<abstract>
<title style='display:none'>Abstract</title>
This extraordinary case showcases the identification of a rare anti-Ena specificity that was assisted by DNA-based red blood cell antigen typing and collaboration between the hospital blood bank in the United States, the home blood center in Qatar, the blood center Immunohematology Reference Laboratory, as well as the American Rare Donor Program (ARDP) and the International Society for Blood Transfusion (ISBT) International Rare Donor Panel. Ena is a high-prevalence antigen, and blood samples from over 200 individuals of the extended family in Qatar were crossmatched against the patient’s plasma with one compatible En(a–) individual identified. The ISBT International Rare Donor Panel identified an additional donor in Canada, resulting in a total of two En(a–) individuals available to donate blood for the patient.
</abstract>

Meeting the transfusion needs of a patient with anti-Ena requires an international effort

<abstract>
<title style='display:none'>Abstract</title>
Individuals with the rare para-Bombay phenotype have inherited defects in producing H associated with <italic>FUT1</italic> and/or <italic>FUT2</italic> genes. We report a case of blood group discrepancy in a para-Bombay patient from a tertiary care hospital of eastern India. A 31-year-old woman with rheumatic heart disease presented with fatigue and breathlessness and was then scheduled for valvuloplasty, for which a blood transfusion request was sent to the blood center. During pre-transfusion testing, red blood cell (RBC) testing showed group O, and serum testing showed strong reactivity with group B RBCs, weak reactivity with group O RBCs, and very weak reactivity with group A RBCs. Saliva inhibition testing and enzyme treatment of RBCs concluded the patient to be of “Ah para-Bombay” phenotype. The patient’s Lewis phenotype was Le(a–b+). This patient’s serum also had cold-reacting anti-IH along with anti-B. This case report highlights the importance of performing an advanced immunohematologic workup, including adsorption, elution, enzyme treatment, and saliva inhibition testing for identification of weak A or B subgroups as well as the rare para-Bombay blood group, when routine ABO typing, using forward and reverse grouping, is inconclusive. Accurate identification of blood group helps in preventing transfusion-related adverse events and encouraging safe transfusion practice.
</abstract>

Blood group discrepancy in Ah para-Bombay phenotype: a rare blood group variant and its clinical significance

<abstract>
<title style='display:none'>Abstract</title>
Red blood cell alloimmunization to antigens other than D, such as C, c, E, e, and antigens in the Kell, MNS, and Duffy blood group systems, has emerged as an important cause of hemolytic disease of the fetus and newborn (HDFN). Antibody screening for these antibodies is not routinely practiced for all antenatal patients in developing countries, mainly because of financial constraints. Here we report a rare case of HDFN due to dual antibodies to Rh and Kidd blood group system antigens: anti-E and anti-Jka. This case report highlights the importance of routine and regular antenatal screening of all pregnant women for proper monitoring and follow-up.
</abstract>

Severe hemolytic disease of the fetus and newborn due to anti-E and anti-Jka

<abstract>
<title style='display:none'>Abstract</title>
This update on the P1PK blood group system (Hellberg Å, Westman JS, Thuresson B, Olsson ML. P1PK: the blood group system that changed its name and expanded. Immunohematology 2013;29:25–33) provides recent findings concerning the P1PK blood group system that have both challenged and confirmed old theories. The glycosphingolipids can no longer be considered the sole carriers of the antigens in this system because the P1 antigen has been detected on human red blood cell glycoproteins. New indications suggest that P1Pk synthase activity truly depends on the DXD motif, and the genetic background and molecular mechanism behind the common P1 and P2 phenotypes were found to depend on transcriptional regulation. Transcription factors bind the <italic>P<xref ref-type="bibr" rid="j_immunohematology-2020-048_ref_001">1</xref>
</italic> allele selectively to a motif around rs5751348 in a regulatory region of <italic>A4GALT</italic>, which enhances transcription of the gene. Nonetheless, unexplained differences in antigen expression between individuals remain.
</abstract>

The P1PK blood group system: revisited and resolved

<abstract>
<title style='display:none'>Abstract</title>
This update of the Cromer (CROM) blood group system (Storry JR, Reid ME, Yazer MH. The Cromer blood group system: a review. <italic>Immunohematology</italic> 2010;26:109–17) includes additional variants to the Cromer system (ISBT021), both new antigens and new molecular bases underlying the null phenotype. The molecule on which the Cromer blood group antigens are carried, CD55 (DAF), is an important receptor for the malaria parasite, <italic>Plasmodium falciparum,</italic> and the role of CD55 in health and disease continues to expand.
</abstract>

The Cromer blood group system: an update

<abstract>
<title style='display:none'>Abstract</title>
The high-prevalence blood group antigen, Sda, had been puzzling blood bankers and transfusionists for at least a decade when it was reported in 1967. The characteristic mix of agglutinates and free red blood cells (RBCs), caused by anti-Sda, is seen with the RBCs from 90 percent of individuals of European descent. However, only 2–4 percent of individuals are truly Sd(a−) and may produce anti-Sda. The antibodies, generally considered insignificant, may cause hemolytic transfusion reactions with high-expressing Sd(a+) RBCs (e.g., the unusual Cad phenotype, which can also be polyagglutinable). The Sda glycan, GalNAcβ1-4(NeuAcα2-3)Gal-R, is produced in the gastrointestinal and urinary systems, while its origin on RBCs is more controversial. According to current theory, Sda is likely to be passively adsorbed in low amounts, except in Cad individuals, where it has been found on erythroid proteins and at higher levels. The long-standing hypothesis that <italic>B4GALNT2</italic> encodes the Sda synthase was confirmed in 2019, since homozygosity for a variant allele with rs7224888:C produces a non-functional enzyme associated with most cases of the Sd(a−) phenotype. Thereby, the SID blood group system was acknowledged as number 038 by the International Society of Blood Transfusion. Although the genetic background of Sd(a−) was settled, questions remain. The genetic background of the Cad phenotype has not yet been determined, and the source of the RBC-carried Sda is unknown. Furthermore, the interest of Sda stretches beyond transfusion medicine. Some tantalizing examples are lowered antigen levels in malignant tissue compared with normal tissue and interference with infectious agents like <italic>Escherichia coli</italic>, influenza virus, and malaria parasites.
</abstract>

SID: a new carbohydrate blood group system based on a well-characterized but still mysterious antigen of great pathophysiologic interest

<abstract>
<title style='display:none'>Abstract</title>
Since publication of the original <italic>Immunohematology</italic> review of the Kidd blood group system in 2015 (Hamilton JR. Kidd blood group system: a review. Immunohematology 2015;31:29–34), knowledge has mushroomed pertaining to gene structure, alleles causing variant and null phenotypes, clinical significance in renal transplant and hemolytic disease of the fetus and newborn, and physiologic functions of urea transporters in non-renal tissues. This review will detail much of this new information.
</abstract>

An update to Kidd blood group system

<abstract>
<title style='display:none'>Abstract</title>
KLF transcription factor 1 (KLF1) and GATA binding protein 1 (GATA1) are transcription factors (TFs) that initiate and regulate transcription of the genes involved in erythropoiesis. These TFs possess DNA-binding domains that recognize specific nucleotide sequences in genes, to which they bind and regulate transcription. Variants in the genes that encode either KLF1 or GATA1 can result in a range of hematologic phenotypes—from benign to severe forms of thrombocytopenia and anemia; they can also weaken the expression of blood group antigens. The Lutheran (LU) blood group system is susceptible to TF gene variations, particularly <italic>KLF1</italic> variants. Individuals heterozygous for <italic>KLF1</italic> gene variants show reduced Lutheran antigens on red blood cells that are not usually detected by routine hemagglutination methods. This reduced antigen expression is referred to as the In(Lu) phenotype. For accurate blood typing, it is important to distinguish between the In(Lu) phenotype, which has very weak antigen expression, and the true Lunull phenotype, which has no antigen expression. The International Society of Blood Transfusion blood group allele database registers <italic>KLF1</italic> and <italic>GATA1</italic> variants associated with modified Lutheran expression. Here, we review <italic>KLF1</italic> and recent novel gene variants defined through investigating blood group phenotype and genotype discrepancies or, for one report, investigating cases with unexplained chronic anemia. In addition, we include a review of the GATA1 TF, including a case report describing the second <italic>GATA1</italic> variant associated with a serologic Lu(a–b–) phenotype. Finally, we review both past and recent reports on variations in the DNA sequence motifs on the blood group genes that disrupt the binding of the GATA1 TF and either remove or reduce erythroid antigen expression. This review highlights the diversity and complexity of the transcription process itself and the need to consider these factors as an added component for accurate blood group phenotyping.
</abstract>

Impact of transcription factors KLF1 and GATA1 on red blood cell antigen expression: a review

<abstract>
<title style='display:none'>Abstract</title>
In pregnancy, D– pregnant women may be at risk of becoming immunized against D when carrying a D+ fetus, which may eventually lead to hemolytic disease of the fetus and newborn. Administrating antenatal and postnatal anti-D immunoglobulin prophylaxis decreases the risk of immunization substantially. Noninvasive fetal <italic>RHD</italic> genotyping, based on testing cell-free DNA extracted from maternal plasma, offers a reliable tool to predict the fetal RhD phenotype during pregnancy. Used as a screening program, antenatal <italic>RHD</italic> screening can guide the administration of antenatal prophylaxis in non-immunized D– pregnant women so that unnecessary prophylaxis is avoided in those women who carry a D– fetus. In Europe, antenatal <italic>RHD</italic> screening programs have been running since 2009, demonstrating high test accuracies and program feasibility. In this review, an overview is provided of current state-of-the-art antenatal <italic>RHD</italic> screening, which includes discussions on the rationale for its implementation, methodology, detection strategies, and test performance. The performance of antenatal <italic>RHD</italic> screening in a routine setting is characterized by high accuracy, with a high diagnostic sensitivity of ≥99.9 percent. The result of using antenatal <italic>RHD</italic> screening is that 97–99 percent of the women who carry a D– fetus avoid unnecessary prophylaxis. As such, this activity contributes to avoiding unnecessary treatment and saves valuable anti-D immunoglobulin, which has a shortage worldwide. The main challenges for a reliable noninvasive fetal <italic>RHD</italic> genotyping assay are low cell-free DNA levels, the genetics of the Rh blood group system, and choosing an appropriate detection strategy for an admixed population. In many parts of the world, however, the main challenge is to improve the basic care for D– pregnant women.
</abstract>

Antenatal <italic>RHD</italic> screening to guide antenatal anti-D immunoprophylaxis in non-immunized D– pregnant women

<abstract>
<title style='display:none'>Abstract</title>
Solid-phase red cell adherence (SPRCA) is a sensitive platform for antibody detection, but nonspecific reactions may occur. One pattern of apparent nonspecific reactivity is a panagglutinin with a negative direct antiglobulin test (DAT). The purpose of this study was to define the clinical characteristics of patients with these nonspecific reactions and their associated serologic findings. Twenty patients with panreactive SPRCA testing results were identified between November 2022 and May 2023. In addition to panagglutinins, these patients had (1) a negative polyethylene glycol (PEG) antibody detection test, (2) a negative PEG autocontrol, and (3) a negative DAT. The strength of SPRCA panreactivity and the results of eluate testing (by tube and SPRCA) were studied. Clinical characteristics of patients included age, sex, and primary diagnosis. Each patient was also assessed for evidence of hemolysis. Fourteen female and six male patients were evaluated (average age 44 years). Primary diagnoses included pregnancy (<italic>n</italic> = 10), acute bleeding (<italic>n</italic> = 4), orthopedic (<italic>n</italic> = 3), and other (<italic>n</italic> = 3). There was no clinical or laboratory evidence of hemolysis. The predominant strength of SPRCA panreactivity was evenly distributed across reaction grades (1+ to 3+). Fifty-five percent of the eluates tested in PEG showed panreactivity, consistent with warm-reactive autoantibodies, while 85 percent of eluates tested by SPRCA were panreactive. Six discrepant cases, in which PEG eluate testing was negative and solid-phase eluate testing showed panreactivity, were associated with weak solid-phase plasma panreactivity (1+). In addition, the reactivity strengths of the eluates tested by SPRCA were invariably more strongly reactive than those eluates tested in PEG. Panagglutination is a distinct SPRCA-only plasma reactivity pattern. Despite a negative PEG tube and DAT, most panagglutinins are warm-reactive autoantibodies. Fortunately, these “interfering” panagglutinins do not appear to be clinically significant and are easily managed by an alternative testing method such as PEG.
</abstract>

Evaluation of solid-phase panreactivity with negative direct antiglobulin testing

<abstract><title style='display:none'>Abstract</title>The antigens of the ABO system were the first to be recognized as blood groups and actually the first human genetic markers known. Their presence and the realization of naturally occurring antibodies to those antigens lacking from the cells made sense of the erratic failure of blood transfusion hitherto and opened up the possibility of a safe treatment practice in life-threatening blood loss. Although initially apparently simple, the ABO system has come to grow in complexity over the years. The mass of knowledge relating to carbohydrate chemistry, enzymology, molecular genetics, and structural and evolutionary biology is now enormous thanks to more than a century of research using ABO as a principal model. This has provided us with data to form a solid platform of evidence-based transfusion and transplantation medicine used every day in laboratories and clinics around the globe. This review aims to summarize key findings and recent progress made toward further understanding of this surprisingly polymorphic system. <italic><bold>Immunohematology</bold></italic><bold>2009;25:48–59.</bold></abstract>

The ABO blood group system revisited: a review and update

<abstract><title style='display:none'>Abstract</title>Although recognized as a serious complication of hemotherapy, few data are available on the incidence of transfusion-associated circulatory overload (TACO). Detailed demographic and clinical information was obtained from records of 382 Medicare patients undergoing total hip or knee replacements (and receiving transfusions) from January 1992 to December 1993 at five Massachusetts hospitals. Seventy-eight percent of the patients were women with a mean age of 77 years. Thirty-two percent had co-morbidities including myocardial or coronary disease. Transfusion-related complications and comorbidities were identified and reviewed by transfusion experts. Patients were excluded from consideration if non-transfusion factors such as myocardial disease could have contributed to the development of acute pulmonary edema. Four (3 females, 1 male) patients (1.05%) developed TACO postoperatively. Mean age of these patients was 84 years (range, 75–101) versus 77 years for non-TACO. The mean intraoperative estimated blood loss was 375 mL. Each patient received only 1–2 units of red blood cells prior to onset of TACO, and in two cases only autologous blood was used. The mean positive fluid balance was 2,480 mL. The mean pretransfusion hematocrit prior to circulatory overload (CO) was 26.0 percent. symptoms were reversed with diuretics. Length of stay was significantly prolonged by these incidents. TACO is a frequent and serious event in an orthopedic surgical setting. It is associated with advanced age, increased health care costs, and may occur in the setting of modest transfusion volumes. The utilization of conservative transfusion criteria and fluid management in the perioperative setting may decrease the incidence of this complication in this population. <bold><italic>Immunohematology</italic></bold> 1996;12:87–89.</abstract>

Massachusetts Peer Review Organization, Inc.

Transfusion-associated circulatory overload in orthopedic surgery patients: a multi-institutional study

Review: ABO blood group system—ABH oligosaccharide antigens, anti-A and anti-B, A and B glycosyltransferases, and <italic>ABO</italic> genes

<abstract><title style='display:none'>Abstract</title>Despite yielding a definitive diagnosis in fewer than 20 percent of anaphylactic transfusion reactions, investigation for IgA deficiency and the presence of presumably pathogenic IgG anti-IgA is useful in patient management. Individuals with demonstrated anti-IgA are thereafter committed to receiving IgA-depleted cellular products or IgA-deficient plasma and derivatives to prevent recurrent severe reactions. Unfortunately, in populations of IgA-deficient individuals screened for anti-IgA, the predictive value of the test in the absence of a prior reaction is quite low. Anti-IgA testing is complex and limited to a few reference laboratories, many of which still employ a labor-intensive hemagglutination assay developed in the late 1960s. Timely decisions regarding further transfusion management of patients experiencing anaphylaxis often rely upon more rapidly obtained assays of the IgA concentration as an indicator of the likelihood of subsequent demonstration of anti-IgA. The scarcity of IgA-deficient banked plasma products and dedicated platelet-pheresis donors has led to the development of American Rare Donor Program policies designed to appropriately allocate these precious resources. The test methods used to establish the diagnosis of IgA deficiency and identify the approximately one-third of these individuals with anti-IgA are discussed, along with the incidence of abnormal tests in various populations. Also presented are testing recommendations for the identification of an IgA-mediated mechanism for transfusion-associated anaphylaxis and qualification of patients to receive rare IgA-deficient plasmacontaining products. <bold><italic>Immunohematology</italic> 2005;21 :226–233.</bold></abstract>

Review: IgA anaphylactic transfusion reactions.Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products

<abstract><title style='display:none'>Abstract</title>Neutrophils are the most abundant white blood cell in blood and play a critical role in preventing infections as part of the innate immune system. Reduction in neutrophils below an absolute count of 500 cells/μL is termed severe neutropenia or agranulocytosis. Drug-induced immune neutropenia (DIIN) occurs when drug-dependent antibodies form against neutrophil membrane glycoproteins and cause neutrophil destruction. Affected patients have fever, chills, and infections; severe infections left untreated can result in death. Treatment with granulocyte colony-stimulating factor can hasten neutrophil recovery. Cumulative data show that severe neutropenia or agranulocytosis associated with exposure to nonchemotherapy drugs ranges from approximately 1.6 to 15.4 cases per million population per year. Drugs most often associated with neutropenia or agranulocytosis include dipyrone, diclofenac, ticlopidine, calcium dobesilate, spironolactone, antithyroid drugs (e.g., propylthiouracil), carbamazepine, sulfamethoxazole-trimethoprim, β-lactam antibiotics, clozapine, levamisole, and vancomycin. Assays used for detection of neutrophil drug-dependent antibodies (DDAbs) include flow cytometry, monoclonal antibody immobilization of granulocyte antigens, enzyme-linked immunosorbent assay, immunoblotting, granulocyte agglutination, and granulocytotoxicity. However, testing for neutrophil DDAbs is rarely performed owing to its complexity and lack of availability. Mechanisms proposed for DIIN have not been rigorously studied, but those that have been studied include drug- or hapten-induced antibody formation and autoantibody production against drug metabolite or protein adducts covalently attached to neutrophil membrane proteins. This review will address acute, severe neutropenia caused by neutrophil-reactive antibodies induced by nonchemotherapy drugs—DIIN. <italic><bold>Immunohematology</bold></italic><bold>2014;30:95–101.</bold></abstract>

Drug-induced immune neutropenia/ agranulocytosis

Review: the molecular basis of the Rh blood group phenotypes

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