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1.  The Influence of Clinical and Biological Factors on Transfusion-Associated Non-ABO Antigen Alloimmunization: Responders, Hyper-Responders, and Non-Responders 
In the context of transfusion medicine, alloimmunization most often refers to the development of antibodies to non-ABO red blood cell (RBC) antigens following pregnancy, transfusion, or transplantation. The development of RBC alloantibodies can have important clinical consequences, particularly in patients who require chronic transfusions. It has been suggested that alloimmunization is more common in some clinical circumstances and patient populations than in others. As such, individuals that develop alloantibodies are frequently referred to as ‘responders’ in the medical literature. In contrast, individuals that do not develop alloantibodies despite repeated exposures to non-self blood group antigens have been referred to as ‘non-responders'. The purpose of this article is to review the phenomenon of RBC alloimmunization in the context of responders and non-responders to: i) establish a basic framework for alloimmunization as reported across several diverse patient populations; ii) more fully explore literature reports which support the concept of responders/non-responders regarding blood group antigen alloimmunization; iii) summarize the mechanisms that have been shown to predispose an individual to alloimmunization to determine how these factors may differentiate ‘responders’ from ‘non-responders'; and iv) briefly discuss some practical approaches to prevent alloimmunization in patients who may be prone to alloantibody development.
PMCID: PMC4280450
Alloimmunization; Responders; Blood group antigens; Immunohematology
2.  Factors Influencing RBC Alloimmunization: Lessons Learned from Murine Models 
Red blood cell (RBC) alloimmunization may occur following transfusion or pregnancy/delivery. Although observational human studies have described the immunogenicity of RBC antigens and the clinical significance of RBC alloantibodies, studies of factors influencing RBC alloimmunization in humans are inherently limited by the large number of independent variables involved. This manuscript reviews data generated in murine models that utilize transgenic donor mice, which express RBC-specific model or authentic human blood group antigens. Transfusion of RBCs from such donors into nontransgenic but otherwise genetically identical recipient mice allows for the investigation of individual donor or recipient-specific variables that may impact RBC alloimmunization. Potential donor-related variables include methods of blood product collection, processing and storage, donor-specific characteristics, RBC antigen-specific factors, and others. Potential recipient-related variables include genetic factors (MHC/HLA type and polymorphisms of immunoregulatory genes), immune activation status, phenotype of regulatory immune cell subsets, immune cell functional characteristics, prior antigen exposures, and others. Although murine models are not perfect surrogates for human biology, these models generate phenomenological and mechanistic hypotheses of RBC alloimmunization and lay the groundwork for follow-up human studies. Long-term goals include improving transfusion safety and minimizing the morbidity/mortality associated with RBC alloimmunization.
PMCID: PMC4280453
RBC; Alloimmunization; Transfusion; Murine models
3.  Genetics of Transfusion Recipient Alloimmunization: Can Clues from Susceptibility to Autoimmunity Pave the Way? 
The search for genetic determinants of alloimmunization in sickle cell disease transfusion recipients was based on two premises: i) that polymorphisms responsible for stronger immune and/or inflammatory responses and hemoglobin βS mutation were co-selected by malaria; and ii) that stronger responder status contributes to development of lupus. We found a marker of alloimmunization in the gene encoding for Ro52 protein, also known as Sjögren syndrome antigen 1 (SSA1) and TRIM21. Surprisingly, the nature of the association was opposite of that with lupus; the same variant of a polymorphism (rs660) that was associated with lupus incidence was also associated with induction of tolerance to red blood cell antigens during early childhood. The dual function of Ro52 can explain this apparent contradiction. We propose that other lupus/autoimmunity susceptibility loci may reveal roles of additional molecules in various aspects of alloimmunization induced by transfusion as well as during pregnancy.
PMCID: PMC4280455
Alloimmunization; Antibodies; Autoimmunity; Red blood cells
5.  Red Blood Cell Alloimmunization in Sickle Cell Disease: Listen to Your Ancestors 
Red blood cell (RBC) alloimmunization occurs in approximately 30% of transfused sickle cell disease patients compared to 2–5% of all transfusion recipients. Because RBC transfusion is an important part of therapy in sickle cell disease, the need for additional antigen matching once alloimmunization occurs is problematic and leads to therapeutic limitations. Thus, identification of risk factors would benefit this patient population. Genome-wide analyses, in particular, methods which take into account genetic ancestry such as admixture mapping, could identify molecular markers which could be used to identify immune responders to transfusion.
PMCID: PMC4280449
Sickle cell disease; Transfusion; Alloimmunization; Genome; Ancestry
6.  A Genome-Wide Screen for Large-Effect Alloimmunization Susceptibility Loci among Red Blood Cell Transfusion Recipients with Sickle Cell Disease 
A selective susceptibility of certain individuals to form multiple alloantibodies in response to red cell transfusion is well-recognized in clinical practice, and is a particular problem in persons with sickle cell disease (SCD). The reason for this differential susceptibility is unclear, but inter-individual genetic differences are likely to contribute.
We conducted a pilot case-control genome-wide association study using 1,000,000 SNPs in 94 alloimmune responders (cases) and non-responders (controls) with SCD in order to identify loci of large effect size associated with alloimmunization.
No loci showed evidence of association at a genome-wide significance cut-off (p < 0.5 × 10–8). SNPs in the ARAP1/STARD10 region showed suggestive association (p < 1 × 10–6), but no association was observed at previously implicated loci TRIM21 or HLA. In analyses of the number of accumulated antibodies, a modest association was found with SNPs in the Toll-like receptor gene TLR10 (p < 1 × 10–4).
Alloimmunization in persons with SCD is unlikely to be mediated by loci of very large effect size; however, larger and more comprehensive studies are required to fully evaluate loci with more moderate effects. This study provides a working approach to such future studies in SCD.
PMCID: PMC4280456
Genome-wide association studies; GWAS; African American; Responders; Genomics
7.  Responder Individuality in Red Blood Cell Alloimmunization 
Many different factors influence the propensity of transfusion recipients and pregnant women to form red blood cell alloantibodies (RBCA). RBCA may cause hemolytic transfusion reactions, hemolytic disease of the fetus and newborn and may be a complication in transplantation medicine. Antigenic differences between responder and foreign erythrocytes may lead to such an immune answer, in part with suspected specific HLA class II associations. Biochemical and conformational characteristics of red blood cell (RBC) antigens, their dose (number of transfusions and pregnancies, absolute number of antigens per RBC) and the mode of exposure impact on RBCA rates. In addition, individual circumstances determine the risk to form RBCA. Responder individuality in terms of age, sex, severity of underlying disease, disease- or therapy-induced immunosuppression and inflammation are discussed with respect to influencing RBC alloimmunization. For particular high-risk patients, extended phenotype matching of transfusion and recipient efficiently decreases RBCA induction and associated clinical risks.
PMCID: PMC4280446
Alloimmunization; Red blood cell antibodies; Red blood cell antigens
9.  REGGI and the American Rare Donor Program 
The American Rare Donor Program (ARDP) was formed in 1998 to provide rare blood units for patients in need. Members of the program identify rare donors and submit donor information for entrance into a database, REGGI. Information on patients in need of rare blood is also submitted and entered into REGGI. REGGI serves to match phenotypes of registered donors with patients having the respective antibodies. A search process for available units ensues, and blood is provided to the patient. This report provides information on REGGI and its use in the ARDP.
PMCID: PMC4264493  PMID: 25538535
Blood donation; Blood products; Donor screening; Donors; Red blood cell antibodies; Red blood cell antigens
10.  Allele Frequencies Database 
This review describes a database for the collection, archiving, sorting, searching and display of gene and allele frequencies for immunogenetic genes.
PMCID: PMC4264510  PMID: 25538537
Data management system; HLA; Immunogenetics; KIR
11.  BGMUT Database of Allelic Variants of Genes Encoding Human Blood Group Antigens 
The Blood group antigen Gene MUTation (BGMUT) database documents variations in genes of human blood group systems. In March 2014, the database, accessible at, listed 1,545 alleles of 44 genes of 34 blood group systems. Besides allelic information, the BGMUT resource also presents comprehensive and current information on blood group systems. This review describes the database and notes its utility for the transfusion medicine and human genetics communities.
PMCID: PMC4264482  PMID: 25538536
Allele; Antigen; Blood group; Database; DNA variation; Mutation
12.  DGTI Register of Rare Donors 
For patients with antibodies against the most common blood groups a rapid and efficient supply of compatible erythrocyte concentrates is self-evident. But typically we have to make the greatest effort providing blood for these patients, which have made antibodies against common blood groups. There are however patients with antibodies against rare blood group antigens that need special blood. The supply of such blood can be very difficult and mostly time-consuming. For this reason we set up a database of blood donors with rare blood groups. Since 2005 the BTS SRC Berne Ltd. has run this database on behalf of the Swiss BTS SRC. After a reorganization and extension of the database, conducted during 2011/2012, the data file was renamed ‘DGTI Register of Rare Donors’ and is now run under the patronage of the German Society for Transfusion Medicine and Immunohematology (DGTI).
PMCID: PMC4264486  PMID: 25538534
DGTI; ISBT; Rare donor; Rare blood groups; Antigen; Phenotype; Bank of frozen blood; Database; Blood group genotyping
13.  The Rhesus Site 
The Rhesus Site is a resource for information of the ‘Rhesus’ blood group. It is intended for specialists and non-specialists. The website details research in the field relevant for transfusion medicine, immunohematology, and molecular research. Link areas guide to important publications and to methodological resources for Rhesus. Many data originally presented at The Rhesus Site have been formally published later. The ‘RhesusBase’ section represents the largest database for RHD alleles; the ‘RhesusSurveillance’ section details the results of the largest prospective observational study on anti-D immunization events in D-positive patients. Visitors to the website are encouraged to explore the intricacies of the most complex blood group gene locus.
PMCID: PMC4264492  PMID: 25538538
Rh-Hr blood group system; Antigen D; Rh blood group; Databases as topic; Immunization
14.  Long-Term Treatment and Transfusion of Normal Blood Components Following Tolerance Induction in Patients with Anti-IgA Anaphylactic Reactions 
In general, patients with significant anti-Ig-A do not tolerate intravenous (i.v.) administration of normal blood products. Here, we present our experiences in the induction of immune tolerance (IIT) and long-term treatment in a series of such patients affected in such a way. The question whether blood components from IgA-deficient donors are required will be discussed.
Ten adult patients (4 females and 6 males; age ranging from 36 to 75 years) with anti-IgA were included in this study. All patients required long-term treatment with blood components. One patient had IgA deficiency and paroxysmal nocturnal hemoglobinuria (PNH), and all other patients had common variable immunodeficiency (CVID). The particle gel immunoassay was used for the detection of anti-IgA. Immune tolerance to IgA was induced by controlled subcutaneous (s.c.) and/or i.v. infusions of IgG preparations.
Prior to IIT, anti-IgA was detectable in plasma samples of all patients and significantly diminished or abolished by controlled s.c. and/or i.v. infusions of IgG. Multiple transfusions with normal blood components could be repeatedly performed with the patient suffering from PNH without any complications. As long as i.v. IgG (IVIgG) infusions were consequently administered as individually required (intervals 2–8 weeks), none of the patients developed reactions during observation (up to 10 years). However, interruption of treatment and re-exposure to IVIgG resulted in adverse reactions.
Patients with significant anti-IgA can be safely desensitized and tolerate long-term IgG substitutions independent of the IgA concentration of the used blood component.
PMCID: PMC4264496  PMID: 25538541
Anti-IgA; IgA anaphylaxis; Anaphylactic reactions; Transfusion reactions; Immune tolerance; IgA deficiency; IVIgG
15.  All Information Is Not Equal: Using the Literature Databases PubMed and The Cochrane Library for Identifying the Evidence on Granulocyte Transfusion Therapy 
To be able to take well-informed decisions or carry out sound research, clinicians and researchers alike require specific information seeking skills matching their respective information needs. Biomedical information is traditionally available via different literature databases. This article gives an introduction to two diverging sources, PubMed (23 million references) and The Cochrane Library (800,000 references), both of which offer sophisticated instruments for searching an increasing amount of medical publications of varied quality and ambition. Whereas PubMed as an unfiltered source of primary literature comprises all different kinds of publication types occurring in academic journals, The Cochrane Library is a pre-filtered source which offers access to either synthesized publication types or critically appraised and carefully selected references. A search approach has to be carried out deliberately and requires a good knowledge on the scope and features of the databases as well as on the ability to build a search strategy in a structured way. We present a specific and a sensitive search approach, making use of both databases within two application case scenarios in order to identify the evidence on granulocyte transfusions for infections in adult patients with neutropenia.
PMCID: PMC4264499  PMID: 25538539
Databases, bibliographic; PubMed; The Cochrane Library; Information seeking behavior; Evidence-based medicine
16.  Unexpected Hypotensive Events during Preparatory Plasmaphereses 
PMCID: PMC4264517  PMID: 25538542
17.  The Effect of Erythropoiesis-Stimulating Agents in Patients with Therapy-Refractory Autoimmune Hemolytic Anemia 
Many patients with autoimmune hemolytic anemia (AIHA) do not respond to standard therapy and/or may develop severe complications which can be of fatal outcome. There is some evidence that erythropoiesis-stimulating agents (ESAs) may be helpful in the management of such patients.
We describe the effect of ESAs in 12 new patients with therapy-refractory AIHA (7 of warm type and 5 of cold type) and review 5 previously reported cases. Serological testing was performed using standard methods.
All patients responded well to treatment with ESAs. At least 5 of the 17 patients demonstrated complete recovery, and none of the patients developed significant adverse reactions due to treatment with ESAs.
The mechanism by which ESAs improves hemolysis in AIHA is not completely clear. In addition to increased production and prolonged RBC survival, it may inhibit eryptosis (programmed cell death). ESAs represent a new option in the treatment of decompensated and/or refractory AIHA of warm and cold type. However, more information is required to assess which patients can be treated with ESAs.
PMCID: PMC4280451
AIHA; Autoimmune hemolytic anemia; Erythropoietin; EPO
18.  Two Novel α 1,2-Fucosyltransferase Alleles in an H-Deficient Phenotype Individual 
Background: Abnormal α1,2-fucosyltransferase activity due to gene mutation results in decreased synthesis of H antigen and leads to an H-deficient phenotype. Here we studied the underlying molecular mechanisms in 7 Chinese blood donors with the H-deficient phenotype. Methods: Red blood cell typing was performed using standard serologic tests, and ABO genotype was analyzed using ABO polymerase chain reaction with sequence-specific primer tests. The coding sequence of the FUT1 gene was amplified using the specific primers. The FUT1 alleles were identified by a pCRII-TOPO carrier for TOPO TA cloning sequencing. Results: The H-deficient phenotype frequency was estimated to be approximately 1/30,000 (6/159,515) in the Chinese Han population. The FUT1 gene mutation was demonstrated in 6 Chinese blood donors with the H-deficient phenotype. In only 1 case, no mutation was detected. Novel FUT1 alleles were found in 1 donor. One of these novel FUT1 alleles showed nucleotide 35C>T and 748C>T site mutations that resulted in amino acid substitution of Ala to Val and Trp to Arg at positions 11 and 250, respectively. Another novel FUT1 allele had a nucleotide 655G>C site mutation, causing amino acid substitution of Leu to Val at position 219. Conclusions: Two novel FUT1 alleles, 35T+748T and 655C, were identified that may greatly diminish the activity of α1,2-fucosyltransferase and result in the H-deficient phenotype.
PMCID: PMC4264483  PMID: 25538540
Blood group; H-deficient phenotype; FUT1 gene
19.  Current Clinical Indications for Plerixafor 
Autologous and allogeneic hematopoietic stem cell (HSC) transplantation are considered the standard of care for many malignancies including lymphoma, multiple myeloma, and some leukemias. In many cases, mobilized peripheral blood has become the preferred source for HSCs. Plerixafor, an inhibitor of the interaction between CX chemokine receptor 4 (CXCR4) and stromal derived factor-1 alpha (SDF-1), has been evaluated in clinical trials and approved by the FDA and EMA. This agent has very modest toxicity and appears to be quite potent at HSC mobilization. Current clinical indications for the use of plerixafor are the subject of this review.
PMCID: PMC3776405  PMID: 24415962
Autologous transplant; Allogeneic transplant; Plerixafor; Chemomobilization; Graft characteristics
21.  Perspectives in Transfusion Medicine and Cellular Therapies 
PMCID: PMC4164064  PMID: 25254017
22.  Monetary Compensation and Blood Donor Return: Results of a Donor Survey in Southwest Germany 
The aim of this study was to compare donor return patterns of non-compensated and compensated German first-time donors to assess the effect of monetary reward on donor return.
We conducted a retrospective analysis of a donor survey of 3,077 non-compensated and 738 compensated German first-time donors. Survey data were pooled and linked with blood donor return rates within the 1st, 2nd, and 3rd year. Logistic regression models were used to estimate differences in the probability of donor return between non-compensated and compensated donors.
In the first 2 years following the initial donation, compensated donors were more likely to return with the odds of giving at least one further donation 1.86 (1st year) and 1.32 (2nd year) times higher for compensated donors than for non-compensated donors. In the 3rd year, there were no significant differences in donor return.
This report, which was based on two non-randomized donor samples, suggests that monetary compensation may increase the likelihood of donors returning in the first months after the initial donation. Monetary reward may therefore be used as a short-term strategy to recruit new donors. The long-term commitment, however, seems not to be affected by monetary reward, and complementary donor retention strategies are needed.
PMCID: PMC4164084  PMID: 25254021
Donors; Donor return; Donor retention; Compensation; Germany
23.  Academic Training of Medical Students in Transfusion Medicine, Hemotherapy, and Hemostasis: Results of a Questionnaire-Based Status Report in Germany 
As a consequence of the German Transfusion Act and the corresponding Hemotherapeutic Guidelines of the German Medical Association, the National Advisory Committee Blood approved a recommendation (votum 29) in 2003 to specify students’ training in transfusion medicine, hemotherapy, and hemostasis. The objective of this study was to assess the current status of teaching in these fields.
A questionnaire-based evaluation was performed at the medical schools in Germany (n = 34). Responses were analyzed by descriptive criteria, except for weekly semester hours of teaching.
Responses were obtained from 30 medical faculties (88%). Among them, 18 had conducted votum 29 (12 ‘completely’, 6 ‘essentially’), while 7 had done so only ‘in part’ and 5 ‘not at all’. 13 of 30 sites (43%) reported that no faculty-related curriculum in transfusion medicine and hemostasis (hemotherapy) exists. At 28 of 30 medical schools (93%), teaching in transfusion medicine, hemotherapy, and hemostasis is integrated into cross-curricular topics of interdisciplinary programs, including lectures. The corresponding semester hours of teaching per week ranged from 0.5 to 12 h/week.
Votum 29 is incompletely established. Consequently, academic teaching in transfusion medicine, hemotherapy, and hemostasis requires structural and conceptual improvement to fulfill legal specifications and regulatory constraints.
PMCID: PMC4164089  PMID: 25254026
Transfusion medicine; Hemotherapy; Hemostasis; Curricula; Academic training
24.  Pathogen Inactivation Technologies for Cellular Blood Components: an Update 
Nowadays patients receiving blood components are exposed to much less transfusion-transmitted infectious diseases than three decades before when among others HIV was identified as causative agent for the acquired immunodeficiency syndrome and the transmission by blood or coagulation factors became evident. Since that time the implementation of measures for risk prevention and safety precaution was socially and politically accepted. Currently emerging pathogens like arboviruses and the well-known bacterial contamination of platelet concentrates still remain major concerns of blood safety with important clinical consequences, but very rarely with fatal outcome for the blood recipient. In contrast to the well-established pathogen inactivation strategies for fresh frozen plasma using the solvent-detergent procedure or methylene blue and visible light, the bench-to-bedside translation of novel pathogen inactivation technologies for cell-containing blood components such as platelets and red blood cells are still underway. This review summarizes the pharmacological/toxicological assessment and the inactivation efficacy against viruses, bacteria, and protozoa of each of the currently available pathogen inactivation technologies and highlights the impact of the results obtained from several randomized clinical trials and hemovigilance data. Until now in some European countries pathogen inactivation technologies are in in routine use for single-donor plasma and platelets. The invention and adaption of pathogen inactivation technologies for red blood cell units and whole blood donations suggest the universal applicability of these technologies and foster a paradigm shift in the manufacturing of safe blood.
PMCID: PMC4164100  PMID: 25254027
Pathogen inactivation; Blood safety; Dengue virus; Chikungunya virus; West Nile virus; Bacteria; Protozoa; Platelet concentrates; Red blood cells; Randomized clinical trial; Hemovigilance
25.  Management of Young Blood Donors 
The emphasis on high-school blood drives and acceptance of 16-year-old blood donors led to more research on physiologic and psychological ways to decrease vasovagal reaction rates in young blood donors and to increase donor retention. Research on how to accomplish this has been advantageous for the blood collection industry and blood donors. This review discussed the current situation and what can be done psychologically, physiologically, and via process improvements to decrease vasovagal reaction rates and increase donor retention. The donation process can be significantly improved. Future interventions may include more dietary salt, a shorter muscle tension program to make it more feasible, recommendations for post-donation muscle tension / squatting / laying down for lightheadedness, more donor education by the staff at the collection site, more staff attention to donors with fear or higher risk for a vasovagal reaction (e.g. estimated blood volume near 3.5 l, first-time donor), and a more focused donation process to ensure a pleasant and safer procedure.
PMCID: PMC4164065  PMID: 25254024
Blood donation; Vasovagal syncope; Donor safety

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