-
Hematology. American Society of... Nov 2018The diagnosis of autoimmune hemolytic anemia (AIHA) can be made with a stepwise approach that aims to identify laboratory and clinical evidence of hemolysis and then... (Review)
Review
The diagnosis of autoimmune hemolytic anemia (AIHA) can be made with a stepwise approach that aims to identify laboratory and clinical evidence of hemolysis and then determine the immune nature of hemolysis with the direct anti-globulin test. Once alternative causes for these findings have been excluded, AIHA is established, and the clinician must search for secondary causes, as well as identify the type of AIHA. Rituximab is now the preferred second-line treatment for primary warm AIHA and first-line treatment for primary cold agglutinin disease (CAD), either as monotherapy or combined with bendamustine. Complement inhibitors have shown utility in stabilizing AIHA patients with acute severe hemolysis. Future prospects are discussed and include the C1s inhibitor BIVV009 (sutimlimab) that is now entering phase 3 studies for CAD.
Topics: Anemia, Hemolytic, Autoimmune; Clinical Trials, Phase III as Topic; Complement Inactivating Agents; Humans; Rituximab
PubMed: 30504336
DOI: 10.1182/asheducation-2018.1.382 -
Journal of Veterinary Internal Medicine Mar 2019Immune-mediated hemolytic anemia (IMHA) is an important cause of morbidity and mortality in dogs. IMHA also occurs in cats, although less commonly. IMHA is considered...
Immune-mediated hemolytic anemia (IMHA) is an important cause of morbidity and mortality in dogs. IMHA also occurs in cats, although less commonly. IMHA is considered secondary when it can be attributed to an underlying disease, and as primary (idiopathic) if no cause is found. Eliminating diseases that cause IMHA may attenuate or stop immune-mediated erythrocyte destruction, and adverse consequences of long-term immunosuppressive treatment can be avoided. Infections, cancer, drugs, vaccines, and inflammatory processes may be underlying causes of IMHA. Evidence for these comorbidities has not been systematically evaluated, rendering evidence-based decisions difficult. We identified and extracted data from studies published in the veterinary literature and developed a novel tool for evaluation of evidence quality, using it to assess study design, diagnostic criteria for IMHA, comorbidities, and causality. Succinct evidence summary statements were written, along with screening recommendations. Statements were refined by conducting 3 iterations of Delphi review with panel and task force members. Commentary was solicited from several professional bodies to maximize clinical applicability before the recommendations were submitted. The resulting document is intended to provide clinical guidelines for diagnosis of, and underlying disease screening for, IMHA in dogs and cats. These should be implemented with consideration of animal, owner, and geographical factors.
Topics: Anemia, Hemolytic, Autoimmune; Animals; Cat Diseases; Cats; Comorbidity; Consensus; Dog Diseases; Dogs; Societies, Veterinary
PubMed: 30806491
DOI: 10.1111/jvim.15441 -
Blood Mar 2021Warm autoimmune hemolytic anemia (wAIHA) is caused by increased erythrocyte destruction by immunoglobulin G (IgG) autoantibodies, with or without complement activation.... (Review)
Review
Warm autoimmune hemolytic anemia (wAIHA) is caused by increased erythrocyte destruction by immunoglobulin G (IgG) autoantibodies, with or without complement activation. Antibody-dependent cell-mediated cytotoxicity by macrophages/activated lymphocytes occurs in the lymphoid organs and spleen (extravascular hemolysis). The ability of the bone marrow (BM) to compensate determines clinical severity. The different pathogenic mechanisms, their complex interplay, and changes over time may explain wAIHA's great clinical heterogeneity and unpredictable course. The disease may be primary, drug induced, or associated with lymphoproliferative neoplasms, autoimmune and infectious diseases, immunodeficiencies, solid tumors, or transplants. Therapeutic interventions include steroids, splenectomy, immunosuppressants, and rituximab; the latter is increasingly used in steroid-refractory cases based on evidence from the literature and a few prospective trials. We present 5 patient case studies highlighting important issues: (1) the diagnosis and proper use of steroid therapy, (2) the concerns about the choice between rituximab and splenectomy in second-line treatment, (3) the need of periodical re-evaluation of the disease to assess the possible evolution of relapsed/refractory cases in myelodysplastic and BM failure syndromes, and (4) the difficulties in managing cases of severe/acute disease that are at high risk of relapse. Incorporating novel targeted therapies into clinical practice will be an exciting challenge in the future.
Topics: Adult; Aged; Anemia, Hemolytic, Autoimmune; Antineoplastic Agents; Disease Management; Female; Humans; Immunologic Factors; Immunosuppressive Agents; Male; Middle Aged; Rituximab; Splenectomy; Steroids
PubMed: 33512406
DOI: 10.1182/blood.2019003808 -
Frontiers in Immunology 2020Autoimmune hemolytic anemias mediated by cold agglutinins can be divided into cold agglutinin disease (CAD), which is a well-defined clinicopathologic entity and a... (Review)
Review
Autoimmune hemolytic anemias mediated by cold agglutinins can be divided into cold agglutinin disease (CAD), which is a well-defined clinicopathologic entity and a clonal lymphoproliferative disorder, and secondary cold agglutinin syndrome (CAS), in which a similar picture of cold-hemolytic anemia occurs secondary to another distinct clinical disease. Thus, the pathogenesis in CAD is quite different from that of polyclonal autoimmune diseases such as warm-antibody AIHA. In both CAD and CAS, hemolysis is mediated by the classical complement pathway and therefore can result in generation of anaphylotoxins, such as complement split product 3a (C3a) and, to some extent, C5a. On the other hand, infection and inflammation can act as triggers and drivers of hemolysis, exemplified by exacerbation of CAD in situations with acute phase reaction and the role of specific infections (particularly and Epstein-Barr virus) as causes of CAS. In this review, the putative mechanisms behind these phenomena will be explained along with other recent achievements in the understanding of pathogenesis in these disorders. Therapeutic approaches have been directed against the clonal lymphoproliferation in CAD or the underlying disease in CAS. Currently, novel targeted treatments, in particular complement-directed therapies, are also being rapidly developed and will be reviewed.
Topics: Anemia, Hemolytic, Autoimmune; Cryoglobulins; Hemolysis; Humans
PubMed: 32318071
DOI: 10.3389/fimmu.2020.00590 -
Frontiers in Immunology 2023Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic disorder, mediated by auto-antibodies, and has a variable clinical course ranging from fully compensated low... (Review)
Review
Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic disorder, mediated by auto-antibodies, and has a variable clinical course ranging from fully compensated low grade hemolysis to severe life-threatening cases. The rarity, heterogeneity and incomplete understanding of severe AIHA complicate the recognition and management of severe cases. In this review, we describe how severe AIHA can be defined and what is currently known of the severity and outcome of AIHA. There are no validated predictors for severe clinical course, but certain risk factors for poor outcomes (hospitalisation, transfusion need and mortality) can aid in recognizing severe cases. Some serological subtypes of AIHA (warm AIHA with complement positive DAT, mixed, atypical) are associated with lower hemoglobin levels, higher transfusion need and mortality. Currently, there is no evidence-based therapeutic approach for severe AIHA. We provide a general approach for the management of severe AIHA patients, incorporating monitoring, supportive measures and therapeutic options based on expert opinion. In cases where steroids fail, there is a lack of rapidly effective therapeutic options. In this era, numerous novel therapies are emerging for AIHA, including novel complement inhibitors, such as sutimlimab. Their potential in severe AIHA is discussed. Future research efforts are needed to gain a clearer picture of severe AIHA and develop prediction models for severe disease course. It is crucial to incorporate not only clinical characteristics but also biomarkers that are associated with pathophysiological differences and severity, to enhance the accuracy of prediction models and facilitate the selection of the optimal therapeutic approach. Future clinical trials should prioritize the inclusion of severe AIHA patients, particularly in the quest for rapidly acting novel agents.
Topics: Humans; Anemia, Hemolytic, Autoimmune; Hemolysis; Steroids; Blood Transfusion; Disease Progression
PubMed: 37795092
DOI: 10.3389/fimmu.2023.1228142 -
Hematology/oncology Clinics of North... Apr 2022Cold agglutinin disease represents a form of immune-mediated hemolytic anemia whereby an IgM protein either monoclonal or polyclonal deposits complement on the surface... (Review)
Review
Cold agglutinin disease represents a form of immune-mediated hemolytic anemia whereby an IgM protein either monoclonal or polyclonal deposits complement on the surface of the red blood cell. Once complement is deposited, the 3rd component of complement is recognized by receptors in the mononuclear phagocyte system resulting in spherocytic extravascular hemolysis. This results in a Coombs positive hemolytic anemia with the peripheral blood film showing agglutination. In many instances, the source is a clonal population of lymphoplasmacytic cells in the bone marrow producing a monoclonal IgM protein. Traditional and emerging therapies directed against the production of the IgM may have a positive effect on hemolytic anemia. Success in the management of cold agglutinin disease with rituximab, fludarabine, bortezomib, and bendamustine has all been reported. Recent studies have demonstrated that the blockade of complement with sutimlimab can stop the hemolysis without the use of systemic chemotherapy.
Topics: Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Hemolysis; Humans; Immunoglobulin M; Rituximab
PubMed: 35282954
DOI: 10.1016/j.hoc.2021.11.001 -
Frontiers in Immunology 2020Autoimmune hemolytic anemia (AIHA) is a greatly heterogeneous disease due to autoantibodies directed against erythrocytes, with or without complement activation. The... (Review)
Review
Autoimmune hemolytic anemia (AIHA) is a greatly heterogeneous disease due to autoantibodies directed against erythrocytes, with or without complement activation. The clinical picture ranges from mild/compensated to life-threatening anemia, depending on the antibody's thermal amplitude, isotype and ability to fix complement, as well as on bone marrow compensation. Since few years ago, steroids, immunesuppressants and splenectomy have been the mainstay of treatment. More recently, several target therapies are increasingly used in the clinical practice or are under development in clinical trials. This has led to the accumulation of refractory/relapsed cases that often represent a clinical challenge. Moreover, the availability of several drugs acting on the different pathophysiologic mechanisms of the disease pinpoints the need to harness therapy. In particular, it is advisable to define the best choice, sequence and/or combination of drugs during the different phases of the disease. In particular relapsed/refractory cases may resemble pre-myelodysplastic or bone marrow failure syndromes, suggesting a careful use of immunosuppressants, and vice versa advising bone marrow immunomodulating/stimulating agents. A peculiar setting is AIHA after autologous and allogeneic hematopoietic stem cell transplantation, which is increasingly reported. These cases are generally severe and refractory to standard therapy, and have high mortality. AIHAs may be primary/idiopathic or secondary to infections, autoimmune diseases, malignancies, particularly lymphoproliferative disorders, and drugs, further complicating their clinical picture and management. Regarding new drugs, the false positivity of the Coombs test (direct antiglobulin test, DAT) following daratumumab adds to the list of difficult diagnosis, together with the passenger lymphocyte syndrome after solid organ transplants. Diagnosis of DAT-negative AIHAs and evaluation of disease-related risk factors for relapse and mortality, notwithstanding improvement in diagnostic approach, are still an unmet need. Finally, AIHA is increasingly described following therapy of solid cancers with inhibitors of immune checkpoint molecules. On the whole, the double-edged sword of new pathogenetic insights and therapies has changed the landscape of AIHA, both providing enthusiastic knowledge and complicating the clinical management of this disease.
Topics: Anemia, Hemolytic, Autoimmune; Animals; Autoantibodies; Autoantigens; Autoimmunity; Erythrocytes; Humans; Predictive Value of Tests; Prognosis; Risk Factors
PubMed: 32655543
DOI: 10.3389/fimmu.2020.00946 -
American Journal of Hematology Apr 2002Red blood cell (RBC) autoantibodies are a relatively uncommon cause of anemia. However, autoimmune hemolytic anemia (AIHA) must be considered in the differential... (Review)
Review
Red blood cell (RBC) autoantibodies are a relatively uncommon cause of anemia. However, autoimmune hemolytic anemia (AIHA) must be considered in the differential diagnosis of hemolytic anemias, especially if the patient has a concomitant lymphoproliferative disorder, autoimmune disease, or viral or mycoplasmal infection. Classifications of AIHA include warm AIHA, cold agglutinin syndrome, paroxysmal cold hemoglobinuria, mixed-type AIHA, and drug-induced AIHA. Characteristics of the autoantibodies are responsible for the various clinical entities. As a result, diagnosis is based on the clinical presentation and a serologic work-up. For each classification of AIHA, this review discusses the demographics, etiology, clinical presentation, laboratory evaluation, and treatment options.
Topics: Anemia, Hemolytic, Autoimmune; Autoantibodies; Cold Temperature; Erythrocytes; Hemoglobinuria, Paroxysmal; Hot Temperature; Humans
PubMed: 11921020
DOI: 10.1002/ajh.10062 -
Blood Advances Jun 2019The terminology applied to autoimmune hemolytic anemia (AIHA) seems inconsistent. We aimed to evaluate the consistency of definitions used for diagnosis and treatment.... (Comparative Study)
Comparative Study
The terminology applied to autoimmune hemolytic anemia (AIHA) seems inconsistent. We aimed to evaluate the consistency of definitions used for diagnosis and treatment. In this systematic review of literature from January 2006 to December 2015, we assessed heterogeneity in the definition of AIHA and its subtypes, refractory disease, disease phase, severity, criteria for treatment response, and response durability. A Medline search for anemia, hemolytic, autoimmune was supplemented with keyword searches. Main exclusions were conference abstracts, animal and non-English studies, and studies with <10 cases. Of 1371 articles retrieved, 1209 were excluded based on titles and abstracts. Two authors independently reviewed 10% and 16% of abstracts and full papers, respectively. After full-paper review, 84 studies were included. AIHA was most frequently (32 [52%] of 61) defined as hemolytic anemia with positive direct antiglobulin test (DAT) and exclusion of alternatives, but 10 of 32 also recognized DAT-negative AIHA. A lower threshold for diagnosis of DAT-negative AIHA was observed in literature on chronic lymphocytic leukemia. Definitions of anemia, hemolysis, and exclusion criteria showed substantial variation. Definitions of primary/secondary cold agglutinin disease/syndrome were not consistent. Forty-three studies provided criteria for treatment response, and other than studies from 1 center, these were almost entirely unique. Other criteria were rarely defined. Only 7, 0, 3, 2, 2, and 3 studies offered definitions of warm AIHA, paroxysmal cold hemoglobinuria, mixed AIHA, AIHA severity, disease phase, and refractory AIHA, respectively. Marked heterogeneity in the time period sampled indicates the need to standardize AIHA terminology.
Topics: Anemia, Hemolytic, Autoimmune; Coombs Test; Erythrocytes; Hemoglobinuria, Paroxysmal; Hemolysis; Humans; Immunoglobulin G; Publications; Severity of Illness Index; Terminology as Topic
PubMed: 31235526
DOI: 10.1182/bloodadvances.2019000036 -
Hematology. American Society of... Dec 2016Primary chronic cold agglutinin disease (CAD) is a well-defined clinicopathologic entity in which a specific, clonal lymphoproliferative B-cell bone marrow disorder... (Review)
Review
Primary chronic cold agglutinin disease (CAD) is a well-defined clinicopathologic entity in which a specific, clonal lymphoproliferative B-cell bone marrow disorder results in autoimmune hemolytic anemia. The immune hemolysis is entirely complement-dependent, predominantly mediated by activation of the classical pathway and phagocytosis of erythrocytes opsonized with complement protein C3b. Typical clinical features in CAD have diagnostic and therapeutic implications. Pharmacologic treatment should be offered to patients with symptom-producing anemia or disabling circulatory symptoms. CAD should not be treated with corticosteroids. Based on an individualized approach, rituximab monotherapy or rituximab-fludarabine in combination is recommended as first-line therapy. Rituximab-bendamustine is still an investigational therapy. Although complement-modulating agents are still to be considered experimental in CAD, therapy with the anti-C1s monoclonal antibody TNT009 seems promising.
Topics: Anemia, Hemolytic, Autoimmune; B-Lymphocytes; Bendamustine Hydrochloride; Complement C3b; Humans; Lymphoproliferative Disorders; Rituximab
PubMed: 27913484
DOI: 10.1182/asheducation-2016.1.226