Transfusion-related Complications Research Articles

Transfusion Requirements in Anesthesia and Intensive Care

Allogeneic blood products are commonly used in perioperative and critically ill patients. This review focuses on the current evidence and emerging data relating to modern transfusion strategies in these patients. Several large randomized trials and meta-analyses found no inferiority of a restrictive strategy as compared to a liberal one in red blood cell (RBC) transfusion. The storage duration of transfused RBC seems to have a minor, if any, impact on patients’ outcome. However, patients requiring massive transfusions might be an exception. The indications and benefits of plasma and platelets transfusions are less clear because robust clinical evidence is missing. In contrast to the established evidence and practice for RBC transfusion, the limited evidence for plasma and platelets transfusions call for incorporating expert opinions and guidelines and for standardized local practice. Targeted hemostatic interventions are preferred over prophylactic fixed-ratio transfusions in terms of efficacy and avoidance of transfusion-related complications.

Red Blood Cell Transfusion Thresholds in Critically Ill Patients.

ABSTRACTAnemia of multifactorial etiology is common among critically ill patients and several arbitrary transfusion thresholds have been proposed. Transfusion of red blood cells has been well established to increase morbidity and even mortality among critically ill patients. Several randomized controlled studies have evaluated the use of a restrictive compared to a more liberal transfusion strategy in the critically ill. A transfusion threshold of 7 g/dL appears to be generally safe, especially in the younger age group without significant comorbidities. Besides, a restrictive transfusion strategy reduces the incidence of transfusion-related complications. However, the decision to transfuse needs to be individualized depending on the clinical situation, balancing putative benefits against possible complications.How to cite this articleChacko J, Brar G. Red Blood Cell Transfusion Thresholds in Critically Ill Patients. Indian J Crit Care Med 2019;23(Suppl 3):S181–S184.

Impact of Red Blood Cell Transfusions on Height and Growth of Adolescents with Sickle Cell Disease & Short Stature

BACKGROUND:Children with sickle cell disease (SCD) commonly have delayed or impaired growth. There are no clear guidelines as how to manage these patients. Current evidence suggests that children who are treated long term with red blood cell (RBC) transfusions (simple red cell or exchange transfusions) for different SCD related complications, achieve better height and growth, although, it is not clear when to start such treatment for the maximum benefit. Timing of such treatment(s) may be critical as to achieve optimum height and growth. Children with SCD who are started transfusion therapy before the age of 14 years, may achieve better height velocity. However, some children may present late during adolescence and whether to adopt measures like regular blood transfusions to improve their growth, remains challenging. We treated adolescents with SCD and delayed growth with regular RBC transfusions and observed the effect on their growth. The major concern of the parents was short stature, and our aim was achievement of better height.Methods:Adolescent patients with SCD being followed at our department, who were observed to have short stature or were referred to us for this problem and received RBC transfusion therapy to improve their growth, were included in this study. They were started on regular RBC transfusions after thorough counseling (parents and patients). They were informed of the likely benefits and possible side effects including usual transfusion related adverse events and particularly the likelihood of iron overload and possible need for iron chelation therapy in future.A chart review was performed recording weight, height, and body mass index (BMI) measurements, timing and length of transfusion therapy along with laboratory parameters. When iron overload (defined as a serum ferritin ≥ 1000 µgm/l) developed, it was treated with deferasirox at an average dose of 20-30mg/kg body weight. RBC transfusions were continued for 3-6 months after achieving the maximum height (plateau phase).Patients were either already receiving hydroxyurea (HU) or were started at the beginning of transfusion therapy. The average dose of HU was 500 mg daily (20mg/kg body weight) at the start of transfusion therapy in all patients and was increased according to the weight gain. Two patients also received growth hormone for a short period.RESULTS:Six patients received RBC transfusion therapy for short stature (5 males). Median age at start of therapy was 15.5 years (range 13.9 -17.4). Patients were treated for a median duration of 32 months (range 23-53). One (female) patient continues to have ongoing transfusions as she has not achieved the maximum height. Median height at start of therapy was 137.25 cm and 152.25 cm at the end of therapy. Pre-therapy median weight was 28 kg and post therapy 38.2 kg. Median increase in height was 16.25 cm (p < 0.025) and median increase in weight 10.15 kg (p=0.007). BMI measurements showed improvement in 5 patients but the increase was modest, likely due to better height gain as compared to weight gain.Five patients received regular RBC transfusions while one patient received exchange transfusions after one year of simple transfusions because of high base line Hb. Four patients were already receiving HU for one year or more, while 2 patients started HU shortly after commencing transfusion therapy.There were no significant SCD related or transfusion related complications during transfusion therapy but all patients developed iron overload and received chelation therapy. However, 3 patients had s/ferritin around or above 1000 µgm/l at the base line. Mean pre-transfusion s/ferritin was 901 µgm/l and 2304 µgm/l at the end of transfusion therapy.CONCLUSIONS:RBC transfusion therapy improved height of all patients with SCD & short stature, even if started during late adolescence. However, the improvement was variable. There were no significant adverse events except iron overload, which developed in all patients and required chelation therapy. RBC Transfusion therapy should be considered in adolescent children with SCD and short stature, even if they present during late adolescence. RBC exchange therapy may be an alternative option to reduce the complication of iron overload and should be explored in further studies. DisclosuresNo relevant conflicts of interest to declare.

Safety and Efficacy of Non-Irradiated Granulocyte Transfusions (GTX) in Neutropenic Patients with Severe or Refractory Abdominal Infections: A Single Center Retrospective Analysis of 119 Transfusions in 22 Patients

Safety and Efficacy of Non-Irradiated Granulocyte Transfusions (GTX) in Neutropenic Patients with Severe or Refractory Abdominal Infections: A Single Center Retrospective Analysis of 119 Transfusions in 22 Patients

Iron Reduction Therapy in Ex-Thalassemics - Long Term Outcome

Introduction: After successful allogeneic hematopoetic stem cell transplantation (aHSCT) for thalassemia major (TM), these “ex-thalassemics” require effective management of pre-existing transfusion related complications. Reduction of iron overload which is prevalent in almost all of these patients is one of the major goals of this therapy. Even though several thousand aHSCTs have been done for TM, there is very limited data on the approach to iron reduction therapy (IRT) and its outcome. We report the outcome of IRT in the largest cohort of ex-thalassemics to be reported so far.Patients & Methods: Patients with TM who had aHSCT between January 2001 and December 2012, and who had IRT (phlebotomy and / or iron chelation - deferoxamine / deferasirox) with at least 3 years follow-up were included in this analysis. The major determinants for initiation of IRT were a stable graft and no other ongoing long term complications such as graft vs host disease or infections. The type of IRT advised depended on the baseline haemoglobin (>10.5g/dl), ease of venous access, level of serum ferritin as well patient / family preferences. Reduction in serum ferritin level was calculated as a function of time.Results: Out of 281 aHSCT for TM during this period, 213 (75.8%) were successful. 149(70.0%) of these could be included in this analysis as per the criteria mentioned above. The median age was 7 years (range:1-18) and 92(61.7%) belonged to Pesaro class 3. Median ferritin at aHSCT was 2480ng/ml (range:866-8921). IRT was reinitiated at a median of 15 months (range:5-53) post aHSCT. 10 patients (6.8%) with a median serum ferritin at aHSCT of 2010ng/ml (range:1216-2830)were treated with phlebotomy alone, while 61(40.9%) with a median serum ferritin at aHSCTof 2161ng/ml (range:1341-7660) received chelation alone and 78 (52.3%) with a median serum ferritin at aHSCT of 2806ng/ml (range:866-8921) were treated with the combination. Reduction in serum ferritin/month [absolute quantity (ng/ml/month)was significantly higher in those who received combination therapy: 87(range:33-195), 129 (range:17-1011) and 147 (range:27-1427) in the phlebotomy, chelation and combination therapy groups, respectively (p=0.031).With a median follow up of 80 months (range:37-182), target ferritin level of less than 300ng/ml was achieved in 59 patients (40%), in a median duration of 41 months (range:3-136) and less than 500ng/ml was achieved in 88 patients (59%) in a median duration of 41 months (range:3-136). (Fig 1a) No significant toxicities related to IRT were noted in this cohort. Comparison of the characteristics of patients who achieved the target ferritin of <500ng/ml] versus those with ongoing IRT [ferritin >500ng/ml) are shown in the table. Patients in class III risk category and starting serum ferritin levels >2500 ng/ml had delayed responses to IRT and required much longer to reach target levels. (Fig 1b) Delay in initiation of IRT, intensity of the protocol and compliance with IRT also affected outcome.Conclusion: Our data shows that IRT ex-thalassemics needs careful attention as soon as possible after aHSCT with the goal of rapid reduction to target levels. A combination of phlebotomy and iron chelators work faster in reducing iron overload. More data is needed to develop the optimal protocols for IRT in ex-thalassemics. DisclosuresNo relevant conflicts of interest to declare.

Minimising Transfusion Therapy and Alloimmunisation in Patients with Sickle Cell Disorder in the Era of Hydroxyurea

In the UK, 700 patients with sickle cell disease are on a transfusion programme1. Red blood cell (RBC) AI occurs in 4.4-76%2 of regularly transfused sickle patients. Contributing factors include repeated transfusions and ethnic differences between sickle cell patients and their donors. This results in higher rates of mismatch in phenotyped and genotyped blood. There is a continued lack of availability of blood products from more compatible ethnic donors.Sickle patients on transfusion programmes are transfused every 3-6 weeks, creating a large burden on healthcare services in terms of time, labour and resources such as extended red cell typing in order to reduce antibody formation. The presence of RBC antibodies in patients can cause significant delays in obtaining cross matched blood and reductions in phenotype matched blood being transfused.The aims of this project were to a) review transfusion use in relation to the use of hydroxyurea (HU) patients treated at Alder Hey (AH) and b) review rates of AI in these patients. At AH we have changed our practice to offer HU from age 9 months as a disease modifying therapy 20-35mg/kg/day.We retrospectively reviewed the use of blood products in our cohort of 60 patients, age between 0-20 years (mean 11yrs). Patients were observed over their life period treated at AH, mean 10.1 patient years, range 0-20years, total of 439 patient years. We studied retrospectively the number of RBC transfusions and the historical presence of antibodies. We then re-tested all patients to determine current antibody status.Prior to commencement of hydroxyurea, 342 units of bloods were transfused to 21 patients over 243 patient years, which is 1.41 units per patient per year.After commencement of hydroxyurea, 114.5 units were transfused to 17 patients in 187.1 patient years, 0.61 units per patient per year.Indications for transfusion included acute chest syndrome, aplastic crisis, prolonged crisis, increased acute anaemia, hydroxyurea induced anaemia, pre-operatively.3 patients in our cohort had previous antibodies. Upon repeat antibody screening, no patients had detectable RBC antibodies.All patients have an extended red cell phenotype as part of their initial workup on referral to our service. Elective, non-acute patients (transfusion programme, pre-operative, hydroxycarbamide induced anaemia) all receive fully phenotyped blood. This cannot be guaranteed in acute situations where patients receive the best matched blood available.This practice of minimising blood transfusion use in patients with sickle cell anaemia can reduce blood product usage and as a result reduce the demand for ethnic minority transfusion donors. The subsequent donor exposure would therefore also decrease transfusion related complication of AI.1 National Haemoglobinopathy Registry Annual Report 2016/172G. da Cunha Gomes, E & A. F. Machado, L & C. de Oliveira, L & F. N. Neto, J. (2018). The erythrocyte alloimmunisation in patients with sickle cell anaemia: a systematic review: Erythrocyte alloimmunisation in sickle cell anaemia. Transfusion Medicine. 10.1111/tme.12543. DisclosuresNo relevant conflicts of interest to declare.

Incidence and Epidemiology of Perioperative Transfusion-Related Pulmonary Complications in Pediatric Noncardiac Surgical Patients: A Single-Center, 5-Year Experience.

Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) are the leading causes of transfusion-related fatalities. While these transfusion-related pulmonary complications (TRPCs) have been well detailed in adults, their burden in pediatric subsets remains poorly defined. We sought to delineate the incidence and epidemiology of pediatric TRPCs after intraoperative blood product transfusion. In this retrospective cohort study, we evaluated all consecutive pediatric patients receiving intraoperative blood product transfusions during noncardiac surgeries between January 2010 and December 2014. Exclusion criteria were cyanotic heart disease, preoperative respiratory insufficiency, extracorporeal membrane oxygenation, and American Society of Anesthesiologists physical status VI. Medical records were electronically screened to identify those with evidence of hypoxemia, and in whom a chest x-ray was obtained within 24 hours of surgery. Records were then manually reviewed by 2 physicians to determine whether they met diagnostic criteria for TACO or TRALI. Disagreements were adjudicated by a third senior physician. Of 19,288 unique pediatric surgical patients, 411 were eligible for inclusion. The incidence of TRPCs was 3.6% (95% confidence interval [CI], 2.2-5.9). TACO occurred in 3.4% (95% CI, 2.0-5.6) of patients, TRALI was identified in 1.2% (95% CI, 0.5-2.8), and 1.0% (95% CI, 0.4-2.5) had evidence for both TRALI and TACO. Incidence was not different between males (3.4%) and females (3.8%; P = .815). Although a trend toward an increased incidence of TRPCs was observed in younger patients, this did not reach statistical significance (P = .109). Incidence was comparable across subsets of transfusion volume (P = .184) and surgical specialties (P = .088). Among the 15 patients experiencing TRPCs, red blood cells were administered to 13 subjects, plasma to 3, platelets to 3, cryoprecipitate to 2, and autologous blood to 3. Three patients with TRCPs were transfused mixed blood components. TRPCs occurred in 3.6% of transfused pediatric surgical patients, with the majority of cases attributable to TACO, congruent with adult literature. The frequency of TRPCs was comparable between genders and across surgical procedures and transfusion volumes. The observed trend toward increased TRPCs in younger children warrants further consideration in future investigations. Red blood cell administration was the associated component for the majority of TRPCs, although platelets demonstrated the highest risk per component transfused. Mitigation of perioperative risk associated with TRPCs in pediatric patients is reliant on further multiinstitutional studies powered to examine patterns and predictors of this highly morbid entity.

Red blood cell transfusion to treat or prevent complications in sickle cell disease: an overview of Cochrane reviews.

This is the protocol for a review and there is no abstract. The objectives are as follows: To summarize the evidence in Cochrane reviews of the effectiveness and safety of red cell transfusions versus no transfusion, or restrictive (to increase the total haemoglobin) versus liberal (to decrease the haemoglobin S level below a specified percentage) transfusion, for treatment or prevention of complications experienced by people with SCD.

Effect of Oral Erythropoietin in Prevention of Anemia of Prematurity

Introduction: Anemia of prematurity (AOP) is a common problem of very low birth weight babies. Blood transfusion is a necessity when it occurs in moderate to severe form putting the child in to the risk of transfusion related complications. Erythropoietin, a potent stimulator of hemopoesis is available in breast milk in good amount and absorbed intact under physiologic condition. In this background oral recombinant human erythropoietin (rhEPO) can be a useful alternative to its subcutaneous administration in prevention of AOP.Objective: To evaluate the efficacy of oral rhEPO in the prevention of AOP in very low birth weight (VLBW) neonates.Methods: This randomized controlled study conducted in the NICU of BSMMU over one year. Total 60 preterm (&lt;34 weeks)VLBW (&lt;1500g) infants were enrolled and randomly divided into Control (group-I), Oral (group-II) and Subcutaneous (group III). Experimental groups (group-II &amp; group-III) received rhEPO 400 IU/Kg, 3 times weekly in oral and subcutaneous (S/C) route respectively and continued for 2 weeks (Total 6 doses). Therapy was initiated 14 days after birth when the baby achieved oral feeding of at least 50 ml/kg/day of breast milk. All infants received oral iron and folic acid supplementation up to 12 weeks of postnatal age. Transfusion data were recorded. Anthropometric and hematological assessments were done at 2, 4, 6 and 12 weeks of age.Results: Baseline clinical characteristics and hematological values were almost similar in all groups. Mean hemoglobin were 11.34±0.68gm/dl, 11.88±0.54gm/dl&amp; 12.12±1.32 gm/dl, the mean hematocrit were 34.11±2.03%, 35.66±1.65% &amp; 36.38±3.97% and the mean reticulocyte were 7.56±2.48%, 9.85±1.50% &amp; 9.22±3.11% in the control, oral and subcutaneous group respectively and the differences are statistically significant (p&lt;0.05).Weight gain was higher in the intervention group at 6 and 12 weeks follow up than the control group(p&lt;0.05).Only 2 (5.25%) infants, one in each of the intervention groups required blood transfusion, compared to 6 (31.5%) infants in control group (p&lt;0.01).Conclusion: Oral EPO is as good as subcutaneous use of EPO in stimulating erythropoesis, maintaining HCT and Hb at high level and is safe in preterm baby.Bangladesh J Child Health 2017; VOL 41 (2) :101-109

Papain-treated panels are a simple method for the identification of alloantibodies in multiple myeloma patients treated with anti-CD38-based therapies.

To report our 2years of experience navigating the interference of anti-CD38 monoclonal antibodies (MAs) in 33 patients and describe papain-treated panels as a complementary method to dithiothreitol (DTT). Novel anti-CD38 MAs are now approved or undergoing clinical trials to evaluate their activity in patients with multiple myeloma. A concern with the use of these drugs is that they interfere with blood bank tests in a group of patients who often require blood transfusions. Clinical data and whole blood samples were collected from patients receiving daratumumab or isatuximab. Routine blood bank serological tests were performed. A total of 9·1% of patients presented with alloantibodies prior to treatment. All patients exhibited nonspecific reactivity in indirect antiglobulin tests, and 26% had positive direct antiglobulin tests after beginning treatment. This interference disappeared in all patients after discontinuing treatment. Papain panels avoided this reactivity and allowed us to identify alloantibodies. Phenotyped blood units were transfused, and no patient suffered any transfusion-related complications. Anti-CD38 MAs produce nonspecific interference in blood bank tests. This interference can be overcome by various methods, including DTT or papain treatment as proposed here. These methods have limitations that can be resolved using phenotyped blood units.

Antigen-Mediated Immune Suppression Is Antigen Specific

Background: Exposure to red blood cell (RBC) alloantigens during pregnancy or transfusion can lead to the development of alloantibodies and result in transfusion-related complications, like hemolytic transfusion reactions, or hemolytic disease of the fetus and newborn. Currently, antibody-mediated immune suppression (AMIS) is the only known methodology to actively inhibit RBC alloantibody formation. The best-known example of AMIS is Rh immune globulin, which is given to Rh(D) negative women to prevent the development of anti-D alloantibodies. Mouse models to elucidate the mechanism by which AMIS occurs have used mice genetically engineered to specifically express the human KEL antigen (KEL RBCs) or the Hel-Ova-Duffy antigen (HOD RBCs) on murine RBCs, and found that AMIS to these two antigens is dependent on antigen loss (also called antigen modulation). As RBCs express many antigens simultaneously, we sought to determine whether AMIS to one antigen can impact the immune response to a completely different antigen on the same RBC by generating mice that express both the KEL and HOD antigens (HOD x KEL RBCs).Methods: WT recipients received polyclonal anti-KEL antibody, a cocktail of two anti-HEL monoclonal antibodies, or PBS, followed by transfusion with WT and HOD x KEL donor RBCs. HOD x KEL RBCs were labeled with the lipophilic dye DiI prior to transfusion, while WT RBCs were labeled with the lipophilic dye DiO and served as a RBC tracer population. RBC survival and levels of detectable IgG, Kel antigen, Hel antigen, Duffy antigen, and complement (C3) on transfused cells were measured by flow cytometry at 10min, 1hr, 2hr, and 4hr, and on days 1, 2, 3, and 5 post-transfusion. Serum was collected on day 5 and analyzed for IgM antibody development by flow-crossmatch using KEL or HOD RBCs.Results: Anti-KEL and anti-HEL treated WT recipients demonstrated significant IgG deposition on transfused HOD x KEL RBCs at 10min post-transfusion. Levels of IgG on transfused RBCs decreased over time but did not correlate with complete RBC clearance. RBC survival was nearly 100% over 5 days in recipients passively immunized with anti-HEL antibodies, while a fraction of RBCs (~20%) were cleared within 4hr post-transfusion but not thereafter (survival plateaued at 80% thru day 5) in anti-KEL immunized recipients. Conversely, decreased bound IgG on transfused RBCs was found to correlate with a decrease in target antigen levels. KEL antigen levels decreased on transfused RBCs in the anti-KEL immunized recipients beginning at 1hr post transfusion, as compared to anti-HEL and PBS recipients. Similarly, HEL antigen expression decreased on transfused RBCs in the anti-HEL immunized recipients, but not in the anti-KEL or PBS recipients, demonstrating that passive immunization causes antigen modulation for the corresponding antigen only. C3 deposition was found to occur on transfused RBCs at 10min post-transfusion in the anti-KEL recipients that remained significantly increased at other time-points, but was not detected on RBCs in the anti-HEL or PBS recipients until day 3, when recipients develop IgM antibodies. Flow crossmatch of serum samples showed that anti-KEL treated recipients did not make anti-KEL IgM but did make anti-HOD IgM, while anti-HEL treated recipients did not make anti-HOD IgM but did make anti-KEL IgM.Conclusions: Although AMIS serves as the basis of a widely successful clinical intervention, the mechanism by which it occurs, including any impact on additional antigens, remains incompletely understood. Here we demonstrate that AMIS is antigen specific - that is, passively acquired antibody can inhibit the immune response only to the corresponding antigen. Specifically, murine RBCs expressing both the human and model RBC antigen KEL and HOD, respectively, demonstrate similar clearance kinetics, antigen modulation, complement deposition, and antibody development after transfusion into WT mice as is observed when KEL-only or HOD-only RBCs are used. Although it is unclear whether these findings apply to all RBC antigens and what relevance this holds for human patients, our study provides insight into the specificity of AMIS that may enlighten development of additional therapeutics based on this mode of immune suppression. DisclosuresNo relevant conflicts of interest to declare.

Primed CD4 T Cells to an Intracellular Alloantigen Facilitate Alloimmunization Following Subsequent Transfusion

Background: While red blood cell (RBC) alloantibodies can increase the probability of transfusion-related complications, not all patients become alloimmunized following transfusion. Several factors have been hypothesized to govern susceptibility to alloimmunization, including general differences in immune function and the potential impact of recipient inflammation at the time of transfusion. However, as individuals that do generate alloantibodies appear to experience an increased rate of additional alloantibody formation following subsequent transfusion, distinct immunological responses induced following exposure to certain antigens expressed by transfused RBCs may directly facilitate the development of alloantibodies following subsequent transfusion. Thus, while CD4 T cell help classically occurs through direct recognition of a peptide that resides within a target B cell antigen, these clinical observations suggest that CD4 T cells that respond to one RBC antigen may directly facilitate immunity to a completely distinct RBC alloantigen following subsequent transfusion. As RBCs express a variety of possible polymorphic antigens, both inside RBCs and at the RBC surface, exposure to alloantigens within RBCs may possess the capability to induce a CD4 T cell response that would be undetectable by clinical serological analysis, but which may facilitate subsequent alloimmunization. To test this, we determined whether cellular adaptive immunity to an intracellular alloantigen might enhance alloimmunization following subsequent RBC transfusion.Methods: B6 recipients were immunized three times a week apart against an intracellular antigen, green fluorescent protein (GFP). Two weeks following the last immunization, recipients were transfused with RBCs expressing the model antigen HOD (a fusion protein consisting of hen egg lysozyme fused to ovalbumin and human Duffy b) and GFP (HOD x GFP RBCs) or RBCs expressing the human Glycophorin A (hGPA) and GFP antigens (hGPA x GFP RBCs). Serum was collected at days 7, 14, 21 and 28 post-transfusion and the levels of anti-HOD or anti-GPA antibodies were determined by incubation of serum with HOD RBCs, GPA RBCs or B6 RBCs, followed by detection with fluorescently labeled anti-IgG antibodies. The adjusted mean fluorescent intensity (MFI) for anti-HOD or anti-GPA antibodies was calculated by subtracting the MFI observed following incubation with B6 RBCs from the MFI observed following incubation with HOD or GPA RBCs, respectively.Results: Recipients that underwent GFP immunization experienced a statistically significant enhancement of anti-HOD IgG compared to non-GFP immunized recipients following subsequent transfusion of HOD x GFP RBCs (p < 0.05), strongly suggesting that prior exposure to a single intracellular antigenic determinant can enhance antibody formation following subsequent exposure to RBCs expressing both the intracellular antigen and a clinically relevant surface antigen. To determine whether immunological priming toward an intracellular antigen can impact RBC alloimmunization toward other cell surface RBC alloantigens, we likewise transfused recipients that had been previously immunized against GFP with RBCs that express hGPA and GFP. Similar to the impact of prior GFP immunization on HOD alloimmunization, prior GFP immunization rendered recipients responsive to the hGPA antigen following transfusion of hGPA x GFP RBCs. Importantly, non-GFP immunized recipients were non-responsive to the hGPA antigen regardless of being expressed on the same RBCs as GFP (p < 0.05), suggesting that prior immunization toward an intracellular antigen may not only enhance subsequent alloimmunization in previously alloimmunized individuals, but also render non-responding recipients responsive to RBC-induced alloimmunization.Conclusion: These results demonstrate that immunity to an intracellular alloantigen can directly influence the immunological outcome following exposure to a subsequent extracellular RBC alloantigen. Moreover, these findings suggest a mechanism whereby alloantibody responders may exhibit an increased rate of additional alloantibody formation and highlight a previously under appreciated mechanism by which cellular adaptive immunity can impact the ability of an individual to respond to unrelated immunogens. DisclosuresChonat:Agios Pharmaceuticals: Honoraria.

Whole-exome sequencing of sickle cell disease patients with hyperhemolysis syndrome suggests a role for rare variation in disease predisposition.

Hyperhemolysis syndrome (HHS) is an uncommon, but life-threatening, transfusion-related complication of red blood cell transfusion. HHS has predominantly been described in patients with sickle cell disease (SCD) and is difficult to diagnose and treat. The pathogenesis of HHS, including its occurrence in only a subset of apparently susceptible individuals, is poorly understood. We undertook whole-exome sequencing (WES) of 12 SCD-HHS patients to identify shared genetic variants that might be relevant to the development of HHS. DNA from adults with SCD having at least one previous episode of HHS were subject to WES. High-quality variants were passed through a series of bioinformatics filters to identify variants that were uncommon among African populations represented in public databases. Recurrent, putative loss-of-function variants occurring in biologically plausible genes were prioritized and then genotyped in a larger, ancestry-matched cohort of non-HHS controls. A rare, heterozygous stop-gain variant (p.Glu210Ter) in MBL2 was significantly enriched among HHS cases (p = 0.002). This variant is predicted to result in a premature termination codon that escapes nonsense-mediated mRNA decay, potentially leading to a novel phenotype. We also observed a complex insertion-deletion variant in the final exon of KLRC3 that was enriched among cases (p = 0.0019), although neither variant was found among seven pediatric SCD-HHS patients. Our results suggest a potential role for rare genetic defects in the development of HHS among adult SCD patients. Such enriched variants may ultimately be useful for identifying high-risk individuals and informing therapeutic approaches in HHS.

Prehospital transfusion of red cell concentrates in a paramedic-staffed helicopter emergency medical service.

The optimal volume and type of intravenous fluid for the treatment of blood loss in the prehospital setting is controversial. The use of red cell concentrates (RCCs) may be associated with improved outcomes; however, the administration of blood products is limited to physicians in many jurisdictions. We sought to describe the characteristics of RCC transfusions in a paramedic-staffed helicopter emergency medical system in Victoria, Australia. We performed a retrospective analysis of all cases where paramedics consulted the responsible physician for approval of RCC transfusion between July 2011 and December 2015 in Victoria, Australia. Ambulance data was retrieved from electronic patient care records and hospital and outcome data was retrieved from a state-wide trauma registry. A total of 180 primary missions was identified where paramedics requested approval for transfusion of RCCs during the study period. A total of 150 patients received prehospital RCCs, of which 136 had suffered trauma. The majority of these patients were male (66.7%) and were involved in a car accident (62.5%). Most (97.4%) patients had an Injury Severity Score ≥12. There were improvements in median systolic blood pressure (80 mmHg vs 94 mmHg, P < 0.001) and shock index (1.50 vs 1.23, P < 0.001) between time of consultation and arrival at hospital. Overall, mortality for trauma patients was 37.7%. There were no transfusion-related complications identified. Prehospital transfusion of RCC by paramedics is feasible. Future studies should compare the outcomes of patients receiving prehospital RCCs with outcomes for patients in which RCCs are administered in hospital.

Combined Application of Tranexamic Acid and Thrombelastography in Pediatric Epilepsy Surgery

Background: Pediatric patients undergoing epilepsy surgeries are under high risks of bleeding, hemodynamic instability and complications related to transfusions. This study aimed to investigate whether combined application of tranexamic acid (TXA) and thrombelastography (TEG) in pediatric epilepsy surgery can decrease blood loss, transfusion requirements and post-operation complications.Methods: Thirty-two pediatric patients undergoing elective epilepsy surgery were randomized into two groups. Group T (Group T=Group Treatment, n=16) was given a loading dose of 10 mg/kg TXA in 15 minutes and then maintained at the speed of 5 mg/kg/h, while Group C (Group C=Group Control, n=16) was given the same dosage of normal saline. TEG tests were performed at the beginning of surgery (T1), opening the dura mater (T2), closing the dura mater (T3) and the end of surgery (T4) in both groups. In Group T, transfusion decision was made according to TEG results; while in Group C, it was made by anesthetist's experience without knowing the TEG results. The volume of blood loss, blood transfusion, post-operative drainage and complications were recorded.Results: In Group T, intraoperative bleeding volume was significantly lower than Group C ([8.23±4.10] ml/kg vs [12.86±5.30] ml/kg, P=0.010]), and subsequently the ratio of transfusion of red blood cells (RBC) (18.75% vs 56.25%, P=0.026), fresh frozen plasma (FFP) (32.15% vs 43.75%, P=0.465) were significantly reduced. Maximal amplitude (MA) value of TEG at T3 (Group T=[61.11±4.58] mm vs Group C=[56.09±8.03] mm, P=0.038) and T4 (Group T=[60.31±6.23] mm vs Group C=[54.08±7.28] mm, P=0.014) in Group T were significantly higher than those in Group C. A significant difference existed between two groups in postoperative drainage volume in the first 24 hours (Group T=[4.19±1.55] ml/kg vs Group C=[5.83±2.07] ml/kg, P=0.017). Postoperative hospital stay was significantly shortened in Group T, compared to Group C ([7.9±2.1] days vs [10.8±3.8] days, P=0.014). No transfusion related complications occurred in both groups.Conclusions: Combined application of TXA and TEG in pediatric epilepsy surgery may decrease blood loss, reduce transfusion requirements. The risk of thromboembolism may not be increased. Citation: Qing-Fang Duan, Wen-Ya Fu, Wei Xiao, Jia-Jian Qi, Guo-Guang Zhao, Yong-Zhi Shan, et al. Combined application of tranexamic acid and thrombelastography in pediatric epilepsy surgery. J Anesth Perioper Med 2017; 4: 213-9. doi: 10.24015/JAPM.2017.0007This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Platelet production from induced pluripotent stem cells

Ex vivo production of human platelets has been pursued as an alternative measure to resolve limitations in the supply and safety of current platelet transfusion products. To this end, induced pluripotent stem cells (iPSCs) are considered an ideal global source, as they are not only pluripotent and self-renewing, but are also available from basically any person, have relatively few ethical issues, and are easy to manipulate. From human iPSCs, megakaryocyte (MK) lines with robust proliferation capacity have been established by the introduction of specified sets of genes. These expandable MKs are also cryopreservable and thus would be suitable as master cells for good manufacturing practice (GMP)-grade production of platelets, assuring availability on demand and safety against blood-borne infections. Meanwhile, developments in bioreactors that physically mimic the in vivo environment and discovery of substances that promote thrombopoiesis have yielded competent platelets with improved efficiency. The derivation of platelets from iPSCs could further resolve transfusion-related alloimmune complications through the manufacturing of autologous products and human leukocyte antigen (HLA)-compatible platelets from stocked homologous HLA-type iPSC libraries or by manipulation of HLAs and human platelet antigens (HPAs). Considering these key advances in the field, HLA-deleted platelets could become a universal product that is manufactured at industrial level to safely fulfill almost all demands. In this review, we provide an overview of the ex vivo production of iPSC-derived platelets toward clinical applications, a production that would revolutionize the blood transfusion system and lead the field of iPSC-based regenerative medicine.

Microparticles from stored red blood cells enhance procoagulant and proinflammatory activity.

The pathomechanisms of morbidity due to blood transfusions are not yet entirely understood. Elevated levels of red blood cell-derived microparticles (RMPs) are found in coagulation-related pathologies and also in stored blood. Previous research has shown that RMPs mediate transfusion-related complications by the intrinsic pathway. We hypothesized that RMPs might play a role in post-transfusion thrombotic complications by enhancing procoagulant activity also through the extrinsic pathway of coagulation. In this laboratory study, blood from 18 healthy volunteers was stimulated with microparticles from expired stored red blood cells. Various clotting parameters were recorded. Flow cytometry, enzyme-linked immunosorbent assays, and real-time polymerase chain reaction were used to investigate possible mediating mechanisms. The addition of RMPs shortened the clotting time from 194 to 161 seconds (p < 0.001). After incubation with RMPs, there was increased expression of tissue factor (TF) on monocytes and in plasma. TF messenger RNA expression increased in a time-dependent and concentration-dependent manner. There was a significant induction of interleukin-1β and interleukin-6. After stimulation with RMPs, there was a significant increase in the number of activated platelets, an increased percentage of PAC-1/CD62P (procaspase activating compound-1/platelet surface P-selectin) double-positive platelets, and an increased number of platelet-neutrophil duplets and platelet-monocyte duplets, indicating enhanced interaction of platelets with neutrophils and monocytes. Levels of CXCL-8 (C-X-C motif chemokine ligand 1) and interleukin-6 were significantly higher after treatment with RMPs. Our results suggest that RMPs trigger coagulation through TF signaling, induce the secretion of proinflammatory cytokines, and induce cell-cell interaction between platelets and neutrophils. Thus, under certain conditions, RMPs could play a role in post-transfusion complications through these mechanisms.

Point-of-care washing of allogeneic red blood cells for the prevention of transfusion-related respiratory complications (WAR-PRC): a protocol for a multicenter randomised clinical trial in patients undergoing cardiac surgery

IntroductionThe transfusion-related respiratory complications, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), are leading causes of transfusion-related morbidity and mortality. At present, there are no effective preventive strategies...

Association Between Allogeneic Blood Transfusion and Postoperative Infection in Major Spine Surgery.

Retrospective cohort study. The objective of this study is to compare the incidence of infection in patients who do and do not receive blood transfusions in major deformity surgery (>8 levels). Postoperative infections increase morbidity and mortality rates in spine surgery and generate additional costs for the health care system. It has been proposed that blood transfusions increase the risk of wound infection, urinary tract infection, pneumonia, and sepsis. A total of 56 patients met the study criteria, receiving spine surgery involving the fusion of 8 levels or more. Patient-specific characteristics, starting and ending hematocrits, number of units transfused and infections including urinary tract infection, wound infection, pneumonia, and sepsis were documented. Differences in infection risk between those who did and did not undergo a transfusion and their 95% confidence intervals were calculated. Groups were similar with respect to baseline and surgical characteristics except for smoking status, operative time, estimated blood loss, and ending hematocrit. The overall infection rate was greater in patients who underwent transfusion than those who did not (36% vs. 10%; P=0.03). Wound infections (n=5) were only observed in those who underwent a transfusion. Smokers were more likely to receive a transfusion and more likely to experience infection. A stratified analysis demonstrated an increased risk of infection associated with transfusion; however, the risk was greater in smokers, suggesting the effect of transfusion on infection could be modified by smoking. Patients undergoing transfusion experienced a significantly longer hospital stay (P=0.01). Allogeneic red blood cell transfusion in major spine surgery could be a risk factor for postoperative infection. This increased risk seems to be magnified in those who smoke. Further studies are warranted, and risks of blood loss and transfusion-related complications in smokers also potentially merit exploration. Level 3.

Implementing a protocol to optimize blood use in a cardiac surgery service: results of a pre-post analysis and the impact of high-volume blood users.

Blood transfusions are a common and costly intervention for cardiac surgery patients. Evidence suggests that a more restrictive transfusion strategy may reduce costs and transfusion-related complications without increasing perioperative morbidity and mortality. A transfusion-limiting protocol was developed and implemented in a cardiovascular surgery unit. Over a 5-year period, data were collected on patient characteristics, procedures, utilization of blood products, morbidity, and mortality, and these were compared before and after the protocol was implemented. After the protocol was put in place, fewer patients required transfusions (38.2% vs. 45.5%, p = 0.004), with the greatest reduction observed in postoperative blood use (29.1% vs. 37.2%, p = 0.001). In-hospital morbidity and mortality did not increase. When patients who received transfusions were stratified by procedure, the protocol was most effective in reducing transfusions for patients undergoing isolated coronary artery bypass grafting (CABG; 4.09 units vs. 2.51 units, p = 0.009) and CABG plus valve surgery (10.32 units vs. 4.77 units, p = 0.014). A small group of patients were disproportionate recipients of transfusions, with approximately 6% of all patients receiving approximately half of the blood products. A protocol to limit transfusions decreased the proportion of cardiothoracic surgery patients who received blood products. A very small group of patients received a large number of transfusions, and within that group the observed mortality was significantly higher than in the general patient population. Current protocols cannot possibly account for these patients, and this should be considered when analyzing the performance of protocols designed to reduce unnecessary transfusions.