Incompatible Red Blood Cell Transfusion Research Articles

Safety and efficacy of least incompatible red cell units in autoimmune hemolytic anemia: A prospective analysis of hemoglobin increment and hemolysis after transfusion

Abstract BACKGROUND: Red blood cell (RBC) transfusion is a challenge in autoimmune hemolytic anemia (AIHA) patients due to pan reactivity and crossmatch incompatibility. Apprehensions about the safety and efficacy of least incompatible (best-matched) red cells are common among treatment providers. AIM: A primary objective was to study the effect of RBC transfusion on hemolysis parameters (hemoglobin [Hb], serum bilirubin, serum lactate dehydrogenase [LDH], and reticulocyte count) in AIHA patients. SETTINGS AND DESIGN: This was a hospital-based prospective observational study conducted on 40 AIHA patients attending the department of internal medicine from January 2020 to July 2021 who received RBC Transfusions. METHODOLOGY: Blood samples were collected for evaluating hemolysis parameters: Hb, reticulocyte count, serum bilirubin, and serum LDH before transfusion and compared with the same parameters within 12 h after transfusion. STATISTICAL ANALYSIS: Analysis was done by SPSS software Version 16. Paired t-test was used to find the effect of RBC transfusion on hemolysis parameters and independent t-test was used to compare the effect of compatible and incompatible RBC transfusions. RESULTS: The median age at presentation was 42 years with a female preponderance (67.5%). Majority of the patients belong to warm AIHA (73%) and Secondary AIHA (60%). Compatible RBC units could be provided to 57% of cases and 43% were transfused with the least incompatible units. The mean pretransfusion Hb in AIHA was 4.3 mg/dl and showed a statistically significant increase after transfusion (P < 0.001). A significant difference between reticulocyte levels of compatible and incompatible transfusions was noted with a P = 0.025. No statistically significant difference noticed in Hb, serum LDH, serum bilirubin levels between compatible and incompatible RBC transfusions. CONCLUSION: RBC transfusions in AIHA patients provide Hb increment similar to other anemic patients. RBC transfusions should not be denied in AIHA patients in view of hemolysis and best-matched units also may be transfused in indicated cases.

Antigen density dictates RBC clearance, but not antigen modulation, following incompatible RBC transfusion in mice

AbstractIncompatible red blood cell (RBC) transfusion can result in life-threatening transfusion complications that can be challenging to manage in patients with transfusion-dependent anemia. However, not all incompatible RBC transfusions result in significant RBC removal. One factor that may regulate the outcome of incompatible RBC transfusion is the density of the incompatible antigen. Despite the potential influence of target antigen levels during incompatible RBC transfusion, a model system capable of defining the role of antigen density in this process has not been developed. In this study, we describe a novel model system of incompatible transfusion using donor mice that express different levels of the KEL antigen and recipients with varying anti-KEL antibody concentrations. Transfusion of KEL+ RBCs that express high or moderate KEL antigen levels results in rapid antibody-mediated RBC clearance. In contrast, relatively little RBC clearance was observed following the transfusion of KEL RBCs that express low KEL antigen levels. Intriguingly, unlike RBC clearance, loss of the KEL antigen from the transfused RBCs occurred at a similar rate regardless of the KEL antigen density following an incompatible transfusion. In addition to antigen density, anti-KEL antibody levels also regulated RBC removal and KEL antigen loss, suggesting that antigen density and antibody levels dictate incompatible RBC transfusion outcomes. These results demonstrate that antibody-induced antigen loss and RBC clearance can occur at distinct antigen density thresholds, providing important insight into factors that may dictate the outcome of an incompatible RBC transfusion.

Evaluation of Efficacy and Safety of Blood Transfusion and Hormone Therapy in 40 Patients with Autoimmune Hemolytic Anemia

To evaluate the efficacy and safety of different types of red blood cell (RBC) transfusion and hormone therapy in patients with autoimmune hemolytic anemia (AIHA). The clinical data and serological characteristics of 40 patients with AIHA treated in our hospital from 2014 to 2018 were collected and analyzed retrospectively. The efficacy and safety of different type of RBC transfusion and hormone therapy were evaluated according to the principle of minimally incompatible RBC transfusion after cross-matching. Among 40 patients with AIHA, the female cases were more than the male cases, the cases of secondary AIHA was more than cases of primary AIHA, and the warm autoantibodies were in the majority. 11 cases of AIHA underwent 26 times minimally incompatible red blood cell transfusions. The total effective rate was 46.2%, the partial efficiency was 23.1%, and total inefficiency was 30.8%. Among them, the same type of non-washing red blood cell group showed efficiency of 42.1%, partial effective rate of 21.1%, and inefficiency of 36.8%; the same type of washed red blood cell group showed efficiency of 57.1%, partial effective rate of 28.6%, and inefficiency of 14.3%. the infusion effects was not significanly different between the two groups, and no hemolytic transfusion reaction occurred. In the hormone-treated group, the complete remission rate was 15.2%, the partial remission rate was 63.6%, and the ineffective rate was 21.2%. Among them, the side effects appeared in 2 patients after using hormones. When AIHA patients need blood transfusion, use the same type of non-washed red blood cells or homologous washed cells is relatively safe, and the difference in efficacy is not significant. The partial remission of patients received hormone therapy is much higher than that of red blood cell transfusion, but the side effects easily happen.

Examining the Role of Complement in Predicting, Preventing, and Treating Hemolytic Transfusion Reactions.

Red blood cell (RBC) transfusion is a critical component of optimal management for a broad range of conditions. Regardless of the indication, pretransfusion testing is required to appropriately match RBC donors and recipients to provide immunologically compatible blood. Although this approach is effective in the vast majority of situations, occasionally, patients will inadvertently receive an incompatible RBC transfusion, which can result in a hemolytic transfusion reaction (HTR). In addition, patients with life-threatening anemia and a complex alloantibody profile, which precludes rapid procurement of compatible RBCs, may also receive incompatible RBCs, placing them at risk for an HTR. Despite the rarity of these clinical situations, when incompatible blood transfusion results in an HTR, the consequences can be devastating. In this review, we will explore the challenges associated with actively preventing and treating acute HTRs following incompatible RBC transfusion. In doing so, we will focus primarily on the role of complement, not only as a key player in HTRs, but also as a potential target for the prevention and treatment of HTRs.

Serological Characteristics of Patients with Autoimmune Hemoly-tic Anemia and Efficacy and Safety of Incompatible Transfusion of Red Blood Cells

To explore the serological characteristics of patients with autoimmune hemolytic anemia（AIHA） and analyze its clinical efficacy and safety of incompatible red blood cell transfusion. Sixty AIHA patients admitted in our hospital from January 2014 to January 2018 were selected. The blood type serological characteristics of 60 patients were analyzed retrospectively. According to the type of autoantibody and the composition of different red blood cells, the efficacy and safety of erythrocyte infusions were evaluated respectively. The screen results of irregular antibody in 60 AIHA patients were positive, and the direct anti-human globulin test also was positive, including 8 cases of cold autoantibodies (13.33%), 49 cases of IgG warm autoantibodies (81.67%), and 3 cases of warm cold double autoantibodies (5%). The irregular anti-body identification test confirmed the existence of homoantiboby in 17 cases (28.33%). Out of 60 cases 34 received incompatible red blood cell (RBC) infusion for 108 time including ABO homotype non washing RBC (81 tirnes) and O type washing RBC (27 times). The infusion results showed that the total [JP2]effective rate was 57.41(62/108), total partial effective rate was 14.81% (16/108) and total ineffective rate was 27.78% (30/108).The infusion of ABO homotype non-washing RBC for 81 time showed that the effective rate was 58.02%[JP] (47/81) , partial effective rate was 12.35 (10/81) and ineffective rate was 29.67% (24/81); the infusion of O type washing RBC for 27 times showed that the effective rate was 55.56% (15/27), partial effective rate was 22.22% (6/27) and ineffective rate was 22.22% (6/27), there was no significant difference in effective rate between 2 kinds of infusion (P>0.05). The comparison of different antibody type infusion showed that in the infusion of IgM cold autoantiboay for 12 times, the effective rate was 41.67% (5/12), partial effective rate was 33.33% (4/12) and ineffective rate was 25% (3/12); in the infusion of IgG warm antoantibody for 93 times. The effective rate was 58.06% (54/93),partial effective rate was 12.90% (12/93) and ineffective rale was 29.04% (27/93), there was also no significant difference in effective rate between 2 kinds of infusion(P>0.05). However, in infusion of cold/warm double autoantibody for 3 times, the effective rate was 100% (3/3), moreover, the hemotytic reaction of infusion was not observed during the treatment . The infusion of ABO homotype non-washing RBC and O type washing RBC both possess the high safely and efficacy for treatment of patients with AIHA, but the use of ABO homotype non-washing RBC can effectively avoid the excessive use of O type washing RBC.

The least incompatible crossmatch red blood cell transfusion by biological compatibility test

Introduction: Pretransfusion testing is an essential serological test to protect the recipient from hemolysis and provide compatible blood product. The final step is the crossmatching test which is done by the transfusion center. Although all products are crossmatched in same cases, compatible products may not be available. Aims and Objectives: This study aimed to determine the safety and efficacy of the least incompatible crossmatched erythrocyte transfusion, through the use of biological in vivo crossmatch testing. Materials and Methods: The study included twenty patients who required transfusion and for whom appropriate red blood cell (RBC) could not be found. Totally, 69 units of least incompatible RBC transfusion from crossmatch incompatible products was administered by applying the “in vivo compatibility” test. Patients were observed during the transfusion with respect to acute hemolytic reactions that could develop. The biochemical hemolysis parameters were examined before and at 24 h after transfusion. Results: All transfusions were completed successfully with no complications or symptoms observed in any case. A statistically significant increase in hematocrit (Hct) and hemoglobin was seen post transfusion (P

Successful treatment of severe idiopathic mixed autoimmune hemolytic anemia with bortezomib and intravenous immunoglobulin

Introduction: Autoimmune hemolytic anemia (AIHA) is a rare and diverse group of acquired hemolytic anemias which results from increased destruction of red blood cells (RBCs) due to autoantibodies directed against antigens on the RBC surface. Currently, there are no clearly defined evidence-based guidelines on the management of AIHA, and current treatment options are based on small retrospective studies, case reports, as well as expert experiences and recommendations. We report a case of severe idiopathic mixed AIHA that responded to a combination of steroids, intravenous immunoglobulin (IVIG) and bortezomib. Case Report: A 25-year-old African American female presented with jaundice, shortness of breath, and abdominal pain. She had splenomegaly on examination and initial work-up was significant for severe anemia (hemoglobin, 3.3 g/dl) and hyperbilirubinemia (total bilirubin, 26.7 mg/dl; direct bilirubin, 21.9 mg/dl). Direct antiglobulin test (DAT) was microscopically positive for anti-IgG and anti-C3d, and cold autoantibodies were identified. An extensive workup for a possible secondary cause of her anemia was non-revealing. She was sequentially treated with prednisone, IVIG, and bortezomib. Marked response was noted as evidenced by improvement in the hemoglobin from a nadir of 3.2 g/dl on admission to 10.1 at discharge. Patient has remained clinically in remission since then. Conclusion: The first line treatment for warm AIHA (w-AIHA) includes glucocorticoids and transfusion of least incompatible RBCs. Steroids are rarely necessary or effective in cold agglutinin AIHA in which case high dose IVIG and plasmapheresis have been used albeit with inconsistent results. Bortezomib is an inhibitor of the 26S proteasome and is approved for the treatment of multiple myeloma. It has been reported to have some activity in rituximabresistant cold agglutinin disease (CAD) due to its activity against the CD20-negative plasma cell compartment that may be responsible for IgG anti-RBC autoantibody production.

High Percentage of Evanescent Red Cell Antibodies in Patients with Sickle Cell Disease Highlights Need for a National Antibody Database.

Alloantibody formation secondary to transfusion in patients with sickle cell disease (SCD) is a well-known phenomenon. Pretransfusion testing (eg, "antibody screening") protects patients from receiving incompatible red blood cell transfusions. Because alloantibodies have a tendency to evanesce (ie, become undetectable over time), however, this phenomenon puts patients at risk of a delayed hemolytic transfusion reaction or even acute hemolysis. We evaluated the records of 71 patients with SCD with alloantibodies detected during a 2-year period to describe their most common specificities and their rate of evanescence. We found that 81% of patients had at least one antibody that was undetectable during the study period; therefore, if patients were transfused with antigen-positive units at a facility that was unaware of their antibody history, life-threatening hemolysis could develop. Evanescence is a real risk for patients with SCD, and national/regional databases of alloantibodies should be considered a priority.

Antigen Density Impacts RBC Survival and Antigen Modulation Following Incompatible RBC Transfusion

Background: While chronic transfusion therapy can signficantly reduce morbidity and mortality in patients with hemoglonbinopathies, transfusion is not without risk. Differences in red blood cell (RBC) antigen distributions between donors and recipients can result in the development of RBC alloantibodies, which can make it difficult, if not impossible, to find compatible blood. As a result, heavily alloimmunized individuals experience greater morbidity and mortality than those who do not possess RBC-induced alloantibodies. While incompatible RBC transfusion can result in fatal hemolytic transfusion reactions (HTRs), these adverse events are not the invariable outcome of incompatible transfusion. Although a variety of factors likely contribute to the likilihood of developing a HTR following incompatible RBC transfusion, variability in the density of the donor antigen may contribute to different outcomes. Using a novel model that utilizes RBC donors with different levels of the KEL antigen, we sought to directly examine the impact of antigen density on RBC clearance following incompatible RBC transfusion.Methods: Wild type C57BL/6 mice (WT) were passively immunized with anti-KEL serum, generated following immunization of WT recipients with KEL RBCS, 2 hours prior to incompatible KEL RBC transfusion. RBC collected from previously generated KEL transgenic mice that express high (KELhi), intermediate (KELmed), and low (KELlo) levels of human KEL glycoprotein antigen, were labeled with chloromethylbenzamido 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), while WT RBC were labeled with fluorescently distinct 3,3'-dihexadecyloxacarbocyanine perchlorate (DiO) to facilitate detection post-transfusion. Passively immunized recipient WT mice were transfused with labeled KEL RBC to WT RBC. Percent KEL RBC survival was measured using flow cytometric analysis at various time points post transfusion by comparing the DiI to DiO ratio. Bound antibody, complement and the KEL antigen were assessed by staining cells with anti-Ig, anti-C3 and anti-KEL followed by flow cytometric analysis.Results: Transfusion of RBCs expressing low, intermediate or high levels of the KEL antigen into non-immunized mice failed to result in any detectable alteration in RBC survival or KEL expression. However, transfusion of KELlo, KELmed and KELhi RBCs into anti-KEL immunized recipients resulted in differential clearance of each population, with KELhi experiencing the most clearance, followed by KELmed and KELlo. Similarly, the level of detectable C3 and bound antibody on KEL positive cells likewise correlated with the initial level of KEL antigen expression, with more C3 and IgG being detected on the surface of KELhi following transfusion into immunized recipients, than KELmed or KELlo. However, KELhi RBCs also experience the most significant alterations in KEL antigen levels following antibody engagement. Regardless of the KEL positive RBC transfused, each population developed a relatively rapid state of resistance to additional anti-KEL-mediated RBC removal.Conclusions: Our results indicate that lower antigen densities may be less efficient in not only facilitating rapid clearance of RBCs following incompatible transfusion, but also antibody-induced antigen modulation. While KELhi RBCs displayed the greatest degree of clearance and antigen modulation, each population developed resistance to antibody-mediate removal, suggesting that once RBC antigen levels fall below a certain threshold, clearance discontinues, regardless of the initial levels of antigen prior to incompatible transfusion. Taken together, these results suggest that antigen density may provide an additional feature of RBC transfusion that may impact the outcome of incompatible transfusion in heavily alloimmunized recipients. DisclosuresNo relevant conflicts of interest to declare.

Complement in Human Disease

As part of innate immunity, the complement system embodies the “first line of defense” to various initial insults, including trauma, infection, hemorrhage, ischemia, and autoimmunity. While of beneficial intention, excessive complement activation can inadvertently damage healthy host tissues and thereby exacerbate the initial pathological events by causing an “innocent bystander effect.” “Complementology” represents a rapidly evolving field. Recent scientific efforts have identified novel complement activation pathways and select complement-inhibiting compounds, which have been shown to ameliorate myriad autoimmune or inflammatory conditions. These findings have renewed the enthusiasm for novel pharmacological strategies targeting numerous inflammatory conditions, which currently elude successful transfer “from bench to bedside,” such as acute lung injury, sepsis, burn, ischemia-reperfusion injury, traumatic brain injury, and kidney disease. The abundant involvement of the complement system in human health and disease is reflected by the wide range of topics covered in this special issue of Clinical and Developmental Immunology. B. Nilsson and N. Ekdahl provide a summarizing article on current indications, techniques, sampling, and interpretations for clinical complement analyses. In addition, an easy-to-follow algorithm is provided for routine laboratory operations. G. Cazander et al. illustrate the success of targeted complement inhibition of complement in wound healing and demonstrate how revesal of complement hyperactivity using several complement inhibitors has resulted in novel and innovative wound care strategies, which may soon be subject of clinical trials. K. J. Welsh et al. challenge recent evidence that complement plays a critical role in the host defense against Mycobacterium tuberculosis. Following aerosol challenge with Mycobacterium tuberculosis, the authors demonstrate that “C7-knockout” mice had markedly reduced liver colony forming units and lung occlusion in conjunction with significantly increased total lymphocytes, decreased macrophages, and increased numbers of CD4+ cells. In line, expression of lung IFN-γ and TNF-α was increased in these animals, underscoring a crucial role of C7 in the disease manifestation of Mycobacterium tuberculosis. S. R. Stowell et al.'s manuscript reviews the role of complement in transfusion-related mortality. This is of particular interest, as excessive complement activation during transfusion represents one of the most common features associated with fatality. The treating physician is furthermore provided with several strategies aiming to immunomodulate the complement system during incompatible red blood cell transfusions. In two reviews, F. Bu et al. and S. F. Heeringa and colleagues review complement involvement in renal disease. Bu reviews the pathogenetic role of genetic variations in complement genes and complement dysregulation at the cell surface results in different forms of atypical hemolytic uremic syndrome, and how this understanding may result in novel complement-modulating treatment approaches. In S. F. Heeringa's paper, the pathogenesis of complement associated glomerulopathies is reviewed. Heeringa describes how defective complement control via the alternative pathway results in glomerular C3 deposition and how this understanding has generated a complement pan-blockade or plasma substitution as potential treatment strategies, which have been proven successful. H. Nishiura et al. shed further light on the importance of the C5a receptor (C5aR) during erythropoiesis. Strikingly, expression and regulation of RP S19 oligomer, which binds to C5aR, may regulate C5aR function as a connector for the erythroblast-macrophage island or for erythroblast differentiation in the bone marrow. D. Rittirsch et al. and J. Charchaflieh et al. review the highly elaborate immune response following trauma and sepsis, which is—at least in part—driven by excessive complement activation and may result in a deadly downward spiral of SIRS, sepsis, septic shock, and multiorgan failure. Recent clinical concepts, such as “damage control surgery,” transition such findings into the clinical setting in an attempt to improve outcome of a highly vulnerable patient population. These manuscripts represent an exciting and insightful snapshot of current complement research. State-of-the-art, existing challenges, and emerging future topics are highlighted in this special issue, which may inspire the reader and help advance the present complement research. We would like to thank all authors, reviewers, and the Editor-in-Chief for making this special issue in Clinical and Developmental Immunology possible. Michael A. Flierl Daniel Rittirsch Markus S. Huber-Lang Philip F. Stahel

Initiation and Regulation of Complement during Hemolytic Transfusion Reactions

Hemolytic transfusion reactions represent one of the most common causes of transfusion-related mortality. Although many factors influence hemolytic transfusion reactions, complement activation represents one of the most common features associated with fatality. In this paper we will focus on the role of complement in initiating and regulating hemolytic transfusion reactions and will discuss potential strategies aimed at mitigating or favorably modulating complement during incompatible red blood cell transfusions.

Pretransfusion compatibility testing for red blood cell administration.

The purpose of pretransfusion compatibility testing is to prevent incompatible red blood cell transfusions that could lead to immune mediated hemolytic transfusion reactions. Some hemolytic transfusion reactions may have serious sequelae including hemoglobinemia, disseminated intravascular coagulation, renal failure, and death. This article reviews the most comprehensive recent analyses of the laboratory methods used during pretransfusion compatibility testing in the United States. Most of the laboratory practice data have been published in the College of American Pathologists Transfusion Medicine Survey Sets and in a national survey called the Pre-Transfusion Testing Survey. This article couples and trends the data of these comprehensive surveys with an assessment of the literature to present the current practice of pretransfusion compatibility testing.

The role of cytokines in blood transfusion reactions

Recent advance in the understanding of the mechanism of hemolytic transfusion reactions results from the investigation of cytokine generation in in vitro models of incompatible red blood cell transfusion. Cytokines with pyrogenic and pro-inflammatory activities as well as cytokines with activating properties for granulocytes, monocytes and endothelial cells are produced in both ‘intravascial’ and ‘extravascular’ types of hemolytic reactions. It has also been demonstrated that cytokines are generated and accumulated in blood components such as platelet concentrates, during storage. A large part of febrile transfusion reactions results from transfusion of stored platelet concentrates containing high cytokine levels and not from antigen-antibody reaction. Prestorage removal of white blood cells, which generate cytokines during storage, from platelet concentrates reduces strongly the reaction incidence and should be standard practice.