and demonstrated a strong association between a cut off of CD117/c-KIT-expressing erythroid precursors ≥3% and ESA response (P = 0.001), independent of red blood cell requirement. From our observations, we hypothesized that a decrease in CD117/c-KIT-expressing erythroid precursors could be a mechanism of ESA failure. Moreover, the fraction of CD117/c-KIT-expressing erythroid precursors was correlated with progression-free survival in low-risk MDS patients (P = 0.018). In vitro, we demonstrated in an EPO dependent cell line that CD117/c-KIT expression is necessary for cell survival under EPO stimulation. The quantification of the CD117/c-KIT-expressing erythroid precursors could be proposed as a new theranostic and prognostic marker in MDS treated by ESA. Future studies will be required to determine whether modulating CD117/c-KIT expression and signaling could be used to improve anemia in MDS. © 2019 International Clinical Cytometry Society.

Late erythropoiesis-stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants.

Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia. Darbepoetin (Darbe) and EPO are currently available ESAs. To assess the effectiveness and safety of late initiation of ESAs, between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm or low birth weight infants. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 5 June 2018), Embase (1980 to 5 June 2018), and CINAHL (1982 to 5 June 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) or low birth weight (< 2500 grams) neonates. We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of the evidence. We include 31 studies (32 comparisons) randomising 1651 preterm infants. Literature searches in 2018 identified one new study for inclusion. No new on-going trials were identified and no studies used darbepoetin.Most included trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions (21 studies (n = 1202); typical risk ratio (RR) 0.72, 95% confidence interval (CI) 0.65 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 66%; RD I² = 58%). The quality of the evidence was very low. We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants). There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%).Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). The quality of the evidence was very low.Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). The quality of the evidence was very low.There were no significant differences in other clinical outcomes including mortality and necrotising enterocolitis. For the outcomes of mortality and necrotising enterocolitis, the quality of the evidence was moderate. Long-term neurodevelopmental outcomes were not reported. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (mL/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment, to prevent donor exposure, is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

To evaluate hemoglobin thresholds of elective surgical patients and blood typing policy for reducing the erythrocyte transfusion in a hospital setting

Introduction: The existing methods to quantify blood requirement in elective surgical procedure are the baseline hemoglobin (Hb) and hematocrit of patients. The risk-based scoring systems available are maximum allowable surgical blood loss and maximum surgical blood ordering schedule employ retrospective data evaluation or patient-specific variables, respectively. The aim of the present study was to evaluate a single institutional data for analyzing red blood cell (RBC) requirement among various surgical diagnoses. The study also evaluated RBC threshold for blood transfusions and efficacy of blood typing policy toward reducing unnecessary transfusions in an institution. Study Design and Methods: This study is a retrospective data evaluation from a single institution of blood transfusion patterns among elective surgical patients. Results: The blood transfusions in surgical diagnoses (n = 259) got integrated under 16 categories. The overall crossmatch-to-transfusion ratio was 1.4, average Hb before transfusion was 9.0 g/dl across the surgical categories, and average erythrocyte transfusion per patient for the various clinical diagnoses was 0.4 blood units. The effective Blood usage was 73.2% of requisitions received and blood typing was performed in 46.3% of total requisitions. Blood typing policy showed a statistically significant improvement in the blood transfusion of crossmatched units in the hospital. A per-unit reduction of blood cost in patients was also observed. Conclusions: The blood transfusion across the surgical categories showed similar Hb thresholds before transfusion. Blood typing policy improved EBU and reduced unnecessary crossmatches and transfusion costs among the patients.

Comparison of Hemoglobin Correction Effects According to Storage Period and Other Factors in the Transfusion of Packed Red Blood Cells in Neonatal Intensive Care Unit Patients

Purpose Preterm infants frequently require red blood cell (RBC) transfusions in neonatal intensive care units (NICU). Storage RBCs undergo many changes during storage periods. We aimed to compare the hemoglobin (Hb) correction effect according to the period of RBC storage and investigate the factors influencing Hb correction. Methods This retrospective study reviewed the medical records of 289 patients who received RBC transfusion more than once in the NICU of Kosin University Gospel Hospital between February 2006 and March 2016. The subjects were classified into two storage groups: short-term (≤7 days, n=88) and long-term (>7 days, n=201), according to the period of RBC storage. We checked Hb levels by complete blood cell count tests conducted within 2 days before and 5 to 9 days after the first transfusion. We compared the Hb difference between the two groups and analyzed the factors influencing Hb correction. Results Excluding the use of an invasive ventilator, there was no significant difference between the two groups in terms of clinical characteristics. There was no significant difference in the Hb correction effect between the two groups (P=0.537). Birth weight greater than 1,500 g, higher weight at transfusion, and larger volume of transfusion were significant prognostic factors affecting greater changes in Hb. In addition, surgeryexperience, higher Hb level at transfusion, and additional blood tests were found to be significantly associated with less changes in Hb. Conclusion The RBC storage period did not affect the Hb correction effect. The Hb correction effect may be diminished in infants with lower birth weight and lower weight at transfusion under unstable clinical conditions. Keywords: Premature birth; Erythrocyte aging; Erythrocyte transfusion; Newborn infant; Hemoglobins

Red Blood Cell Allo-Antibodies after Allogeneic Hematopoietic Stem Cell Transplantation

IntroductionPatients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) may require red blood cell (RBC) transfusions. AB0 blood group barrier is the clinically most important RBC group in transfusion medicine and HSCT and patients always receive AB0 compatible RBC transfusions. Some patients however develop allo-antibodies against minor RBC antigens. To date there is only limited information about the specificity, immuniser and risk factors for the development of RBC allo-antibodies. In this retrospective single centre study we aimed to identify specificities, risk factors and clinical significance of the development of RBC allo-antibodies in HSCT patients.MethodsIn this study, we examined the occurrence of RBC alloantibodies in all consecutive patients treated with allogeneic HSCT at the University Hospital Basel between 1996 and 2017 receiving RBC transfusions. RBC and PLT components were all leukocyte depleted. As of 2012, all PLT components were pathogen reduced using the Intercept Blood system. AB0 and extended RBC typing of donor/ recipient pairs, the total number of RBC transfusions and their blood group typing (AB0 and extended RBC antigen typing when available) and the detection of RBC allo-antibodies were analysed and related to clinical outcome parameters.Results1314 donor/ recipient pairs were analysed. 110 (13%) of patients developed RBC allo-antibodies, 66 patients (5%) prior to HSCT, and 103 (8%) developed the first RBC allo-antibody after HSCT. 8 patients (0.6%) with an RBC allo-antibody before HSCT developed further RBC allo-antibodies after HSCT. Most patients developed only one RBC allo-antibody but in single patients up to 6 antibodies could be detected. The median time between HSCT and the detection of the antibody was 61 days, corresponding to the phase of the most intensive immunosuppressive treatment. In 60% of the patients developing RBC allo-antibodies after HSCT, the antibody was neither directed against the stem cell donor nor the recipient. In these cases, immunization occurred most likely by RBC transfusion. Anti-Rhesus-group antibodies are the most common antibodies (57%).>10 RBC transfusions and the development of GvHD were risk factors for the development of antibodies. There was no significant difference in the occurrence of RBC allo-antibodies between donor type (related vs. unrelated), age or sex of the recipient.Only few patients showed significant haemolysis in the period of the detection of the antibody. The direct antiglobulin test (DAT) was positive in 66% of the cases. Haemolysis defined as an increase of bilirubin, LDH or reticulocytes and a haemoglobin drop of more than 10 g/l could only be reported in 6% of the cases with antibodies detected.The development of RBC allo-antibodies per se has no effect on the survival of patients (1y-survival 70±3% (without antibody) versus 68 ± 9%). However, evidence of haemolysis (even without drop of haemoglobin) in the context of allo-antibodies, is associated with significantly worse survival (1y- survival 75 ± 10% versus 42 ± 20%).ConclusionAllo-Antibodies after HSCT significantly contribute to the difficulties in transfusion management of these patients. Formation of RBC allo-antibodies is not frequent, but patients showing haemolysis after the development of an RBC allo-antibody show decreased survival. Most RBC allo-antibodies appear to be induced by RBC transfusion rather than by minor blood group mismatching between donor/ recipient pairs. DisclosuresHeim:Novartis: Research Funding.

Red Cell Alloimmunisation Is Associated with Increased Red Cell Transfusion Requirements in Myelodysplastic Syndrome

Up to 90% of MDS patients require red blood cell (RBC) transfusions. Literature addressing incidence and impact of alloimmunization in MDS is limited. We previously reported that 11% RBC-transfused MDS patients develop alloantibodies and RBC-transfusion requirement increases following alloimmunization (Singhal et al Haematologica 2017).This study aims to assess mechanism of increased RBC transfusion requirement following alloimmunization in MDS patients by comparing RBC-transfusion requirement following single and multiple alloantibodies, and impact of autoantibody on transfusion requirement.Primary MDS (PMDS), oligoblastic acute myeloid leukemia (AML) and therapy-related myeloid neoplasm (t-MN) patients enrolled in the SA-MDS registry (n=1002) between Nov 1991-Jun 2017, followed up for >3 months, received at least 1 unit of RBC and did not develop alloantibodies before first RBC transfusion were selected for analysis. Cumulative incidence (CI) of RBC-alloimmunization and clinical impact of alloimmunization including autoantibody formation and change in RBC-transfusion requirements was assessed. We also assessed risk factors for alloimmunization using recursive partitioning and Cox-regression.Seven hundred and sixty-two patients (76%) were eligible for analysis; 584 (76.5%) PMDS, 56 (7.3%) oligoblastic AML and 123 (16%) were t-MN. The median age was 72 years (range 18-97) and 489 (64%) were males. According to the Revised International Prognostic Scoring System (IPSS-R), 44.9% and 54.9% patients were classified as IPSS-R Very low/Low risk and Intermediate/High/Very high risk, respectively. The CI of alloimmunization in RBC-transfused patients was 15% (Fig 1A) and alloantibodies were most commonly against K (32%), E (26%), C (18%), Jka (10%) & Duffy (3%) antigens. Interestingly, 53% (53/99) of alloimmunized patients had single alloantibody while 46% (46/99) had multiple alloantibodies detected simultaneously or subsequently.RBC requirement was significantly higher in alloimmunized compared to non-alloimmunized patients (80±95 vs 41±58, p<0.0001; Fig 1B). This difference is unlikely due to difference in overall survival (OS) as median OS of the two groups was not significantly different (27.5 vs 33.7 months; p=0.2). Importantly, RBC requirement of alloimmunized patients significantly increased after alloantibody formation (22±38 vs 57±82, p<0.0001; Fig 1C). This increase is unlikely to be due to difference in follow-up period before and after alloimmunization (12.3 vs 10.7 months; p=0.9).RBC transfusion requirement increased following single (24±44 vs 49±91; p=0.005; Fig 1D) and multiple (21±31 vs 67±70; p<0.0001; Fig 1E) alloantibody formation. RBC requirement prior to alloimmunization was not significantly different between patients with single and multiple alloantibodies (24±44 vs 21±31; p=0.9); however following alloimmunization, it was higher in patients with multiple alloantibodies compared to single alloantibody (49±91 vs 67±70; p=0.06).Increase in RBC requirement following alloimmunization could partly be due to autoantibody formation.The 12-month CI of autoantibody formation was significantly higher in alloimmunized patients compared to non-alloimmunized (31 vs 1.7%; p<0.0001; Fig 1F) and 26% of autoantibodies were detected within 3 months of alloimmunization indicating temporal relation between alloimmunization and autoantibody formation. Within alloimmunized patients, more patients with multiple alloantibodies developed autoantibodies as compared to patients with single alloantibody (67% vs 31%; p<0.001). We then compared impact of autoantibodies on RBC transfusion requirements. Baseline RBC requirement in alloimmunized patients with and without autoantibodies was not significantly different (25.4±34.6 vs 20.4±41.5; p=0.2). However, RBC transfusion requirement following alloimmunization was significantly higher in patients developing autoantibodies compared to patients without autoantibodies (82.51±110 vs 35.61±35.93; p=0.003).In our large cohort of 1002 patients, 15% of RBC transfused patients develop alloantibodies, most commonly against Rh and Kell. The RBC transfusion requirement increases after alloimmunization, most probably due to formation of multiple subsequent alloantibodies and autoantibodies. Hence, we recommend extended phenotype matched RBC transfusion to MDS patients. [Display omitted] DisclosuresRoss:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Hiwase:Celgene: Research Funding; Novartis: Research Funding.

The Medalist Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions

The Medalist Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions

Characteristics and Outcome of DAT-Negative Autoimmune Hemolytic Anemia: Results from a French Multicentre Observational Study

IntroductionThe direct antiglobin test (DAT) is a highly sensitive method (92 to 97%) for the diagnosis of autoimmune hemolytic anemia (AIHA). The diagnosis of DAT-negative AIHA (DN-AIHA) is one of exclusion but the definition of DN-AIHA is not consensual and guidelines on the minimal set of tests that should be performed to rule out other causes of hemolysis are lacking. In this study, we report the baseline characteristics and outcome of a series of both adult and pediatric cases of presumed DN-AIHA based on pre-defined diagnostic criteria. The main characteristics of adult' DN-AIHAs have also been compared with those of adult patients with a DAT positive warm AIHA (wAIHA).MethodsPatients aged ≥ 5 years with presumed AIHA and negative DAT test performed with an anti- IgG, anti-C3, anti-IgM and an anti-IgA by column agglutination method were retrospectively recruited in France throughout the network of the French national referral center for adult' immune cytopenias and the screening of DAT results in 2 referral laboratories from the French Blood Centre.DN-AIHA cases were defined as highly probable (negative extensive work-up) or probable (negative minimal work-up but underlying compatible context, see Figure). Response to therapy was defined as complete (CR, hemoglobin (Hb) ≥ 120 g/L and no features of active hemolysis), or partial (PR, Hb ≥ 100 g/L, with an increase of at least 20 g/L from baseline and persistent hemolysis) in the absence of any recent transfusion. Adults with primary DN-AIHA (i.e, the cases) were compared to wAIHA controls recruited from the database of the national referral center (matched on age and gender) in a 1 to 2 ratio. Mann-Whitney and Fisher exact tests were used for the comparisons.ResultsIn total, 23 adults (median age 61 years [range 19-86]) and 7 children (15 years [7-17]) with a male/female ratio of 1.5, diagnosed between 2003 and 2018, were included. All of them fulfilled the pre-defined inclusion criteria (18 highly probable, 12 probable DN-AIHA).Most DN-AIHA (57%) were secondary and associated to an underlying disease including: a clonal lymphoproliferative disorder (n=9), a myelomonocytic leukemia (n=2), a viral infection (n=3), an ulcerative colitis (n=1), a primary immune deficiency (n=1), an antiphospholipid syndrome (n=1). DN-AIHA was associated with another immune cytopenia in 4 patients (immune thrombocytopenia in 3).At diagnosis, the median hemoglobin level was 71 g/L [28-96], the reticulocyte count 221 G/L [79-500], the total bilirubin 51 µmol/L [8-221], the LDH 1.6 times the normal level [1-6]. Hemoglobinuria was reported in 8 patients. Spherocytes and red blood cell aggregates were observed on the blood film in respectively 9 and 2 patients. Most patients (83%) required red blood cell (RBC) transfusion and received a total of 8 [1-70] RBC packed units, and up to 5 [1-39] per month.Twenty eight patients (93%) received corticosteroids. The overall initial response rate was 82% (CR in 25%, PR in 57%) but a relapse occurred at tapering in 65% (at a median daily dose of 15 [10-40] mg of prednisone). A second-line treatment was required in 62% including: rituximab (n=17, R in 33%), immunosuppressors (n=4), splenectomy (n=3, CR in 2), treatment of associated clonal disorder (n=3; polychemotherapy, azacitidine, ibrutinib; R in 100%). After a median follow-up of 54 weeks, 10% of patients had died due to progression of malignancy (n=2) or infection (n=1), whereas 30% were in complete remission.The baseline biological parameters, the overall response to corticosteroids did not differ significantly between adult with primary DN (n=10) and wAIHA (n=20). However, patients suffering from DN-AIHA required more RBC packed units than DAT-positive wAIHA (p<0.05).DiscussionDN-AIHA is a rare condition that remains a diagnostic challenge since it requires an extensive negative work-up to rule out any other cause of congenital or acquired hemolytic anemia. Next Generation Sequencing analyses are now increasingly used to detect the presence of relevant variants and somatic mutations and may be helpful to sort out some previously unexplained hemolytic anemia. Consensual definition criteria for DN-AIHA are needed to avoid misdiagnosis and the use of inappropriate therapies. The management of DN-AIHA is not standardized and mostly extrapolated from the one of wAIHA. Steroids, splenectomy and/or the treatment of an underlying disease may lead to a complete and durable remission. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effects of tranexamic acid on short-term and long-term outcomes of on-pump coronary artery bypass grafting: Randomized trial and 7-year follow-up.

Safety evaluations of tranexamic acid (TXA) remain sparse, especially with respect to its impact on long-term outcomes in patients undergoing on-pump coronary artery bypass grafting (CABG). We hypothesized that the effects of TXA on perioperative bleeding and allogeneic transfusion and its impact on long-term clinical outcomes of patients receiving on-pump CABG are superior to those in the control group. In this prospective, randomized, placebo-controlled trial, 210 patients undergoing primary and isolated on-pump CABG were randomly assigned to receive TXA or a corresponding volume of saline solution. Randomly assigned patients were followed up at 1, 3, 5, and 7years after hospital discharge. Finally, 163 patients fulfilled the 7-year follow-up. The primary outcome was allogeneic red blood cell (RBC) transfusion. Long-term mortality and morbidity were also evaluated. Compared with placebo, TXA reduced the allogeneic RBC requirement in terms of the volume transfused (4.20±4.06 vs 6.25±4.86units; P<0.01), ratio exposed (52.0% vs 71.6%; P<0.01), and blood loss volume (879.0±392.5 vs 1154.0±582.8mL; P<0.01). Except for myocardial infarction, there were no significant differences in mortality or morbidity between the two groups during the 7-year follow-up. The TXA group had a lower rate of myocardial infarction than did the placebo group (0.0% vs 4.9% at 84months; P=0.03). Tranexamic acid significantly decreased postoperative bleeding and allogeneic transfusion in patients undergoing on-pump CABG. The 7-year follow-up suggested that the use of TXA was safe and might play a potential role in the prevention of long-term myocardial infarction.

Effect of preoperative warming on intraoperative hypothermia: a randomized-controlled trial.

The purpose of this study was to evaluate the effects of preoperative forced-air warming on intraoperative hypothermia. In this randomized-controlled trial, adult patients scheduled for elective, non-cardiac surgery under general anesthesia were stratified by scheduled surgical duration (< 2.5 hr or ≥ 2.5 hr) and then randomized to a pre-warming group using a BairPaws™ forced-air warming system for at least 30 min preoperatively or to a control group with warmed blankets on request. All patients were warmed intraoperatively via convective forced-air warming blankets. Perioperative temperature was measured using the SpotOn™ temperature system consisting of a single-use disposable sensor applied to the participant's forehead. The primary outcome was the magnitude of intraoperative hypothermia calculated as the area under the time-temperature curve for core temperatures < 36°C between induction of general anesthesia and leaving the operating room. Secondary outcomes included surgical site infections, packed red blood cell requirements, and 24 hr postoperative opioid consumption. Two hundred participants were analyzed (101 control; 99 pre-warmed). Pre-warmed participants had a lower median [interquartile range] magnitude of hypothermia than controls (0.00 [0.00-0.12] °C·hr-1 vs 0.05 [0.00-0.36] °C·hr-1, respectively; median difference, -0.01°C·hr-1; 95% confidence interval, -0.04 to 0.00°C·hr-1; P = 0.005). There were no between-group differences in the secondary outcomes. A minimum of 30 min of preoperative forced-air convective warming decreased the overall intraoperative hypothermic exposure. While redistribution hypothermia still occurs despite pre- and intraoperative forced-air warming, their combined application results in greater preservation of intraoperative normothermia compared with intraoperative forced-air warming alone. www.clinicaltrials.gov (NCT02177903). Registered 25 June 2014.

Post-operative stress hyperglycemia is a predictor of mortality in liver transplantation

BackgroundA significant association is known between increased glycaemic variability and mortality in critical patients. To ascertain whether glycaemic profiles during the first week after liver transplantation might be associated with long-term mortality in these patients, by analysing whether diabetic status modified this relationship.MethodObservational long-term survival study includes 642 subjects undergoing liver transplantation from July 1994 to July 2011. Glucose profiles, units of insulin and all variables with influence on mortality are analysed using joint modelling techniques.ResultsPatients registered a survival rate of 85% at 1 year and 65% at 10 years, without differences in mortality between patients with and without diabetes. In glucose profiles, however, differences were observed between patients with and without diabetes: patients with diabetes registered lower baseline glucose values, which gradually rose until reaching a peak on days 2–3 and then subsequently declined, diabetic subjects started from higher values which gradually decreased across the first week. Patients with diabetes showed an association between mortality and age, Model for End-Stage Liver Disease score (MELD) score and hepatitis C virus; among non-diabetic patients, mortality was associated with age, body mass index, malignant aetiology, red blood cell requirements and parenteral nutrition. Glucose profiles were observed to be statistically associated with mortality among patients without diabetes (P = 0.022) but not among patients who presented with diabetes prior to transplantation (P = 0.689).ConclusionsGlucose profiles during the first week after liver transplantation are different in patients with and without diabetes. While glucose profiles are associated with long-term mortality in patients without diabetes, after adjusting for potential confounding variables such as age, cause of transplantation, MELD, nutrition, immunosuppressive drugs, and units of insulin administered, this does not occur among patients with diabetes.

Treatment strategy for acquired aplastic anemia

"The guidelines for the diagnosis and treatment of aplastic anemia (AA) in Japan" have recently been revised. Former stage 2 has been divided into stage 2a, which does not require red blood cell (RBC) transfusions, and stage 2b, which requires <2 units of RBC transfusions per month. In addition, the guidelines recommend treating stage 2b similar to stages 3 or higher severity. The standard immunosuppressive therapy for transfusion-dependent AA has been changed from ATG plus cyclosporine (CsA) to ATG+CsA+eltrombopag. For patients with stage 1 and stage 2b AA, initiating CsA as early as possible after the diagnosis is recommended. Notably, high-dose (200 mg/kg) cyclophosphamide (CY), which has been used as the standard conditioning regimen for allogeneic stem cell transplantation (SCT), is less frequently used than a reduced-dose CY regimen that contains fludarabine for avoiding cardiotoxicity. Among transplant regimens from alternative donors, HLA-haploidentical SCT from related donors using post-transplant CY is presently garnering recognition because of its low transplant-related mortality and the low incidence of chronic GVHD.

Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial

Myelodysplastic syndromes are characterised by ineffective erythropoiesis leading to anaemia. Sotatercept (ACE-011) is a novel activin receptor type IIA fusion protein that acts as a ligand trap to neutralise negative regulators of late-stage erythropoiesis. The aim of the study was to establish a safe and effective dose of sotatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes. This open-label, multicentre, dose-ranging, phase 2 trial took place at 11 treatment centres in the USA and France. Eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low-risk or intermediate-1-risk myelodysplastic syndromes, had anaemia requiring red blood cell (RBC) transfusions, and were ineligible for, or refractory to, erythropoiesis-stimulating agents (ESAs). Patients were not eligible if they had chromosome 5q deletion myelodysplastic syndromes without documented failure of lenalidomide. Patients were randomly assigned to receive either 0·1 or 0·3 mg/kg sotatercept subcutaneously, using a permuted-block method with stratification for serum erythropoietin concentration and transfusion burden. Patients were assigned to 0·5, 1·0, and 2·0 mg/kg groups in a non-randomised fashion. The primary efficacy endpoint was the proportion of patients who achieved haematological improvement-erythroid (HI-E), according to International Working Group 2006 criteria. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT01736683 and at EU Clinical Trials Register, number 2012-002601-22, and is ongoing. Between Dec 5, 2012, and July 22, 2015, 74 patients were enrolled into the study (seven to receive 0·1 mg/kg sotatercept, six to 0·3 mg/kg, 21 to 0·5 mg/kg, 35 to 1·0 mg/kg, and five to 2·0 mg/kg). 36 (49%; 95% CI 38-60) of 74 patients achieved HI-E; 29 (47%; 95% CI 35-59) of 62 patients with a high transfusion burden achieved HI-E (RBC-transfusion reduction from baseline of 4 or more units for at least 56 days), and seven (58%; 95% CI 32-81) of 12 patients with a low transfusion burden achieved HI-E (haemoglobin increase of 1·5 g/dL or more sustained for at least 56 days in the absence of transfusions). The most commonly reported adverse events were fatigue in 19 (26%) of 74 patients and peripheral oedema in 18 (24%) of 74 patients. Grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 25 (34%) of 74 patients; four (5%) patients had grade 3-4 TEAEs that were considered to be treatment related. The most common grade 3-4 TEAEs were lipase increase and anaemia, which each occurred in three (4%) of 74 patients. 17 (23%) of 74 patients had at least one serious TEAE, and one patient died from a treatment-emergent subdural haematoma due to a fall. Sotatercept, a novel activin-receptor fusion protein, was well tolerated and effective for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes in whom previous ESA treatment had failed. Treatment with sotatercept could be beneficial for these patients who have few available treatment options. Celgene Corporation.

Darbepoetin Alfa for the Treatment of Anemic Patients with Myelodysplastic Syndrome: A Belgian Single-Arm, Companion Trial to the Arcade Phase 3 Study

Darbepoetin Alfa for the Treatment of Anemic Patients with Myelodysplastic Syndrome: A Belgian Single-Arm, Companion Trial to the Arcade Phase 3 Study

Efficacy of Lenalidomide in Myelodysplastic/Myeloproliferative Neoplasms with Ring Sideroblasts

Background: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) with ring sideroblasts and thrombosis (MDS/MPN-RS-T), include the dysplastic features of Refractory Anemia with Ring Sideroblasts (RARS) and the myeloproliferative features of essential thrombocythemia (ET) and are characterized by a high rate (50%) of JAK2 V617F mutations or rarely by the presence of mutations in exon 10 of the MPL (myeloproliferative leukemia) gene or in exon 9 of the calreticulin gene. We previously demonstrated that RARS-T differed from RARS and ET from a clinical, biological and prognostic point of view and that the presence of high rates of splicing factor 3B subunit 1 (SF3B1) mutations in RARS-T and the absence of these mutations in ET strengthened the hypothesis that RARS-T was a distinct entity. We also reported in a large series of patients (n=200) that the risk of thrombosis was higher in RARS-T than in RARS patients without a high platelet count, leading clinicians to reduce the platelet count in almost 33% of RARS-T patients. However, due to the presence of anemia, the use of the cytoreductive agents usually used in ET is limited since they worsen the cytopenia. This explains why it is difficult to treat patients who harbor both anemia and thrombocytosis. Lenalidomide, an immunomodulatory agent frequently used in low-risk MDS, has very rarely been tested in MDS/MPN-RS-T patients, with conflicting results. Objective : To test the effect of Lenalidomide on MDS/MPN-RS-T Patients: Here, we report our experience using lenalidomide in two women who presented with JAK2 V617F negative MDS/MPN-RS-T. Results: The first patient was a 78 year-old woman, with a complete blood count (CBC) showing hemoglobin 80 g/L, platelet count 686 G/L and leukocytes 6 G/L. The second was a 58 year-old woman whom initial CBC showed hemoglobin 113 g/L, platelet count 1,600 G/L, leukocytes 8.2 G/L. In both cases the bone marrow aspirates showed erythroid hyperplasia with myelodysplasic features and 64% and 24% of ring sideroblasts respectively, associated with marked dysmegakaryopoiesis, leading to the diagnosis of MDS/MPN-RS-T. No excess of blast cells was noted. Bone marrow cytogenetics showed in both cases a normal 46XX karyotype. A Lys700Glu SF3B1 mutation was noted for one patient (not tested for the second), without the JAK2 V617F or MPL exon10 or CALR mutations. In the first patient, blood transfusions were initiated for one year, however, due to an increase in dependence on red blood cell transfusions, treatment with lenalidomide (5 mg daily 21/28days) was started and led to a decrease in the platelet count from 686 to 220 G/L associated with an regular improvement in hemoglobin levels from 80 to 100 g/L within the first 28 weeks of lenalidomide (only 6 units of red blood cells were transfused along this period). Finally, no transfusion was required in the subsequent 47 weeks since the hemoglobin level was above 90 g/L. However, due to a low hemoglobin level, red blood cell transfusions were reinitiated, but with a lower frequency (2 units of red blood cells every 2 months), in association with lenalidomide. Altogether, over the 20 months of treatment with lenalidomide, the red blood cell requirement was drastically reduced. However, grade IV neutropenia was observed (granulocytes 0.5 G/L) but without any infectious disease, leading to stop the treatment. In the second patient, a watch-and-wait strategy was initiated, but due to an increase in the platelet count > 2,000 G/L, hydroxyurea (500 mg/day) was started, worsening the anemia to 108 g/l then 84 g/l leading to the use of erythropoietin once/week. Hydroxyurea was then stopped due to its adverse effects on hemoglobin, leading to the increase in the platelet count to 3,622 G/L. A treatment with lenalidomide (5 mg daily 21/28days) was then started and secondarily improved to 10 mg daily 21/28days since very well tolerated. A marked decrease in the platelet count was noted, from 3,622 to 985 G/L whereas hemoglobin level rised up from 92 to 115 g/L. Off note, for this patient erythropoietin treatment was maintained every 2 weeks in combination with lenalidomide. Conclusion: This two-cases experience confirms the partial efficacy of lenalidomide in MDS/MPN-RS-T in normalizing (case 1) or markedly reducing (case 2) the platelet count and allowing of independence from blood transfusion (at least for 10 months in case 1). Disclosures No relevant conflicts of interest to declare.

A novel association between high red blood cell alloimmunization rates and hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder associated with multiple arteriovenous malformations. HHT patients may require red blood cell (RBC) transfusion due to spontaneous hemorrhage or surgical bleeding. Because HHT-associated hemorrhage often occurs in submucosa we hypothesized that RBC alloimmunization rates in HHT patients may be higher than those observed in other transfused patients and investigated this in a retrospective study. Eighty-five patients with HHT who were transfused at our tertiary care facility were identified. A group of randomly selected, chronically transfused patients without HHT were used as controls (n = 207). RBC transfusion and alloantibody data were extracted from medical records. Alloimmunization rates among patients with HHT were significantly higher than those of controls (15.29% vs. 2.42%; p < 0.001), while HHT patients received fewer RBC transfusions at our institution compared to controls (4.27 units vs. 8.84 units; p < 0.0001). Anti-E, -K, and -c were the three most common alloantibodies identified in HHT patients. There was a trend for HHT patients to make more antibodies per alloimmunized patient than controls (2.38 alloantibodies vs. 1.60 alloantibodies), although this difference was not significant (p = 0.37). To our knowledge, this is the first study to evaluate RBC alloimmunization rates in patients with HHT. It is unclear whether the high alloimmunization rates observed are due to lifetime transfusion burden, underlying disease pathophysiology, or other variables. Additional studies are needed to evaluate the generalizability of our findings to other HHT populations and to consider the utility of prophylactic antigen matching for C/E/K.

Assessment of rotational thromboelastometry for the prediction of red blood cell requirements in orthotopic liver transplantation.

In liver transplantation most studies were designed to predict massive transfusion rather than whether or not transfusion is required. We hypothesized that (presurgery) data from thromboelastometry may predict perioperative blood requirements. A post-hoc analysis of data from a controlled trial was performed with the primary end point of predicting zero red blood cells. Of the 92 patients studied, 6 were excluded because of incomplete EXTEM and/or FIBTEM data. The multivariate models included preoperative variables with a P value <0.10 in the univariate model: age, MELD score, hemoglobin, plasma fibrinogen, platelet count, activated partial thromboplastin time, INR, EXTEM maximum clot amplitude after 10 minutes, EXTEM an FIBTEM maximum clot firmness, plasma creatinine, and donor data. Blood was transfused to 58% of patients during the surgical procedure and to 34% in the first 24 hours postoperatively. The final model was selected using a backward approach, and fractional polynomials were explored to assess model improvement for the prediction. Hemoglobin was a strong predictor: each 1 g/dL of hemoglobin increase reduced the risk of blood transfusion by 52%. An EXTEM maximum amplitude at 10 min was also a predictor of Red Blood requirement, showing a 64% risk reduction for values between the first quartile (35 mm) and the second quartile (41 mm) but no further improvement for the third and fourth quartiles and resulting in a prediction (ROC AUC of 0.815 [0.771-0.859]). Presurgical EXTEM maximum amplitude at 10 min <35 mm is highly predictive of red blood administration during liver transplantation.

Prophylactic Plasma Transfusion Is Not Associated With Decreased Red Blood Cell Requirements in Critically Ill Patients.

Critically ill patients frequently receive plasma transfusion under the assumptions that abnormal coagulation test results confer increased risk of bleeding and that plasma transfusion will decrease this risk. However, the effect of prophylactic plasma transfusion remains poorly understood. The objective of this study was to determine the relationship between prophylactic plasma transfusion and bleeding complications in critically ill patients. This is a retrospective cohort study of adults admitted to the intensive care unit (ICU) at a single academic institution between January 1, 2009 and December 31, 2013. Inclusion criteria included age ≥18 years and an international normalized ratio measured during ICU admission. Multivariable propensity-matched analyses were used to evaluate associations between prophylactic plasma transfusion and outcomes of interest with a primary outcome of red blood cell transfusion in the ensuing 24 hours and secondary outcomes of hospital- and ICU-free days and mortality within 30 days of ICU discharge. A total of 27,561 patients were included in the investigation with 2472 (9.0%) receiving plasma therapy and 1105 (44.7%) for which plasma transfusion was prophylactic in nature. In multivariable propensity-matched analyses, patients receiving plasma had higher rates of red blood cell transfusion (odds ratio: 4.3 [95% confidence interval: 3.3-5.7], P < .001) and fewer hospital-free days (estimated % increase: -11.0% [95% confidence interval: -11.4, -10.6%], P < .001). There were no significant differences in ICU-free days or mortality. These findings appeared robust, persisting in multiple predefined sensitivity analyses. Prophylactic administration of plasma in the critically ill was not associated with improved clinical outcomes. Further investigation examining the utility of plasma transfusion in this population is warranted.

Preprocedural platelet transfusion for patients with thrombocytopenia undergoing interventional radiology procedures is not associated with reduced bleeding complications.

Platelet (PLT) transfusion before interventional radiology procedures is commonly performed in patients with thrombocytopenia. However, it is unclear if PLT transfusion is associated with reduced bleeding complications. This is a retrospective cohort study of adults undergoing interventional radiology procedures between January 1, 2009, and December 31, 2013. Baseline characteristics, coagulation variables, transfusion requirements, and procedural details were evaluated. Propensity-matched analyses were used to assess relationships between PLT transfusions and the outcomes of interest, including a primary outcome of periprocedural red blood cell (RBC) transfusion during the procedure or within the first 24 hours after procedure. A total of 18,204 participants met inclusion criteria, and 2060 (11.3%) had a PLT count of not more than 100×109 /L before their procedure. Of these, 203 patients (9.9) received preprocedural PLTs. There was no significant difference in RBC requirements between those receiving or not receiving preprocedural PLTs in propensity-matched analysis (odds ratio [OR],1.45; 95% confidence interval [CI], 0.95-2.21; p=0.085). PLT transfusion was associated with increased rates of intensive care unit admission (OR [95% CI],1.57 [1.07-2.32]; p=0.022). In patients with thrombocytopenia undergoing interventional radiology procedures, preprocedural PLT transfusion was not associated with reduced periprocedural RBC requirements. These findings suggest that prophylactic PLT transfusions are not warranted in nonbleeding patients with preprocedural PLT counts exceeding 50×109 /L. Future clinical trials are needed to further define relationships between prophylactic PLT administration and bleeding complications, especially at more severe levels of thrombocytopenia or in the presence of PLT dysfunction.