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Topical Collection "Diagnosis and Management of Autoimmune Hemolytic Anemias"

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A topical collection in Journal of Clinical Medicine (ISSN 2077-0383). This collection belongs to the section "Hematology".

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Prof. Dr. Wilma Barcellini

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Guest Editor

UOC Ematologia, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy
Interests: autoimmune hemolytic anemias; congenital hemolytic anemias; paroxysmal nocturnal hemoglobimuria(EPN); hematology

Dr. Bruno Fattizzo

E-Mail Website
Co-Guest Editor

IRCCS Ca Granda Ospedale Maggiore Policlinico Department Hematology, Milan, Italy
Interests: autoimmune hemolytic anemias; congenital hemolytic anemias; paroxysmal nocturnal hemoglobimuria(EPN); primary autoimmune hemolytic anemia (AIHA); hematology
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Dear Colleagues,

Autoimmune hemolytic anemia (AIHA) is a rare and clinically heterogeneous disease ranging from mild to life-threatening hemolysis. It has been historically recognized as an autoantibody-mediated condition, where warm IgG, cold IgM, or both cause antibody-dependent intra- or extravascular hemolysis. More recently, the role of the final effectors of immune hemolysis, i.e., the complement cascade and the reticuloendothelial system, has gained attention. In addition, the importance of bone marrow compensation has emerged as a pivotal factor, and there is evidence that inadequate reticulocytosis correlates with very severe anemia and worse outcome. These observations have paved the way to novel targeted therapies in combination with current treatments based on steroids, rituximab, and splenectomy.

The clinical picture of AIHA is further complicated by the presence of several underlying conditions including infections, lymphoproliferative neoplasms, autoimmune diseases, immunodeficiencies, and tumors, whose diagnosis may either precede or follow that of AIHA. More recently, AIHA has been associated with bone marrow transplantation and with novel biologic anti-cancer drugs. Furthermore, AIHA presentation and related complications may be risk factors for disease refractoriness and mortality. The importance of assessing the presence of these conditions is crucial, since specific treatments may be required, and the risk of infectious and thrombotic complications may vary depending on the diagnosed condition.

Prof. Dr. Wilma Barcellini
Dr. Bruno Fattizzo
Guest Editor

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Keywords

primary autoimmune hemolytic anemia (AIHA)
AIHA secondary to lymphoproliferative neoplasms
AIHA secondary to other autoimmune diseases
AIHA secondary to immunodeficiencies
direct antiglobulin test
thrombosis
AIHA therapy
drug-associated AIHA.

Published Papers (11 papers)

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2021

Jump to: 2020

Open AccessArticle

Autoimmune Hemolytic Anemia as a Complication of Congenital Anemias. A Case Series and Review of the Literature

and

J. Clin. Med. 2021, 10(15), 3439; https://doi.org/10.3390/jcm10153439 - 02 Aug 2021

Cited by 3 | Viewed by 1559

Abstract

Congenital anemias may be complicated by immune-mediated hemolytic crisis. Alloantibodies are usually seen in chronically transfused patients, and autoantibodies have also been described, although they are rarely associated with overt autoimmune hemolytic anemia (AIHA), a serious and potentially life-threatening complication. Given the lack of data on the AIHA diagnosis and management in congenital anemias, we retrospectively evaluated all clinically relevant AIHA cases occurring at a referral center for AIHA, hemoglobinopathies, and chronic hemolytic anemias, focusing on clinical management and outcome. In our cohort, AIHA had a prevalence of 1% (14/1410 patients). The majority were warm AIHA. Possible triggers were recent transfusion, infection, pregnancy, and surgery. All the patients received steroid therapy as the first line, and about 25% required further treatment, including rituximab, azathioprine, intravenous immunoglobulins, and cyclophosphamide. Transfusion support was required in 57% of the patients with non-transfusion-dependent anemia, and recombinant human erythropoietin was safely administered in one third of the patients. AIHA in congenital anemias may be challenging both from a diagnostic and a therapeutic point of view. A proper evaluation of hemolytic markers, bone marrow compensation, and assessment of the direct antiglobulin test is mandatory. Full article

Open AccessReview

The Role of Novel Agents in Treating CLL-Associated Autoimmune Hemolytic Anemia

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J. Clin. Med. 2021, 10(10), 2064; https://doi.org/10.3390/jcm10102064 - 12 May 2021

Cited by 6 | Viewed by 1906

Abstract

Autoimmune cytopenias (AICs) have been reported as a common complication in chronic lymphocytic leukemia (CLL) with autoimmune hemolytic anemia (AIHA), accounting for most cases. According to iwCLL guidelines, AICs poorly responsive to corticosteroids are considered indication for CLL-directed treatment. Chemo-immunotherapy has classically been employed, with variable results, and little data are available on novel agents, the current backbone of CLL therapy. The use of idelalisib in the setting of AICs is controversial and recent recommendations suggest avoiding idelalisib in this setting. Ibrutinib, through ITK-driven Th1 polarization of cell-mediated immune response, is known to produce an immunological rebalancing in CLL, which stands as a fascinating rationale for its use to treat autoimmunity. Although treatment-emergent AIHA has rarely been reported, ibrutinib has shown rapid and durable responses when used to treat AIHA arising in CLL. There is poor evidence regarding the role of BCL-2 inhibitors in CLL-associated AICs and the use of venetoclax in such cases is debated. Furthermore, their frequent use in combination with anti-CD20 agents might represent a confounding factor in evaluating their efficacy. In conclusions, because of their ability to mitigate an immunological dysregulation that is (at least partly) responsible for autoimmunity in CLL, to date BTK-inhibitors stand out as the most suitable choice when treatment of autoimmune cytopenias is required. Full article

Open AccessReview

Epidemiology of Secondary Warm Autoimmune Haemolytic Anaemia—A Systematic Review and Meta-Analysis

Stinne Tranekær

Dennis Lund Hansen

and

Henrik Frederiksen

J. Clin. Med. 2021, 10(6), 1244; https://doi.org/10.3390/jcm10061244 - 17 Mar 2021

Cited by 4 | Viewed by 2267

Abstract

Background: Warm autoimmune haemolytic anaemia (wAIHA) is a haemolytic disorder, most commonly seen among adults and is classified as either primary or secondary to an underlying disease. We describe the age and sex distribution and the proportion of secondary wAIHA. Method: We retrieved 2635 published articles, screened abstracts and titles, and identified 27 articles eligible for full-text review. From these studies, we extracted data regarding number of patients, sex distribution, age at diagnosis, number of patients with secondary wAIHA, and whether the patients were diagnosed through local or referral centres. All data were weighted according to the number of included patients in each study. Results: 27 studies including a total of 4311 patients with wAIHA, of which 66% were females, were included. The median age at diagnosis was 68.7 years, however, wAIHA affected all ages. The mean proportion of secondary wAIHA was 49%, most frequently secondary to systemic lupus erythematosus. The proportions of secondary wAIHA reported from primary vs. referral centres were 35% vs. 59%, respectively. Conclusion: This review consolidates previously reported gender distribution. The higher proportion of secondary wAIHA in referral centres suggests that the most severely affected patients are disproportionally more frequent in such facilities. Full article

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Open AccessArticle

Secondary Hemophagocytic Lymphohistiocytosis and Autoimmune Cytopenias: Case Description and Review of the Literature

Bruno Fattizzo

Marta Ferraresi

Juri Alessandro Giannotta

and

Wilma Barcellini

J. Clin. Med. 2021, 10(4), 870; https://doi.org/10.3390/jcm10040870 - 20 Feb 2021

Cited by 5 | Viewed by 1657

Abstract

Hemophagocytic lymphohistocytosis (HLH) is a rare hyperinflammatory condition which may be primary or secondary to many diseases, including hematologic malignancies. Due to its life-threatening evolution, a timely diagnosis is paramount but challenging, since it relies on non-specific clinical and laboratory criteria. The latter are often altered in other diseases, including autoimmune cytopenias (AIC), which in turn can be secondary to infections, systemic autoimmune or lymphoproliferative disorders. In the present article, we describe two patients presenting at the emergency department with acute AICs subsequently diagnosed as HLH with underlying diffuse large B cell lymphoma. We discuss the diagnostic challenges in the differential diagnosis of acute cytopenias in the internal medicine setting, providing a literature review of secondary HLH and AIC. Full article

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Open AccessReview

Diagnosis and Management of Autoimmune Hemolytic Anemia in Patients with Liver and Bowel Disorders

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J. Clin. Med. 2021, 10(3), 423; https://doi.org/10.3390/jcm10030423 - 22 Jan 2021

Cited by 7 | Viewed by 3094

Abstract

Anemia is a common feature of liver and bowel diseases. Although the main causes of anemia in these conditions are represented by gastrointestinal bleeding and iron deficiency, autoimmune hemolytic anemia should be considered in the differential diagnosis. Due to the epidemiological association, autoimmune hemolytic anemia should particularly be suspected in patients affected by inflammatory and autoimmune diseases, such as autoimmune or acute viral hepatitis, primary biliary cholangitis, and inflammatory bowel disease. In the presence of biochemical indices of hemolysis, the direct antiglobulin test can detect the presence of warm or cold reacting antibodies, allowing for a prompt treatment. Drug-induced, immune-mediated hemolytic anemia should be ruled out. On the other hand, the choice of treatment should consider possible adverse events related to the underlying conditions. Given the adverse impact of anemia on clinical outcomes, maintaining a high clinical suspicion to reach a prompt diagnosis is the key to establishing an adequate treatment. Full article

Open AccessReview

Autoimmune Hemolytic Anemia in the Pediatric Setting

Aikaterini Voulgaridou

and

Theodosia A. Kalfa

J. Clin. Med. 2021, 10(2), 216; https://doi.org/10.3390/jcm10020216 - 09 Jan 2021

Cited by 6 | Viewed by 4333

Abstract

Autoimmune hemolytic anemia (AIHA) is a rare disease in children, presenting with variable severity. Most commonly, warm-reactive IgG antibodies bind erythrocytes at 37 °C and induce opsonization and phagocytosis mainly by the splenic macrophages, causing warm AIHA (w-AIHA). Post-infectious cold-reactive antibodies can also lead to hemolysis following the patient’s exposure to cold temperatures, causing cold agglutinin syndrome (CAS) due to IgM autoantibodies, or paroxysmal cold hemoglobinuria (PCH) due to atypical IgG autoantibodies which bind their target RBC antigen and fix complement at 4 °C. Cold-reactive antibodies mainly induce intravascular hemolysis after complement activation. Direct antiglobulin test (DAT) is the gold standard for AIHA diagnosis; however, DAT negative results are seen in up to 11% of warm AIHA, highlighting the need to pursue further evaluation in cases with a phenotype compatible with immune-mediated hemolytic anemia despite negative DAT. Prompt supportive care, initiation of treatment with steroids for w-AIHA, and transfusion if necessary for symptomatic or fast-evolving anemia is crucial for a positive outcome. w-AIHA in children is often secondary to underlying immune dysregulation syndromes and thus, screening for such disorders is recommended at presentation, before initiating treatment with immunosuppressants, to determine prognosis and optimize long-term management potentially with novel targeted medications. Full article

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Open AccessReview

Infectious Complications in Autoimmune Hemolytic Anemia

Juri Alessandro Giannotta

Bruno Fattizzo

Francesca Cavallaro

and

Wilma Barcellini

J. Clin. Med. 2021, 10(1), 164; https://doi.org/10.3390/jcm10010164 - 05 Jan 2021

Cited by 10 | Viewed by 3629

Abstract

Autoimmune hemolytic anemia (AIHA) may be frequently challenged by infectious complications, mainly as a result of immunosuppressive treatments administered. Furthermore, infectious agents are known triggers of AIHA onset and relapse. Although being risk factors for mortality, infections are an underestimated issue in AIHA. This review will collect the available evidence on the frequency and type of infectious complications in AIHA, detailing the risk related to each treatment (i.e., steroids, rituximab, splenectomy, classic immunosuppressive agents, and new target drugs). Moreover, we will briefly discuss the infectious complications in AIHA secondary to other diseases that harbor an intrinsic infectious risk (e.g., primary immunodeficiencies, systemic autoimmune diseases, lymphoproliferative disorders, solid organ and hematopoietic stem cell transplants). Finally, viral and bacterial reactivations during immune suppressive therapies will be discussed, along with suggested screening and prophylactic strategies. Full article

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2020

Jump to: 2021

Open AccessReview

Rituximab Use in Warm and Cold Autoimmune Hemolytic Anemia

Irina Murakhovskaya

J. Clin. Med. 2020, 9(12), 4034; https://doi.org/10.3390/jcm9124034 - 13 Dec 2020

Cited by 6 | Viewed by 6034

Abstract

Autoimmune hemolytic anemia is a rare condition characterized by destruction of red blood cells with and without involvement of complement. It is associated with significant morbidity and mortality. In warm autoimmune hemolytic anemia, less than 50% of patients remain in long-term remission following initial steroid therapy and subsequent therapies are required. Cold agglutinin disease is a clonal hematologic disorder that requires therapy in the majority of patients and responds poorly to steroids and alkylators. Rituximab has a favorable toxicity profile and has demonstrated efficacy in autoimmune hemolytic anemia in first-line as well as relapsed settings. Rituximab is the preferred therapy for steroid refractory warm autoimmune hemolytic anemia (wAIHA) and as part of the first- and second-line treatment of cold agglutinin disease. This article reviews the mechanism of action of rituximab and the current literature on its role in the management of primary and secondary warm autoimmune hemolytic anemia and cold agglutinin disease. Full article

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Open AccessReview

New Insights in Autoimmune Hemolytic Anemia: From Pathogenesis to Therapy

Wilma Barcellini

Anna Zaninoni

Juri Alessandro Giannotta

and

Bruno Fattizzo

J. Clin. Med. 2020, 9(12), 3859; https://doi.org/10.3390/jcm9123859 - 27 Nov 2020

Cited by 33 | Viewed by 10821

Abstract

Autoimmune hemolytic anemia (AIHA) is a highly heterogeneous disease due to increased destruction of autologous erythrocytes by autoantibodies with or without complement involvement. Other pathogenic mechanisms include hyper-activation of cellular immune effectors, cytokine dysregulation, and ineffective marrow compensation. AIHAs may be primary or associated with lymphoproliferative and autoimmune diseases, infections, immunodeficiencies, solid tumors, transplants, and drugs. The direct antiglobulin test is the cornerstone of diagnosis, allowing the distinction into warm forms (wAIHA), cold agglutinin disease (CAD), and other more rare forms. The immunologic mechanisms responsible for erythrocyte destruction in the various AIHAs are different and therefore therapy is quite dissimilar. In wAIHA, steroids represent first line therapy, followed by rituximab and splenectomy. Conventional immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine) are now considered the third line. In CAD, steroids are useful only at high/unacceptable doses and splenectomy is uneffective. Rituximab is advised in first line therapy, followed by rituximab plus bendamustine and bortezomib. Several new drugs are under development including B-cell directed therapies (ibrutinib, venetoclax, parsaclisib) and inhibitors of complement (sutimlimab, pegcetacoplan), spleen tyrosine kinases (fostamatinib), or neonatal Fc receptor. Here, a comprehensive review of the main clinical characteristics, diagnosis, and pathogenic mechanisms of AIHA are provided, along with classic and new therapeutic approaches. Full article

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Open AccessReview

Difficult Cases of Autoimmune Hemolytic Anemia: A Challenge for the Internal Medicine Specialist

Bruno Fattizzo

Juri Alessandro Giannotta

Fabio Serpenti

and

Wilma Barcellini

J. Clin. Med. 2020, 9(12), 3858; https://doi.org/10.3390/jcm9123858 - 27 Nov 2020

Cited by 8 | Viewed by 9082

Abstract

Autoimmune hemolytic anemia (AIHA) is diagnosed in the presence of anemia, hemolysis, and direct antiglobulin test (DAT) positivity with monospecific antisera. Many confounders of anemia and hemolytic markers should be included in the initial workup (i.e., nutrients deficiencies, chronic liver or kidney diseases, infections, and cancers). Besides classical presentation, there are difficult cases that may challenge the treating physician. These include DAT negative AIHA, diagnosed after the exclusion of other causes of hemolysis, and supported by the response to steroids, and secondary cases (infections, drugs, lymphoproliferative disorders, immunodeficiencies, etc.) that should be suspected and investigated through careful anamnesis physical examination, and specific tests in selected cases. The latter include autoantibody screening in patients with signs/symptoms of systemic autoimmune diseases, immunoglobulins (Ig) levels in case of frequent infections or suspected immunodeficiency, and ultrasound/ computed tomography (CT) studies and bone marrow evaluation to exclude hematologic diseases. AIHA occurring in pregnancy is a specific situation, usually manageable with steroids and intravenous (iv) Ig, although refractory cases have been described. Finally, AIHA may complicate specific clinical settings, including intensive care unit (ICU) admission, reticulocytopenia, treatment with novel anti-cancer drugs, and transplant. These cases are often severe, more frequently DAT negative, and require multiple treatments in a short time. Full article

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Open AccessReview

Evans’ Syndrome: From Diagnosis to Treatment

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J. Clin. Med. 2020, 9(12), 3851; https://doi.org/10.3390/jcm9123851 - 27 Nov 2020

Cited by 34 | Viewed by 6985

Abstract

Evans’ syndrome (ES) is defined as the concomitant or sequential association of warm auto-immune haemolytic anaemia (AIHA) with immune thrombocytopenia (ITP), and less frequently autoimmune neutropenia. ES is a rare situation that represents up to 7% of AIHA and around 2% of ITP. When AIHA and ITP occurred concomitantly, the diagnosis procedure must rule out differential diagnoses such as thrombotic microangiopathies, anaemia due to bleedings complicating ITP, vitamin deficiencies, myelodysplastic syndromes, paroxysmal nocturnal haemoglobinuria, or specific conditions like HELLP when occurring during pregnancy. As for isolated auto-immune cytopenia (AIC), the determination of the primary or secondary nature of ES is important. Indeed, the association of ES with other diseases such as haematological malignancies, systemic lupus erythematosus, infections, or primary immune deficiencies can interfere with its management or alter its prognosis. Due to the rarity of the disease, the treatment of ES is mostly extrapolated from what is recommended for isolated AIC and mostly relies on corticosteroids, rituximab, splenectomy, and supportive therapies. The place for thrombopoietin receptor agonists, erythropoietin, immunosuppressants, haematopoietic cell transplantation, and thromboprophylaxis is also discussed in this review. Despite continuous progress in the management of AIC and a gradual increase in ES survival, the mortality due to ES remains higher than the ones of isolated AIC, supporting the need for an improvement in ES management. Full article

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Published Papers (11 papers)

2021

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2020

Jump to: 2021

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