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Giant cell hepatitis associated with autoimmune hemolytic anemia (GCH-AHA) is a rare but severe disease of infancy defined by an acute liver injury, histologically characterized by a widespread giant cell transformation and by an autoimmune hemolysis. GCH-AHA is thought to be immune-mediated being however a distinct entity from juvenile autoimmune hepatitis. In particular, GCH-AHA displays a less favorable response to conventional immunosuppressive treatment compared to classical juvenile autoimmune hepatitis, carrying a higher risk of mortality. In fact, since his first description, conventional therapy with prednisone with azathioprine has been used as first line treatment, however with frequent relapses during tapering, as well as severe side effects related to its prolonged use at high doses in early age. Due to the frequent occurrence of relapse, several immunosuppressive drugs have been tried as second line therapy with doubtful success. In case of severe liver dysfunction and/or severe anemia, transitory remission has been achieved with intravenous immunoglobulins administration, however with temporary response. B-cell depletion treatment, mostly with chimeric anti-CD20 monoclonal antibody (rituximab; RTX) has been used since 2004 with encouraging results mostly in refractory cases as second-line therapy. In this issue, the report of a series of 20 children with GCH-AHA from Shanghai, China, confirms the previous treatment experiences of a greater efficacy in obtaining complete remission of RTX or RTX treatment regimens compared to conventional regimens, with a good safety. To date, published experience with this rare disease suggests that RTX should be considered the cornerstone of treatment for complicated or relapsing cases of GCH-AHA and given the increasing evidence on its efficacy and safety, RTX might be even an acceptable option as first line therapy beside conventional treatment, to drastically reduce the cumulative steroids exposure and its side effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The article analyses data on the occurrence of hematological abnormalities in severe acute respiratory syndrome 2 infection. Among these hematological abnormalities, the majority of patients develop a hypercoagulable state associated with thromboembolic complications and poor prognosis. Approximately one-third of patients with severe acute respiratory syndrome 2 infection are diagnosed with mild to severe thrombocytopenia. Another hematological autoimmune disease observed in patients with coronavirus disease 2019 is autoimmune hemolytic anemia. A clinical case with the development of autoimmune hemolytic anemia in the setting of coronavirus infection was described. The diagnosis was based on the presence of anemia, reticulocytosis, a significant decrease in haptoglobin levels, and a positive antiglobulin test (Coombs test). Given the comorbidity, the risks of adverse effects of severe coronavirus disease were high, despite this, it was possible to achieve clinical and hematological remission of autoimmune hemolytic anemia by prescribing pathogenetic therapy with anti-CD-20 monoclonal antibody (rituximab), recombinant erythropoietin and glucocorticoid hormones. This clinical case demonstrates the possibility of successful treatment of patients with severe hemolytic anemia. Special attention should be paid to the discrepancy between the severity of the condition and objective data. This case demonstrates the need for a more in-depth approach to each patient with anemia associated with coronavirus disease infection, namely, in the presence of anemic syndrome, it is imperative to include a full range of laboratory tests., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Introduction: During the last decades, the pathogenesis of cold agglutinin disease (CAD) has been well elucidated and shown to be complex. Several documented or investigational therapies have been made available. This development has resulted in major therapeutic advances, but also in challenges in choice of therapy., Areas Covered: In this review, we address each step in pathogenesis: bone marrow clonal lymphoproliferation, composition and effects of monoclonal cold agglutinin, non-complement mediated erythrocyte agglutination, complement-dependent hemolysis, and other effects of complement activation. We also discuss the heterogeneous clinical features and their relation to specific steps in pathogenesis, in particular with respect to the impact of complement involvement. CAD can be classified into three clinical phenotypes with consequences for established treatments as well as development of new therapies. Some promising future treatment approaches - beyond chemoimmunotherapy and complement inhibition - are reviewed., Expert Opinion: The patient's individual clinical profile regarding complement involvement and hemolytic versus non-hemolytic features is important for the choice of treatment. Further development of treatment approaches is encouraged, and some candidate drugs are promising irrespective of clinical phenotype. Patients with CAD requiring therapy should be considered for inclusion in clinical trials.

Various autoimmune diseases have been reported to develop as a result of a coronavirus disease 19 (COVID-19) infection. There have been some reports of COVID-19-triggered autoimmune hepatitis and autoimmune hemolytic anemia infection, but none have reported simultaneous onset of these diseases. A 15-year-old girl was admitted to our hospital with severe liver injury and anemia. Three weeks before admission, her father was diagnosed with COVID-19, after which she became aware of a sore throat. Two weeks later, she visited her doctor for malaise. She was referred to our hospital due to severe anemia, elevated hepatobiliary enzymes, and jaundice. A COVID-19 polymerase chain reaction test was positive at the time of referral. She was diagnosed with autoimmune hemolytic anemia based on decreased hemoglobin and haptoglobin, positive direct Coombs test, and increased urinary urobilinogen. Blood tests were positive for antinuclear antibodies, and a liver biopsy revealed interface hepatitis and plasma cell infiltration, consistent with autoimmune hepatitis. Based on these findings, a diagnosis of autoimmune hepatitis and autoimmune hemolytic anemia triggered by COVID-19 infection was made. Steroid therapy was initiated, which resulted in rapid improvement of blood markers and symptoms., (© 2024. Japanese Society of Gastroenterology.)

Background: Cold agglutination syndrome is a subtype of autoimmune hemolytic anemia. The condition is referred to as "cold" because the antibodies become active and induce hemolysis at cold temperatures, typically 3-4 °C, which is not always the case in other kinds of autoimmune hemolytic anemia. Whereas primary cold agglutination syndrome may occur in the absence of underlying conditions, secondary cold agglutination syndrome is associated with the presence of underlying infections, including coronavirus disease 2019., Case Presentation: We report the case of a 69-year-old Japanese woman with periodontitis who was referred to our hospital with complaints of brown-colored urine and chest pain. Her hemoglobin level was 6.1 g/dL. Computed tomography revealed multiple lung abscesses. Her direct antibody test results were positive (2+) for anti-complement direct antiglobulin and negative for immunoglobulin G, and her cold agglutinin titer was elevated at 1:4096. Workup for anemia revealed a positive result for cold agglutination syndrome. The patient had received the fourth dose of coronavirus disease 2019 vaccination. Nasopharyngeal swab test for detecting severe acute respiratory syndrome coronavirus 2 using a real-time reverse-transcription polymerase chain reaction gave a cycle threshold value of 42.3, and the level of virus-specific immunoglobulin G was elevated at 7.71 S/C (normal range -1.4 S/C)., Conclusion: A decrease in hemoglobin in patients with coronavirus disease 2019 may be associated with secondary cold agglutination syndrome. The patient was hypothesized to have developed multiple lung abscesses with secondary cold agglutination syndrome following coronavirus disease 2019. Thus, following coronavirus disease 2019, patients can develop secondary cold agglutination syndrome, which could worsen owing to associated bloodstream bacterial infections., (© 2024. The Author(s).)

The brown recluse spider ( Loxosceles reclusa ) is endemic to the southcentral Midwest and the Southern United States. A bite from a brown recluse spider may result in symptoms that range from local skin necrosis to systemic complications such as acute haemolytic anaemia, disseminated intravascular coagulopathy, rhabdomyolysis and death. Although rare, systemic loxoscelism is a clinical diagnosis of exclusion that should be considered in a patient with acute autoimmune haemolytic anaemia. We describe a case of a young man with autoimmune haemolytic anaemia secondary to systemic loxoscelism successfully treated with intravenous immunoglobulin and steroids., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

We report here the case of a 50-year-old man who was first diagnosed with myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 2019, resulting in complete remission. However, he was diagnosed in 2021 with several autoimmune disorders, including autoimmune hepatitis (AIH), Hashimoto's thyroiditis (HT), and autoimmune hemolytic anemia (AIHA). This is referred as multiple autoimmune syndrome (MAS), which is a rare occurrence after allo-HSCT, as previously noted in the literature. Despite being treated with glucocorticoids, cyclosporine A, and other medications, the patient did not fully recover. To address the glucocorticoid-refractory MAS, a four-week course of rituximab (RTX) at a weekly dose of 100mg was administered, which significantly improved the patient's condition. Thus, this case report underscores the importance of implementing alternative treatments in patients with post-transplant autoimmune diseases, who are glucocorticoid-refractory or glucocorticoid-dependent, and highlights the effectiveness of RTX as second-line therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xie, Xu, Xu, Zhang, Lin and Yang.)

Background: Red cell alloimmunization remains a challenge for individuals with sickle cell disease (SCD) and contributes to increased risk of hemolytic transfusion reactions and associated comorbidities. Despite prophylactic serological matching for ABO, Rh, and K, red cell alloimmunization persists, in part, due to a high frequency of variant RH alleles in patients with SCD and Black blood donors., Study Design and Methods: We compared RH genotypes and rates of alloimmunization in 342 pediatric and young adult patients with SCD on chronic transfusion therapy exposed to >90,000 red cell units at five sites across the USA. Genotyping was performed with RHD and RHCE BeadChip arrays and targeted assays., Results: Prevalence of overall and Rh-specific alloimmunization varied among institutions, ranging from 5% to 41% (p = .0035) and 5%-33% (p = .0002), respectively. RH genotyping demonstrated that 33% RHD and 57% RHCE alleles were variant in this cohort. Patients with RHCE alleles encoding partial e antigens had higher rates of anti-e identified than those encoding at least one conventional e antigen (p = .0007). There was no difference in anti-D, anti-C, or anti-E formation among patients with predicted partial or altered antigen expression compared to those with conventional antigens, suggesting that variant Rh on donor cells may also stimulate alloimmunization to these antigens., Discussion: These results highlight variability in alloimmunization rates and suggest that a molecular approach to Rh antigen matching may be necessary for optimal prevention of alloimmunization given the high prevalence of variant RH alleles among both patients and Black donors., (© 2024 AABB.)

Cold agglutinins produced in the setting of B cell neoplasms, such as lymphoplasmacytic lymphoma and plasma cell myeloma, can mediate autoimmune haemolytic anemia. Transfusion of these patients can exacerbate cold agglutinin-mediated haemolysis. Moreover, the workup for these reactions represents a diagnostic challenge due in part to false negative direct antiglobulin tests (DATs). Here, we report an anaemic patient who after a red blood cell (RBC) transfusion performed without blood warming, experienced a DAT-negative haemolytic transfusion reaction, and was later diagnosed with IgA-multiple myeloma, which showed an uncommon granular pattern by CD138 immunohistochemistry. Extensive workup excluded other diagnostic possibilities, including the presence of Donath-Landsteiner antibodies and cryoglobulins. Successful treatment with CyBorD (cyclophosphamide, bortezomib and dexamethasone) achieved complete remission, and additional RBC transfusions using warmers were completed uneventfully., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cold agglutinin syndrome (CAS) is a hemolytic anemia mediated by antibodies, mainly IgM, whose maximum activity occurs at 4 °C. It happens secondary to infectious, autoimmune or neoplastic diseases, due to the formation of antibodies that cross-react against erythrocyte antigens, particularly of the I system. Here, we describe a case of CAS associated to Epstein-Barr virus (EBV) reactivation in a patient with primary human immunodeficiency virus (HIV) infection., Clinical Case: 22-year old man with no medical history, hospitalized due to mononucleosis and anemic syndrome. Hemoglobin of 3.7 g/dL and elevation of lactate dehydrogenase were documented. In the peripheral blood smear it was observed spherocytosis, polychromasia and nucleated erythrocytes. EBV infection was confirmed with serology and viral load, as well as seronegative HIV infection with positive viral load. The C3d monospecific direct antiglobulin test was positive and an irregular antibody screening revealed the presence of an anti-I antibody. The patient received transfusion support and conservative treatment, with remission of the symptoms 2 weeks after admission., Conclusions: Cold agglutinin syndrome is a rare, potentially fatal complication of infectious mononucleosis, which should be considered in the face of findings suggestive of hemolysis in order to initiate support measures in a timely manner., (Licencia CC 4.0 (BY-NC-ND) © 2024 Revista Médica del Instituto Mexicano del Seguro Social.)

Autoimmune hemolytic anemia (AIHA) is caused by autoantibodies that can be divided into two types-warm and cold-depending on their thermal amplitudes. The pathology differs depending on the type of autoantibody involved; however, the underlying etiology can differ even when the pathology is the same. Therefore, understanding the underlying mechanisms and making an accurate diagnosis is critical, as inappropriate treatment not only results in treatment failure, but can also cause life-threatening complications and reduce patient quality of life. Corticosteroids are the first-line treatment for warm AIHA, but have limited efficacy against cold agglutinin disease (CAD). Moreover, long-term and high-dose administration of corticosteroids increases risk of infection, fracture, and thromboembolism. A novel therapeutic agent for CAD targeting the complement system is effective only against hemolysis, but does not improve symptoms induced by red blood cell aggregation. In addition, elderly patients who present with either warm AIHA or CAD should also be assessed for possible malignancy. This review discusses the etiologies and pathological conditions associated with AIHA and describes the recommendations for diagnosis and treatment according to the Japanese guideline for AIHA revised in 2022.

Introduction: Inborn errors of immunity (IEIs) are inherited disorders that present with increased susceptibility to infections as well as noninfectious complications. Due to the aberrant immune functions of patients with IEI, autoimmune cytopenia (AIC) may be the initial finding, which makes diagnosis a challenge. We aimed to evaluate the clinical course, laboratory findings, and treatment response of AIC in children with IEI., Methods: Data of children with autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenic purpura (ITP) were obtained from a retrospective chart review of IEI patients diagnosed and followed in our center. Demographic and clinical features and therapeutic outcomes were evaluated. Immunologic findings were compared between patients with AIHA, ITP, and Evans syndrome (ES). The patients were also divided into two subgroups based on the presence or absence of immune dysregulation diseases (IDDs), and all data were compared between these two groups., Results: Out of 562 patients with IEI, 6% (n: 34) had AIC which were ITP (23.5%), AIHA (35.5%), and ES (41.2%). AIC was the initial finding in 50% of these 34 patients. Patients with ES had a higher mean percentage of CD8+ T lymphocytes than ITP patients (40.77 ± 20.21% vs. 22.33 ± 12.48%, p = 0.011). Patients with IDDs were more likely to develop ES (p = 0.004), lymphoproliferation (p = 0.005), and resistance to first-line therapy (p = 0.021) than other IEI groups., Conclusion: This study shows that AIC may be the initial finding of IEI, particularly when lymphoproliferation and resistance to first-line therapy co-occur. Therefore, detailed investigation should be offered to all patients to avoid diagnostic delay., (© 2023 S. Karger AG, Basel.)

Autoimmune hemolytic anemia (AIHA) can be life-threatening, if hemoglobin (Hb) levels continue to decline after established treatments with glucocorticoids, rituximab, intravenous immunoglobulins, and plasmapheresis. Impaired regulatory T cells (Treg) are proposed to alleviate AIHA development through decreased binding of CTLA-4 to antigen-presenting cells. Abatacept is a fusion protein with a CTLA-4 domain and is approved for use in rheumatoid arthritis. It mimics the immunosuppressive CTLA-4 effect of Treg. Thus, application of abatacept in refractory AIHA might be reasonable. A 54-year-old woman with known AIHA was admitted to our clinic due to therapy-refractory hemoglobin decrease to 4.0 g/dl. Previously, multiple courses of glucocorticoids, rituximab, azathioprine, mycophenolate mofetil, cyclophosphamide, bortezomib, and a splenectomy failed to stop or stabilize hemoglobin levels and hemolysis. A new immunosuppressive therapy with cyclosporine was initiated and erythropoiesis was stimulated with darbepoetin alfa. Again, therapy failed even though we tried to support immunosuppressive therapy by reducing the amount of pathogenic antibody through plasmapheresis. We stopped the treatment with cyclosporine and applied abatacept instead. After seven days hemoglobin stabilized at 4.3 g/dl and no further red blood cells transfusions were necessary. About one month later hemolysis aggravated again and azathioprine was added to the ongoing abatacept treatment. Finally, the combination of abatacept and azathioprine led to a long-lasting increase of the Hb level above 11 g/dl six months later. Abatacept can be applied to overcome therapy refractory autoimmune hemolytic anemia but should be combined with an additional immunosuppressive medication such as azathioprine.

Objectives: Primary cold agglutinin disease is a type of autoimmune hemolytic anemia caused by circulating antibodies against I antigen, a carbohydrate expressed on most cells, including red blood cells. The underlying disease has been characterized in recent years as a distinct B-cell lymphoproliferative disease of the bone marrow, occurring mostly in the elderly. The disease has been now been included as a separate entity in the most recent classifications of mature B-cell neoplasms., Methods: A review of the characteristics of cold agglutinin disease is provided, with an emphasis on the pathology features., Results: A detailed description of the histopathology, immunophenotype, and genetics of cold agglutinin disease is provided and compared to other B-cell lymphoproliferative diseases in the bone marrow with similar features., Conclusions: Recognition of the pathology features of cold agglutinin disease allows to distinguish it from other diseases, especially lymphoplasmacytic lymphoma and marginal zone lymphoma., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia. This study aimed to identify disease-related symptoms and impacts important to patients with CAD, and to develop a novel CAD-specific patient-reported outcome measure., Methods: Adults with CAD were randomly selected from a United States patient panel to participate in concept elicitation (CE) interviews to identify important symptoms and impacts or cognitive debriefing (CD) interviews to assess the comprehension and relevance of the draft item set., Results: Overall, 37 adults were included (mean [range] age 67.2 [35-87] years). In CE interviews (n = 16), the most frequently reported CAD-related symptoms were reactions to cold environments and fatigue (both 93.8%). CAD had negative impacts on enjoyable activities (81.3%) and daily activities (75.0%). Following CE, standard survey methodological principles were used to develop a draft item pool of 14 concepts. Items were refined through three iterative rounds of CD interviews (n = 21), yielding 11 final items: fatigue; cold sensitivity; dyspnea; wearing extra clothing; limited physical, social, and enjoyable activities; difficulty with usual activities; mood; frustration; and anxiety/stress., Conclusions: The novel 11-item CAD-Symptoms and Impact Questionnaire provides a measure of the symptoms and impacts of CAD that are important to patients., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Autoimmune hemolytic anemia (AIHA) is a group of diseases characterized by immune-mediated lysis of mature red blood cells (RBCs). It is mainly classified into primary and secondary types based on etiology and mechanisms underlying autoantibody production. AIHA is diagnosed using morphological observation of bone marrow smears under a light microscope and monospecific direct antiglobulin test to detect hemolysis. Here, we retrospectively studied ultrastructural abnormalities of nucleated erythroid cells in bone marrows from 10 patients with AIHA using transmission electron microscopy. Our results revealed severe damage and injury to nucleated erythroid cells, including morphological irregularity, pyknosis, karyolysis, expansion of perinuclear cisternae and cytoplasmic lysis. These results indicate that aberrant immunity attacks not only mature RBCs but also nucleated erythroid cells, and ineffective hematopoiesis is partly involved in the pathogenesis of AIHA.

Background and Aim: Autoimmune hemolytic anemias (AIHA) constitute a rare and heterogeneous group of diseases whose therapy differs according to the type of antibody involved in the genesis of the disease and the existence or not of an identified cause. With the aim of providing a practical guide for the therapy of AIHA, we summarize the emergency therapy and general measures habitually used in all forms of AIHA, as well as the specific treatment of the most frequent primary forms of AIHA: primary warm AIHA and AIHA from cold agglutinin disease (AIHA from CAD). We discuss the dependence of the treatment of the secondary forms on their underlying causes and the changes in the treatment of the primary forms in recent years., Methods: We examined the options available for the treatment of primary warm AIHA and AIHA from CAD., Results: We found many differences and only one similarity in their treatment., Discussion: The differences, particularly due to the non-responsiveness of AIHA from CAD to many treatments useful for primary warm AIHA, such as steroids, splenectomy and immunosuppressive agents, must be considered in the face of each, single case of AIHA. Preliminary identification of the type of antibody involved in the genesis of the disease and careful exclusion of a secondary form are particularly important. Rituximab plays a central role in the treatment of primary warm AIHA and AIHA from CAD., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Coronavirus disease 2019 (COVID-19) vaccines are considered to be safe. Only few cases of vaccine-induced immune thrombocytopenia or immune hemolysis have been reported so far. Evans syndrome (ES) is a very rare syndrome characterized mainly by warm autoimmune hemolytic anemia (wAIHA) and immune thrombocytopenia (ITP)., Case Presentation: We present a case of a 47-year-old male with a history of wAIHA, diagnosed in 1995 and successfully treated with glucocorticoids, with sustained remission. ITP was diagnosed in May 2016. Due to refractoriness to glucocorticoids, intravenous immunoglobulins (IVIGs), azathioprine and vinblastine, he was splenectomised in April 2017, resulting in complete remission. In May 2021, eight days after the second dose of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine, he experienced mucocutaneous bleeding. Blood tests showed platelet count (PC) of 8×109/L, while his hemoglobin (Hb) was normal (153 g/L). He was treated with prednisone and azathioprine, without response. On day 28 after vaccine administration, weakness, jaundice and dark brown urine occurred. His laboratory tests: PC 27×109/L, Hb 45 g/L, reticulocytes 10.4%, total bilirubin 106.6 μmol/L, direct bilirubin 19.8 μmol/L, lactate dehydrogenase 633 U/L, haptoglobin ˂0.08 g/L, and positive Coombs test were consistent with ES relapse. After treatment with glucocorticoids, azathioprine and IVIGs, his blood count finally improved (PC 490×109/L, Hb 109 g/L) and remained stable on day 40 of hospitalization., Conclusions: Although it is unclear whether the relationship between COVID-19 vaccination and relapse of ES in our patient is coincidental or causal, it highlights the need for monitoring of serious outcomes following vaccination., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2023 Mirjana Cvetković, Nikola Pantić, Marijana Virijević, Zlatko Pravdić, Nikica Sabljić, Mirjana Mitrović, Nada Suvajdžić-Vuković.)

Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia often overlooked as a potential etiology of hemolysis and is challenging to diagnose because of the complicated testing methods required. We performed a systematic review of all reported cases to better assess the clinical, immunohematologic, and therapeutic characteristics of PCH. We systematically analyzed PubMed, Medline, and EMBASE to identify all cases of PCH confirmed by Donath-Landsteiner (DL) testing. Three authors independently screened articles for inclusion, and systematically extracted epidemiologic, clinical, laboratory, treatment, and outcomes data. Discrepancies were adjudicated by a fourth author. We identified 230 cases, with median presentation hemoglobin of 6.5 g/dL and nadir of 5.5 g/dL. The most common direct antiglobulin test (DAT) result was the presence of complement and absence of immunoglobulin G (IgG) bound to red blood cells, although other findings were observed in one-third of cases. DL antibody class and specificity were reported for 71 patients, of which 83.1% were IgG anti-P. The use of corticosteroids is common, although we found no significant difference in the length of hospitalization for patients with and without steroid therapy. Recent reports have highlighted the use of complement inhibitors. Among patients with follow-up, 99% (213 of 216) were alive at the time of reporting. To our knowledge, this represents the largest compilation of PCH cases to date. We discovered that contemporary PCH most commonly occurs in children with a preceding viral infection, corticosteroid use is frequent (but potentially ineffective), and DAT results are more disparate than traditionally reported., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenia (ITP) are two uncommon haematologic autoimmune conditions that can rarely arise secondary to vaccination. Prior studies using the US Centers for Disease Control's (CDC) Vaccine Adverse Event Reporting System (VAERS) have demonstrated this infrequency, but contemporary data as well as comparison with current information regarding SARS-CoV-2 vaccination has not been assessed. In this study, we reviewed VAERS database reports from 1990 to 2022 to characterize the incidence and clinical and laboratory findings of non-SARS-CoV-2-associated AIHA and ITP and SARS-CoV-2 vaccine-associated AIHA and ITP. We discovered a total of 863 AIHA and ITP reports following vaccination with 15 non-SARS-CoV-2 and four SARS-CoV-2 vaccines submitted to the CDC VAERS database. AIHA and ITP reporting was low for both groups, with a large proportion excluded due to a lack of clinical details. ITP was reported the most frequently in both groups and was significantly more common with measles-mumps-rubella (MMR) vaccination (p < 0.001) in the non-SARS-CoV-2 group. AIHA and ITP cases were higher in the SARS-CoV-2 vaccine group, though ultimately still very infrequent. Autoimmune haematologic disease is vanishingly rare after immunization and rates are lower than in the general population according to passive reporting., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

COVID-19 mRNA vaccines manufactured by Pfizer-BioNTech and Moderna have been approved in many countries, and have been administered since 2020. Recent reports of mRNA vaccination exacerbating autoimmune hematologic disorders, such as immune thrombocytopenia or autoimmune hemolytic anemia, have caught the attention of the general public, resulting in alarm over the risks of serious consequences. Meanwhile, in very rare cases, vaccination was reported to trigger new onset of hemolytic anemia. However, it remains unknown whether this was a transient reaction or a persistent event, because all cases reported to date were immediately treated with corticosteroids or rituximab. Here, we present a case of newly diagnosed cold agglutinin disease after a third COVID-19 mRNA vaccination. The patient was followed for 4 months without treatment and continued to exhibit high levels of cold agglutinin and aggregation of red blood cells. The present case indicates that the disease can become chronic, and provides insights into the pathogenesis and treatment strategies., (© 2022. Japanese Society of Hematology.)

Autoimmune hemolytic anemia (AIHA) is caused by the production of autoantibodies against RBCs. COVID-19 vaccines can reduce the risk of severe disease, however, various adverse effects such as AIHA were observed following vaccination. This review aimed to assess the relationship of AIHA and COVID-19 vaccination using the PRISMA guidelines. Among 18 cases included in this review, new post-vaccination AIHA development was reported in 11 patients (7 women and 4 men) with a median age of 67.0 years. In 7 of 11 and 3 of 11 cases, the onset of symptoms occurred after first and second vaccine dose with median times of 7 and 14 days, respectively. In 1 of 11 cases, the AIHA occurred on Day 17 after booster vaccination. Ten of 11 and 1 of 11 AIHA patients received mRNA- and vector-based vaccine, respectively. After vaccination, 9 of 11, 1 of 11, and 1 of 11 AIHA patients developed warm IgG, cold IgM, and mixed autoantibodies against RBCs, respectively. Significant AIHA exacerbation was reported in seven patients (four women and three men) with a median age of 73.0 years. In 4 of 7 and 2 of 7 exacerbated AIHA cases, the onset of symptoms occurred after first and second vaccine dose with median times of 7 and 3 days, respectively. In 1 of 7 exacerbated AIHA cases, the onset of symptoms was observed on Day 2 after booster vaccination. All exacerbated AIHA cases received mRNA-based vaccines; 3 of 7 and 4 of 7 exacerbated AIHA cases developed IgG and IgM against RBCs, respectively. This review provides a comprehensive explanation regarding the AIHA development and exacerbation after COVID-19 vaccination., (© 2022 John Wiley & Sons Ltd.)

Thrombotic complications are a hallmark of antiphospholipid syndrome (APS). These vascular - arterial, venous, and/or small vessel - complications are well described and known to hematologists and healthcare providers caring for patients with this disease. In this review, we shed light on other hematological manifestations of the disease, including bleeding, thrombocytopenia, autoimmune hemolytic anemia, and thrombotic microangiopathy syndromes. While these manifestations are not bona fide clinical criteria for the diagnosis of APS, they frequently interact and contribute to the complexity of clinical management of APS., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Autoimmune haemolytic anaemia (AIHA) is a decompensated acquired haemolysis caused by the host's immune system acting against its own red cell antigens. The aim of this national survey is to capture real-world data of clinical practices in AIHA by collecting responses from clinical haematologists across India., Methodology: In this cross-sectional study, a structured, 26-question online survey was conducted in India by few members of the special interest group in immunohaematology between January and March, 2022. The final survey consisted of questions covering place of work, amount of AIHA cases being evaluated by the haematologist over preceding years, basic demographic, clinical and laboratory features of the patients being treated under them etc. Descriptive statistical analysis was performed during the assessment., Results: The survey response rate was 48.2% (53/110), 69.8% (37/53) have diagnosed and managed more than 10 AIHA cases in the last 3 years with a female preponderance. There was considerable variability in response. While 56.6% (30/53) of respondents do have the access to the facilities to subtype AIHA cases; 32.1% (17/53) of clinicians would prefer administering high dose steroids for 6 weeks or more in non-responding patients, and only 45.3% (24/53) would assess the risks of thrombosis in AIHA. There is unanimous agreement among the participants that health-related quality of life should be taken into consideration in patients and the need for a national registry of patients with AIHA in India., Conclusion: The current national survey showed that some aspects of AIHA management were consistent; others were less so, but also significant variations were observed in certain clinical practices, where the evidence base is limited. A joint effort is needed to establish a national patient registry by including both clinical haematologists and transfusion medicine specialists which could potentially standardise AIHA management and future research in India., (Copyright © 2022 Société française de transfusion sanguine (SFTS). Published by Elsevier Masson SAS. All rights reserved.)

The development and exacerbation of autoimmune diseases following coronavirus disease 2019 (COVID-19) vaccination have been reported; however, there are few reports of autoimmune hemolytic anemia (AIHA). A 75-year-old woman was admitted to the emergency department 46 days after receiving her third dose of the mRNA-1273 COVID-19 vaccine because of fatigue and general weakness. Initial laboratory analyses revealed severe hemolytic anemia with positive direct and indirect Coombs test and elevation of serum indirect bilirubin and lactate dehydrogenase. The patient had no underlying disease after a close examination and was diagnosed with warm AIHA, which was thought to be associated with COVID-19 vaccination. The anemia improved daily after the administration of prednisolone. Clinicians should be aware of the possibility of AIHA being caused by COVID-19 vaccination, and monotherapy with prednisolone should be considered in cases of severe anemia.

A 68-year-old man was referred to our hospital with dizziness and mild fever one week after receiving the second dose of the COVID-19 mRNA vaccine (BNT162b2). Laboratory tests showed hemolytic anemia and a positive direct Coombs test, and he was diagnosed with autoimmune hemolytic anemia (AIHA). On admission, the patient had impaired consciousness with auditory hallucinations, and a head MRI scan showed multiple high-signal areas on diffusion-weighted imaging, suggesting multiple recent infarctions. Echocardiography also showed decreased wall motion in the inferior and posterior walls. A skin biopsy to investigate the cause revealed many platelets and fibrin thrombi in the capillaries and small veins, which was considered the cause of the organ damage. After starting prednisolone (1 mg/kg) for AIHA, hemolytic anemia as well as impaired consciousness, and decreased wall motion rapidly improved. Microthrombosis after BNT162b2 mRNA vaccination is rare, and autoimmune abnormalities appeared to contribute to onset in this case.

Cold agglutinin disease (CAD) is a rare form of acquired autoimmune hemolytic anemia driven mainly by antibodies that activate the classical complement pathway. Several patients with CAD experience its development or exacerbation of hemolysis after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or after receiving the SARS-CoV-2 mRNA vaccine. Therefore, these patients cannot receive an additional SARS-CoV-2 mRNA vaccination and have a higher risk of severe SARS-CoV-2 infection. Sutimlimab is a monoclonal antibody that inhibits the classical complement pathway of the C1s protein and shows rapid and sustained inhibition of hemolysis in patients with CAD. However, whether sutimlimab could also inhibit hemolysis caused by SARS-CoV-2 mRNA vaccination is uncertain. Here, we present the case of a 70-year-old man with CAD who repeatedly experienced a hemolytic crisis after receiving SARS-CoV-2 mRNA vaccines. The patient eventually underwent SARS-CoV-2 mRNA vaccination safely, without hemolytic attack, under classical pathway inhibition therapy with sutimlimab. This report suggests that appropriate sutimlimab administration can suppress SARS-CoV-2 mRNA vaccination-induced CAD exacerbation, and that it could be a preventive strategy to minimize hemolytic attacks in susceptible populations.

Objectives: Describe the development of warm autoimmune hemolytic anemia warm (AIHA) secondary to a brown recluse spider ( Loxosceles reclusa ) bite is known as systemic loxoscelism; and review epidemiology, clinical manifestations, diagnostic work-up, pathophysiology, and treatment options associated with warm AIHA secondary to systemic loxoscelism., Methods: Cases series of two cases of warm AIHA due to systemic loxoscelism and a review of the current literature: epidemiology, clinical manifestations, diagnostic work-up, pathophysiology, and treatment options associated with warm AIHA secondary to systemic loxoscelism., Results: Presented here are two cases of warm AIHA due to systemic loxoscelism. Each patient was generally healthy appearing and presented with symptomatic anemia in the setting of brown recluse spider bites. Both patients were eventually found to have warm AIHA. Upon recognition of the diagnosis, the patients were started on corticosteroids and aggressive intravenous fluid hydration. In addition, they received transfusions of packed red blood cells. Their clinical courses improved, and they recovered to eventually be discharged home., Conclusion: Envenomation by a brown recluse spider, Loxosceles reclusa , can result in systemic loxoscelism which can cause warm AIHA. The diagnosis of warm AIHA is confirmed by the direct antiglobulin/Coomb's test. Warm AIHA can be a life-threatening disease process. Hemodynamic support with intravenous fluids and RBC transfusion is the initial step in the management of these patients. Corticosteroids are the mainstay of current management. Second line treatments include rituximab. Rarely patients require splenectomy for refractory disease. Corticosteroids should be tapered over a three-month period.

Background and Objectives: Sickle cell disease (SCD) patients are commonly treated with red blood cell (RBC) transfusion. Pretransfusion tests commonly involve limited serological antibody testing. RBC alloimmunization to RBC antigens is a frequently encountered complication seen in chronically transfused patients. Genetic factors such as the human leukocyte antigen (HLA) are known to influence and regulate immune responses. HLAs are highly polymorphic and play an essential role in regulating immune responses, including RBC alloimmunization. The aim of this study was to conduct a systematic review and meta-analysis to evaluate the association between HLA Class II allelic polymorphisms with the possible risk of developing RBC alloantibodies., Materials and Methods: Four databases were systematically searched for relevant studies between the years 2000 and 2021 following the PRISMA guidelines. Four articles met the eligibility and quality criterion, and three alleles, HLA-DRB1*04, HLA-DRB1*15 and HLA-DQB1*03, that were found to be potentially associated with an increased risk in alloantibody formation were included., Results: The primary outcome measure was alloimmunization by RBC antigen exposure in multiply transfused SCD patients. The total estimate of alloimmunization of the SCD patients was 2.33 (95% CI, 1.58-3.44), demonstrating susceptibility to RBC alloantibody formation. Heterogeneity between the studies was insignificant, suggesting the differences associated with random sampling errors. The results showed that SCD patients carry an increased risk of producing RBC alloantibodies., Conclusion: A strategy to prevent RBC alloimmunization is genotyping for genetically susceptible SCD patients receiving multiple transfusions. Early identification of genetic variants that can potentially increase the risk of RBC alloimmunization could aid in the screening process and selection of phenotypically matched RBC units., (© 2022 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Management of hemolytic disease of the fetus and newborn relies on monitoring of maternal antibody titers, fetal ultrasound, and fetal middle cerebral artery peak systolic velocity studies and is generally treated by intrauterine transfusion (IUT). Few studies have explored fetal and neonate physiological responses to IUT. Our objective was to examine fetal erythropoietic response and to examine neonatal erythropoietic effects after treatment. Thirty-six patients treated from 2005 to 2015 were identified retroactively. The time course of treatment, including gestational age and number of IUT, and timing of delivery were reviewed. Fetal reticulocyte count and neonatal hemoglobin and reticulocyte counts were analyzed for each IUT. For each gestational week, reticulocyte count decreased by ∼8.6% (95% confidence interval [CI]: 5.3-12.0). In the neonatal period, there was significant correlation between hemoglobin at birth and number of transfusions (Spearman correlation 0.473, 95% CI: 0.113-0.715, P =0.01) as well as reticulocyte count at birth and number of transfusions (Spearman correlation: 0.393, 95% CI: 0.058-0.642, P =0.02). IUT appears to have a direct and measurable effect on fetal reticulocyte production which persists in neonates., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID). CVID is a heterogenous condition and clinical manifestations may vary from increased susceptibility to infections to autoimmune manifestations, granulomatous disease, polyclonal lymphoproliferation, and increased risk of malignancy. Autoimmune manifestations may, at times, be the first and only clinical presentation of CVID, resulting in diagnostic dilemma for the treating physician. Autoimmune cytopenias (autoimmune haemolytic anaemia and/or thrombocytopenia) are the most common autoimmune complications seen in patients with CVID. Laboratory investigations such as antinuclear antibodies, direct Coomb's test and anti-platelet antibodies may not be useful in patients with CVID because of lack of specific antibody response. Moreover, presence of autoimmune cytopenias may pose a significant therapeutic challenge as use of immunosuppressive agents can be contentious in these circumstances. It has been suggested that serum immunoglobulins must be checked in all patients presenting with autoimmune cytopenia such as immune thrombocytopenia or autoimmune haemolytic anaemia. It has been observed that patients with CVID and autoimmune cytopenias have a different clinical and immunological profile as compared to patients with CVID who do not have an autoimmune footprint. Monogenic defects have been identified in 10-50% of all patients with CVID depending upon the population studied. Monogenic defects are more likely to be identified in patients with CVID with autoimmune complications. Common genetic defects that may lead to CVID with an autoimmune phenotype include nuclear factor kappa B subunit 1 (NF-kB1), Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA), cytotoxic T lymphocyte antigen 4 (CTLA4), Phosphoinositide 3-kinase (PI3K), inducible T-cell costimulatory (ICOS), IKAROS and interferon regulatory factor-2 binding protein 2 (IRF2BP2). In this review, we update on recent advances in pathophysiology and management of CVID with autoimmune cytopenias., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chawla, Barman, Tyagi, Jindal, Sharma, Rawat and Singh.)

This report describes a case of Autoimmune Hemolytic Anemia that was possibly induced by COVID-19 in a patient with history of Chronic Liver Disease and Diabetes Mellitus. Autoimmune responses like hemolytic anemia are known to be triggered by viral infections. COVID-19 is reported to be inducing Autoimmune Hemolytic Anemia in susceptible individuals. This is a case report of a 65 year old male with history of chronic alcoholism, who tested positive for COVID-19 infection which was treated as per protocols and was uncomplicated at the time of discharge. After about three months he presented with complaints of breathlessness which on laboratory evaluation revealed Direct Coombs test positive hemolytic anemia. Anemia improved with blood transfusion and steroid administration but patient eventually developed hepatorenal syndrome and expired., (© Journal of the Association of Physicians of India 2011.)

Background and Objectives: The transfusion of D-negative red blood cells (RBCs) to D-negative patients has been widely adopted to prevent anti-D alloimmunization, especially in women of childbearing age. Still, transfusion of D-positive RBCs to D-negative recipients is occasionally inevitable in practice, and the resulting incidence of anti-D in different D-negative groups of patients has not been well summarized., Materials and Methods: We searched the relevant literature using PubMed, Cochrane Library, and Embase databases from inception date to 30 September 2021. We looked for studies of anti-D occurring in D-negative recipients who received D-positive RBC transfusions. The anti-D incidence was summarized with 95% confidence intervals (CIs). Data with similar characteristics were combined using a random-effects model., Results: About 42 studies (2226 cases), which found anti-D, the exact volume of D-positive RBC transfused, and the follow-up time for anti-D detection, met the inclusion criteria. The pooled anti-D incidence was 64% (95% CI, range 55%-74%) in volunteers receiving small volumes of D-positive RBCs, 84% (95% CI, 74%-94%) in those receiving whole units, 26% (95% CI, 19%-32%) in mixed patients, 12% (95% CI, 8%-16%) in oncology patients, 27% (95% CI, 13%-40%) in trauma patients, 4% (95% CI, 0%-8%) in immune-compromised transplant patients, and 6% (95% CI, 1%-39%) in those with AIDS., Conclusion: Compared with the high frequency of anti-D in healthy D-negative volunteers given D-positive RBCs, we found a lower rate of anti-D immunization in various D-negative patients and almost none in transplant and AIDS patients., (© 2022 International Society of Blood Transfusion.)