Evans syndrome (ES) is a rare and chronic autoimmune disease characterized by the concomitant or sequential association of auto-immune hemolytic anemia (AIHA) with immune thrombocytopenia (ITP), and less frequently autoimmune neutropenia. Coronavirus disease 2019 (Covid-19) may cause various hematologic conditions. COVID-19 may also induce Evans syndrome via immune mechanisms. Here, we describe the case of a patient developing Evans syndrome as initial presentation of Covid-19 infection.

Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia often overlooked as a potential etiology of hemolysis, and is challenging to diagnose due to 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 (IQR 4.8-9.0 g/dL) and nadir of 5.5 g/dL (IQR 4.4-7.2 g/dL). The most common direct antiglobulin test (DAT) result was the presence of complement and absence of IgG bound to red blood cells, though other findings were observed in one-third of cases. Seventy-one patients had DL antibody class and specificity reported, of which 83.1% were IgG anti-P. The use of corticosteroids is common, though 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. Amongst patients with follow-up, 99% (213/216) were alive at the time of reporting. To our knowledge, this represents the largest compilation of PCH cases to date. We discovered 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.

Relapsing or occurring de novo autoimmune hemolytic anemia (AIHA) during pregnancy or puerperium is a poorly described condition. Here we report 45 pregnancies occurring in 33 women evaluated at 12 centers from 1997 to 2022. Among the 20 women with AIHA diagnosis before pregnancy, 10 had a relapse. Additional 13 patients developed de novo AIHA during gestation/puerperium (two patients had AIHA relapse during a second pregnancy). Among 24 hemolytic events, anemia was uniformly severe (median Hb 6.4 g/dL, range 3.1-8.7) and required treatment in all cases (96% steroids +/- intravenous immunoglobulin, IVIG, 58% transfusions). The response was achieved in all cases and was complete in 65% of cases. Antithrombotic prophylaxis was administered in eight patients (33%). Rituximab was administered in four patients, and cyclosporine was added in one after delivery. The rate of maternal complications was 15%, including premature rupture of membranes, placental detachment, and preeclampsia. Early miscarriages occurred in 13% of pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and two perinatal deaths. In conclusion, the occurrence of AIHA does not preclude the ability to carry a healthy pregnancy, provided close monitoring, prompt therapy, and awareness of potential maternal and fetal complications.

Therapeutic options for rare congenital (hemoglobinopathies, membrane and enzyme defects, congenital dyserythropoietic anemia) and acquired anemias [warm autoimmune hemolytic anemia (wAIHA), cold agglutinin disease CAD, paroxysmal nocturnal hemoglobinuria (PNH), and aplastic anemia (AA)] are rapidly expanding. The use of luspatercept, mitapivat and etavopivat in beta-thalassemia and pyruvate kinase deficiency (PKD) improves transfusion dependence, alleviating iron overload and long-term complications. Voxelotor, mitapivat, and etavopivat reduce vaso-occlusive crises in sickle cell disease (SCD). Gene therapy represents a fascinating approach, although patient selection, the toxicity of the conditioning regimens, and the possible long-term safety are still open issues. For acquired forms, wAIHA and CAD will soon benefit from targeted therapies beyond rituximab, including B-cell/plasma cell targeting agents (parsaclisib, rilzabrutinib, and isatuximab for wAIHA), complement inhibitors (pegcetacoplan and sutimlimab for CAD, ANX005 for wAIHA with complement activation), and inhibitors of extravascular hemolysis in the reticuloendothelial system (fostamatinib and FcRn inhibitors in wAIHA). PNH treatment is moving from the intravenous anti-C5 eculizumab to its long-term analog ravulizumab, and to subcutaneous and oral proximal inhibitors (anti-C3 pegcetacoplan, factor D and factor B inhibitors danicopan and iptacopan). These drugs have the potential to improve patient convenience and ameliorate residual anemia, although patient compliance becomes pivotal, and long-term safety requires further investigation. Finally, the addition of eltrombopag significantly ameliorated AA outcomes, and data regarding the alternative agent romiplostim are emerging. The accelerated evolution of treatment strategies will need further effort to identify the best candidate for each treatment in the precision medicine era.

Tuberculosis (TB) has varied manifestations, but autoimmune hemolytic anemia (AIHA) due to TB is rare. Direct antibody test (DAT) or Coombs negative AIHA is also rare. We report a case of a 14-year-old boy who presented with hemolytic anemia and pneumonia. The Coombs test was repeatedly negative. After ruling out the possible infectious and noninfectious causes by extensive investigations, he was diagnosed as DAT-negative AIHA by monospecific antibody test with 4°C low ionic strength saline washes and column agglutination method which revealed the presence of IgG-2+ antibodies. Bronchoalveolar lavage fluid for acid-fast bacilli and gene Xpert was also positive. It is important to recognize TB as a cause of AIHA in South Asian countries where its incidence is high.

The application of flow cytometry (FC) is diverse and this powerful tool in used in multiple disciplines such as molecular biology, immunology, cancer biology, virology, and infectious disease screening. FC analyzes a single cell or a particle very rapidly as they flow past single or multiple lasers while suspended in buffered solution. FC has a great impact in the field of transfusion medicine (TM) due to its ability to analyze individual cell population and cell epitopes by sensitive, reproducible, and objective methodologies. The main uses of FC in TM are detection of fetomaternal hemorrhage, diagnosis of paroxysmal nocturnal hemoglobinuria, quantification of D antigen, detection of platelet antibody, quality control of blood components, for example, residual leukocyte counts and evaluation of CD34-positive hematopoietic progenitor cells in stem cell grafts. In recent years, FC has been implemented as an alternative method for the detection and characterization of red cell autoantibodies in autoimmune hemolytic anemia. Many workers considered FC as a very good complement when aberrant expression of various erythrocyte antigens needs to be elucidated. It has been extensively used in the resolution of ABO discrepancies and chimerism study. FC has also been used successfully in various platelet immunological studies. In the recent past, FC has been used in several studies to assess the platelet storage lesions and elucidate granulocyte/monocyte integrity and immunology. FC analysis of CD34+ stem cells is now the method of choice to determine the dosage of the collected progenitor cells. The technique is vastly used to evaluate residual leukocytes in leukodepleted blood components. We conclude that flow cytometers are becoming smaller, cheaper, and more user-friendly and are available in many routine laboratories. FC represents a highly innovative technique for many common diagnostic and scientific fields in TM. Finally, it is the tool of choice to develop and optimize new cellular and immunotherapeutic trials.

Haptens are small molecules that only elicit an immune response when bound to proteins. Haptens initially bind to self-proteins and activate innate immune responses by complex mechanisms via inflammatory cytokines and damage-associated molecular patterns and the subsequent upregulation of costimulatory signals such as cluster of differentiation 86 (CD86) on dendritic cells. Subsequent interactions between CD86 and CD28 on T cells are critically important for properly activating naive T cells and inducing interleukin 2 production, leading to the establishment of adaptive immunity via effector and memory T cells. Accumulating evidence revealed the involvement of haptens in the development of various autoimmune-like diseases such as allergic, inflammatory, and autoimmune diseases including allergic contact dermatitis, atopy, asthma, food allergy, inflammatory bowel diseases, hemolytic anemia, liver injury, leukoderma, and even antitumor immunity. Therefore, the development of in vitro testing alternatives to evaluate in advance whether a substance might lead to the development of these diseases is highly desirable. This review summarizes and discusses recent advances in chemical- and drug-induced allergic, inflammatory, and autoimmune diseases via haptenation and the possible molecular underlying mechanisms, as well as in vitro testing alternatives to evaluate in advance whether a substance might cause the development of these diseases.

Classically, deficiencies of vitamin B12 and folate are associated with megaloblastic anaemia. Additionally, vitamin B12 is able to cause a haemolytic anaemia in the form of pseudo-thrombotic microangiopathy (pseudo-TMA). Here, we present a case of a middle-aged woman with a history of Roux-en-Y gastric bypass who presented with dyspnoea and fatigue and was found to have thrombocytopenia and a non-immune haemolytic anaemia. Work-up for haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, paroxysmal nocturnal haemoglobinuria, infection, malignancy and autoimmune conditions was unremarkable. Her haemolytic anaemia and thrombocytopenia resolved with folate replenishment. She was diagnosed as likely having pseudo-TMA secondary to folate deficiency.

In this article, we report the rare phenomenon of erythrophagocytosis by neutrophils in peripheral blood smear of a 56-year-old male patient with concurrent myelodysplastic syndrome and cold agglutinin disease.

Evans syndrome is a rare autoimmune disease, characterized by at least two immune cytopenias, most frequently anemia and thrombocytopenia and rarely immune neutropenia. It has a variable clinical presentation and is rarely diagnosed in adults. It can be idiopathic or secondary to lymphoproliferative disease, infections, autoimmune diseases, drugs, and immunodeficiencies in about 50% of cases. It is characterized by a chronic, relapsing, potentially fatal course due to its hemorrhagic complications as well as complications associated with the long-term immunosuppressive treatment required to control the disease, such as infectious diseases, and cardiovascular and renal complications. Its prognosis depends on the underlying cause. Because of its rarity, the treatment is empirical, based mostly on case series and recommendations for the treatment of other immune cytopenias. The underlying disease and demographic characteristics also play an important role in choosing the treatment, which should be adapted individually to each patient. We present a case of an elderly patient with idiopathic autoimmune hemolytic anemia and thrombocytopenia, refractory to various treatment options.

The B cell antigen receptor (BCR)-repertoire is capable of recognizing a nearly unlimited number of antigens. Inevitably, the random nature of antibody gene segment rearrangement, needed in order to provide mature B cells, will generate autoreactive specificities. Once tolerance mechanisms fail to block the activation and differentiation of autoreactive B cells, harmful autoantibodies may get secreted establishing autoimmune diseases. Besides the hallmark of autoimmunity, namely IgG autoantibodies, IgM autoantibodies are also found in many autoimmune diseases. In addition to pathogenic functions of secreted IgM the IgM-BCR expressing B cell might be the initial check-point where, in conjunction with innate receptor signals, B cell mediated autoimmunity starts it fateful course. Recently, pentameric IgM autoantibodies have been shown to contribute significantly to the pathogenesis of various autoimmune diseases, such as rheumatoid arthritis (RA), autoimmune hemolytic anemia (AIHA), pemphigus or autoimmune neuropathy. Further, recent studies suggest differences in the recognition of autoantigen by IgG and IgM autoantibodies, or propose a central role of anti-ACE2-IgM autoantibodies in severe COVID-19. However, exact mechanisms still remain to be uncovered in detail. This article focuses on summarizing recent findings regarding the importance of autoreactive IgM in establishing autoimmune diseases.

The complement system is a tightly regulated, cascading protein network representing a key component linking the innate and humoral immune systems. However, if misdirected or dysregulated, it can be similarly damaging to host-tissue. The role of complement dysregulation on vascular endothelial cells has been well established in atypical hemolytic uremic syndrome (aHUS), a thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and target organ injury. Yet, a great deal of complexity exists around the role of complement in TMA associated with other diseases. A further complicating factor is the cross-talk between complement, neutrophils, and coagulation pathways in the pathophysiology of TMA. Advancements in the understanding of the etiopathogenesis of aHUS paved the way for the successful development of anticomplement therapies (complement C5 inhibitors), which have revolutionized the treatment of aHUS. Therefore, a clearer understanding of the role of the complement system in TMA associated with other conditions will help to identify patients who would benefit from these therapies. This review aims to provide an assessment of the nature and extent of complement involvement in TMA associated with autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, and scleroderma renal crisis. Defining the role of complement in TMA in these conditions will help to guide timely diagnosis and management.

Thymomas are a rare neoplasm of the anterior mediastinum and often associated with paraneoplastic syndromes. Though myasthenia gravis is the most common and well-known, the list of reported paraneoplastic syndromes occurring with thymoma is extensive and ever-growing. Paraneoplastic syndromes can involve nearly every organ system, including hematologic abnormalities affecting any or all cell lines. This can present challenges to the clinician in terms of diagnosis, prognostic impact, and management. We present the case of a previously healthy 41-year-old female who was diagnosed with thymoma and three rare hematologic paraneoplastic syndromes: pure red cell aplasia (PRCA), autoimmune hemolytic anemia (AIHA), and T-cell large granular lymphocytic leukemia (T-LGLL). To the best of our knowledge, there have been only four other reported cases of PRCA and AIHA in a single patient with thymoma, all of which were treated with thymectomy. Upfront surgical resection was not possible in the present case and thus the patient was alternatively treated with corticosteroids and octreotide, which proved successful in resolving the anemia. The authors present this case to share these findings of an alternative treatment strategy for thymoma-associated PRCA and AIHA and to highlight the importance of careful monitoring with routine blood work for these complex patients.

Wilson disease is a disorder of copper metabolism that, when untreated, can present with hepatic, neurologic, or psychiatric disturbances – or a combination of these – in individuals ages three years to older than 70 years. Manifestations in untreated individuals vary among and within families. Liver disease can include recurrent jaundice, simple acute self-limited hepatitis-like illness, autoimmune-type hepatitis, fulminant hepatic failure, or chronic liver disease. Neurologic presentations can include dysarthria, movement disorders (tremors, involuntary movements, chorea, choreoathetosis), dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement), dysautonomia, seizures, sleep disorders, or insomnia. Psychiatric disturbances can include depression, bipolar disorder / bipolar spectrum disorder, neurotic behaviors, personality changes, or psychosis. Other multisystem involvement can include the eye (Kayser-Fleischer rings), hemolytic anemia, the kidneys, the endocrine glands, and the heart.

The use of blood products to resuscitate injured and massively bleeding patients in the prehospital and early in-hospital phase of the resuscitation is increasing. Using group O red blood cells (RBC) and low titer group O whole blood (LTOWB) avoids an immediate hemolytic reaction from recipient's naturally occurring anti-A and - B, but choosing the RhD type for these products is more nuanced and requires the balancing of product availability and survival benefit against the risk of D-alloimmunization, especially in females of childbearing potential (FCP) due to the possible future occurrence of hemolytic disease of the fetus and newborn (HDFN). Recent models have estimated the risk of fetal/neonatal death from HDFN resulting from D-alloimmunization of an FCP during her trauma resuscitation at between 0-6.5% depending on her age at the time of the transfusion and other societal factors including trauma mortality, her age when she becomes pregnant, frequency of different RHD genotypes in the population, and the probability that the woman will have children with different fathers; this is counterbalanced by an approximately 24% risk of death from hemorrhagic shock. This review will discuss the different models of HDFN outcomes following RhD-positive transfusion as well as the results of recent surveys where the public was asked about their preferences for urgent transfusion in light of the risks of fetal/neonatal adverse events.

Patients with cold agglutinin disease who undergo total hip arthroplasty (THA) are rarely encountered. Patients with cold agglutinin disease are very sensitive to cold ambient temperatures and require scrupulous perioperative body-temperature management. However, THA requires a cementing procedure that exposes patients to cold temperatures during surgery and may result in autoimmune hemolytic anemia in these patients. Thus, perioperative management of patients with cold agglutinin disease undergoing THA requires more than just scrupulous systemic temperature management. Here, we present the successful perioperative management of a patient with severe cold agglutinin disease who underwent THA with a cemented stem.

We herein report the unusual case of a 52-year-old female with systemic scleroderma who was admitted to the emergency department (ED) with renal dysfunction and hypertension. Following a decline in hemoglobin (Hb) and platelet (Plt) count, the diagnosis of scleroderma renal crisis (SRC) with associated microangiopathic hemolytic anemia was made. Renal replacement therapy using hemodialysis was required. Systemic scleroderma is a chronic autoimmune multisystem vasculopathy affecting several vessel beds, including distal extremities, kidneys, and lungs. Microangiopathic hemolytic anemia occurs in almost half of patients who develop scleroderma renal crisis. This association is thought to be related to the activation of the complement system via the classical pathway. Based on that, we administered a C5 blocker (eculizumab) to our patient and reported an unprecedented positive outcome.