Immune Hemolysis: Diagnosis and Treatment Recommendations

doi:10.1053/j.seminhematol.2015.05.001

Seminars in Hematology

Volume 52, Issue 4, October 2015, Pages 304-312

https://doi.org/10.1053/j.seminhematol.2015.05.001 Get rights and content

Autoimmune hemolytic anemia (AIHA) is a heterogeneous disease usually classified as warm, cold [cold agglutinin disease (CAD)] or mixed, according to the thermal range of the autoantibody. Diagnosis is based on the direct antiglobulin test (DAT), typically positive with anti-IgG antisera in warm AIHA and anti-C3d in CAD. Diagnostic pitfalls are due to IgA autoantibodies, warm IgM, low-affinity IgG, or IgG below the threshold of sensitivity, and about 5% of AIHA remains DAT-negative. The treatment of AIHA is still not evidence-based. Corticosteroids are the first-line therapy for warm AIHA. For refractory/relapsed cases, the choice is between splenectomy (effective in ~70% cases but with a presumed cure rate of 20%) and rituximab (effective in ~70%–80% of cases), which is becoming the preferred second-line treatment, and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil). Rituximab is now recommended as first-line treatment for CAD. Additional therapies are intravenous immunoglobulins, danazol, and plasma exchange, with alemtuzumab and high-dose cyclophosphamide as the last options.

Section snippets

Diagnostic Aspects of AIHA

The diagnosis is usually simple and based on the presence of hemolytic anemia and serologic evidence of anti-erythrocyte autoantibodies by the DAT, which can be performed with various methods with different sensitivity/sensibility, level of automation, and diffusion among laboratories. The DAT tube is the gold standard traditional agglutination technique, usually performed with broad-spectrum Coombs’ reagents. It is worth recommending to perform the test with monospecific antisera and to

Clinical Aspects

Although the extent of hemolysis depends on the autoantibody pathogenicity (class, thermal amplitude, affinity, efficiency in activating complement), the degree of anemia is also determined by the efficacy of the erythroblastic response. It is important to bear in mind that AIHA with reticulocytopenia may often represent a clinical emergency with extremely high transfusion needs. Reticulocytopenia, reported in 39% of children¹⁰ and about 20% of adults, particularly in severe cases,4, 14 may be

Treatment of Warm AIHA

The most common treatment options for warm AIHA are listed in Table 3. Corticosteroids represent the first-line treatment and should be given at the initial dose of prednisone 1–1.5 mg/kg/d for 1–3 weeks until hemoglobin levels >10 g/dL are reached. After stabilization of hemoglobin, prednisone should be gradually and slowly tapered off, over a period no shorter than 4–6 months. Side effects should be treated rather than discontinuing the drug too early, as patients receiving low doses of

Treatment of CAD

The decision to treat CAD should be reserved for patients with symptomatic anemia, transfusion dependence, and/or disabling circulatory symptoms. In fact, non-severe asymptomatic forms may require only protection against cold exposure and occasional transfusion support during winter.1, 15, 19, 50 Erythrocyte transfusions can safely be given in CAD, provided appropriate precautions are taken; in particular, the patient and the extremity chosen for infusion should be kept warm, and the use of an

Supportive Therapy

Patients with AIHA may often require RBC transfusion to achieve and/or maintain clinically acceptable hemoglobin values until specific treatments become effective. The decision to transfuse should depend not only on the hemoglobin level, but rather on the patient’s clinical status and comorbidities (particularly ischemic heart or severe pulmonary disease), the acuteness of onset, the rapidity of progression of the anemia, the presence of hemoglobinuria or hemoglobinemia, and other

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Cited by (38)

Impact of baseline fluorescent antinuclear antibody positivity on the clinical outcome of patients with primary autoimmune hemolytic anemia
2023, Hematology, Transfusion and Cell Therapy
Citation Excerpt :
As per the departmental protocol, all the patients with mild disease were started on oral prednisolone 1 mg/kg/day, with a taper over several weeks. Those with moderate and severe disease were treated with pulse methylprednisolone therapy at 15–30 mg/kg/day for 3–5 days, followed by oral prednisolone.4,3 The steroid responses at 3 months were recorded.
Autoimmune haemolytic anaemia (AIHA) is an autoimmune disorder that can present in primary or secondary forms. The literature looking at impact of baseline fluorescent antinuclear antibody (FANA) positivity on outcomes of AIHA patients is infrequent.
To study the impact of baseline FANA positivity in patients with primary AIHA.
A prospective cohort study involving 29 consecutive primary AIHA patients presenting to the Haematology department from 2013 to 2015 was analysed. After recording baseline investigations including fluorescent ANA, all patients were treated as per the standard therapeutic protocols. Clinical remission, disease free survival, relapse, mortality were compared between the FANA positive and FANA Negative AIHA groups.
Baseline FANA positivity was found in 17 patients (58.62%). Both the groups were comparable in terms of age, sex, Hemoglobin, LDH at presentation, number of lines of treatment needed and duration of follow up. Evan's syndrome was seen in six of FANA positive patients which was statistically significant (0 v/s 6, p = 0.023). FANA positive patients had significantly higher rates of relapse per patient month follow up (1.22 v/s 3.57, p = 0.023) and lower rates of complete response (83.33% v/s 35.29%, p = 0.0118) and relapse free survival at five years. Morbidity and mortality were numerically higher in FANA positive patients.
Baseline FANA positivity among AIHA patients was found to be associated with lower complete response rates and higher relapse rates with possible higher rates of morbidity. Presence of FANA will give us prognostic value and help us in deciding the treatment options.
Autoimmune haemolytic anaemias: A retrospective study of 93 patients
2020, Medicina Clinica
Las anemias hemolíticas autoinmunes (AHAI) son enfermedades poco frecuentes y heterogéneas en su fisiopatología y comportamiento clínico, siendo el manejo de las mismas fundamentalmente empírico.
Realizamos un estudio observacional, retrospectivo y multicéntrico de 93 pacientes diagnosticados de AHAI en 9 hospitales españoles entre 1987 y 2017, con una mediana de seguimiento de 28 meses.
Mediana de edad de 67 años; un 85% de AHAI por anticuerpos calientes y un 64% AHAI primarias. Los valores de hemoglobina más bajos al diagnóstico se relacionaron con edad < 45 años y el tipo serológico IgG+C. Un 92% recibieron tratamiento de primera línea, un 54% de segunda línea y un 27% de tercera línea. Las AHAI calientes fueron tratadas en primera línea con esteroides, con respuestas globales del 83% y completas del 58%. El rituximab en monoterapia o asociado a esteroides se administró a 34 pacientes con respuestas globales cercanas al 100% (respuestas completas 40-60%), relegando la esplenectomía a tercera línea. El tratamiento inmunosupresor se administró en pacientes con enfermedades autoinmunes o en dependientes de corticoides.
Encontramos altas tasas de respuesta a esteroides, con tratamientos muy prolongados que provocan efectos secundarios y corticodependencia en un tercio de los pacientes. La asociación de esteroides con rituximab en primera línea podría estar indicada en pacientes con bajos niveles de hemoglobina y tipo serológico IgG+C. Las altas tasas de recaída hacen necesario el desarrollo de estudios aleatorizados con nuevos fármacos o la asociación con los ya existentes, que permitan mayor duración de las respuestas y con menores efectos secundarios.
Autoimmune haemolytic anaemia (AIHA) is an infrequent and heterogeneous disease in its pathophysiology and clinical behaviour, therefore it is generally managed empirically.
We conducted an observational, retrospective and multicentre study of 93 patients diagnosed with AHAI in 9 Spanish hospitals between 1987 and 2017, with a median follow-up of 28 months.
Median age of 67 years; 85% AHAI for hot antibodies and 64% primary AHAI. The lowest haemoglobin values at diagnosis related to patients under 45 years of age and serological type IgG+C. Of the patients, 92% received first line treatment, 54% second line, and 27% third line. The warm AHAI were treated in first line with steroids, with overall responses of 83% and complete of 58%. Rituximab in monotherapy or in association with steroids was administered to 34 patients with overall responses close to 100% (complete responses 40-60%), relegating splenectomy to the third line. The immunosuppressive treatment was administered in patients with autoimmune diseases or in corticoid-dependent patients.
We found high rates of response to steroids, with very prolonged treatments that cause side effects and corticoid dependence in a third of patients. The combination of steroids with rituximab in the first line, could be indicated in patients with low levels of haemoglobin and serological type IgG+C. The high relapse rates make necessary the development of randomised studies with new drugs or the combination with existing ones, which allow longer response times and with fewer side effects.
Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting
2020, Blood Reviews
Autoimmune hemolytic anemias (AIHAs) are rare and heterogeneous disorders characterized by the destruction of red blood cells through warm or cold antibodies. There is currently no licensed treatment for AIHA. Due to the paucity of clinical trials, recommendations on diagnosis and therapy have often been based on expert opinions and some national guidelines. Here we report the recommendations of the First International Consensus Group, who met with the aim to review currently available data and to provide standardized diagnostic criteria and therapeutic approaches as well as an overview of novel therapies. Exact diagnostic workup is important because symptoms, course of disease, and therapeutic management relate to the type of antibody involved. Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup, and any causes of secondary AIHA have to be diagnosed. Corticosteroids remain first-line therapy for warm-AIHA, while the addition of rituximab should be considered early in severe cases and if no prompt response to steroids is achieved. Rituximab with or without bendamustine should be used in the first line for patients with cold agglutinin disease requiring therapy. We identified a need to establish an international AIHA network. Future recommendations should be based on prospective clinical trials whenever possible.
Predictors of autoimmune hemolytic anemia in beta-thalassemia patients with underlying red blood cells autoantibodies
2019, Blood Cells, Molecules, and Diseases
In beta-thalassemia patients, erythrocyte autoantibodies can remain silent or lead to Autoimmune Hemolytic Anemia (AIHA).The aim of this study was to identify predictors of AIHA in beta-thalassemia patients with positive Direct Antiglobulin Test (DAT), in Tunisia.
This longitudinal prognosis study was carried out on beta-thalassemia patients with a positive confirmed DAT. Predictors of AIHA were identified the Kaplan-Meier method. A Cox model analysis was used to identify independent predictors.
Among 385 beta thalassemia patients, 87 developed positive DAT (22.6%). Autoimmune hemolytic anemia was occurred in 25 patients. Multivariate analysis showed that AIHA was independently associated with beta-thalassemia intermedia and similar family history of AIHA. Splenectomy in patients with positive DAT was independently associated with an increased risk of AIHA (HR = 6.175, CI: 2.049–18.612, p < 0.001). The risk of developing AIHA was higher during the first 72 transfusions. Autoimmune hemolytic anemia was significantly associated with polyspecific DAT (anti-complement and anti-IgG), blood group AB and prior alloimmunization. Whereas transfusion by phenotypic and leukoreduced blood was a protective factor.
In summary, splenectomy after autoimmunization, prior alloimmunization, DAT specificity (IgG with complement), thalassemia intermedia, AB blood group and family history of AIHA were strongly associated with AIHA. Leukoreduced blood transfusion had a proven preventive role.
Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: A first-in-human trial
2019, Blood
Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis. This trial tested the hypothesis that the anti-C1s antibody sutimlimab would ameliorate hemolytic anemia. Ten patients with cold agglutinin disease participated in the phase 1b component of a first-in-human trial. Patients received a test dose of 10-mg/kg sutimlimab followed by a full dose of 60 mg/kg 1 to 4 days later and 3 additional weekly doses of 60 mg/kg. All infusions were well tolerated without premedication. No drug-related serious adverse events were observed. Seven of 10 patients with cold agglutinin disease responded with a hemoglobin increase >2 g/dL. Sutimlimab rapidly increased hemoglobin levels by a median of 1.6 g/dL within the first week, and by a median of 3.9 g/dL (interquartile range, 1.3-4.5 g/dL; 95% confidence interval, 2.1-4.5) within 6 weeks (P = .005). Sutimlimab rapidly abrogated extravascular hemolysis, normalizing bilirubin levels within 24 hours in most patients and normalizing haptoglobin levels in 4 patients within 1 week. Hemolytic anemia recurred when drug levels were cleared from the circulation 3 to 4 weeks after the last dose of sutimlimab. Reexposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia. All 6 previously transfused patients became transfusion-free during treatment. Sutimlimab was safe, well tolerated, and rapidly stopped C1s complement–mediated hemolysis in patients with cold agglutinin disease, significantly increasing hemoglobin levels and precluding the need for transfusions. This trial was registered at www.clinicaltrials.gov as #NCT02502903.
Complement Activation and Inhibition in Autoimmune Hemolytic Anemia: Focus on Cold Agglutinin Disease
2018, Seminars in Hematology
The classical complement pathway and, to some extent, the terminal pathway, are involved in the immune pathogenesis of autoimmune hemolytic anemia (AIHA). In primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, the hemolytic process is entirely complement dependent. Complement activation also plays an important pathogenetic role in some warm-antibody AIHAs, especially when immunoglobulin M is involved. This review describes the complement-mediated hemolysis in AIHA with a major focus on CAD, in which activation of the classical pathway is essential and particularly relevant for complement-directed therapy. Several complement inhibitors are candidate therapeutic agents in CAD and other AIHAs, and some of these drugs seem very promising. The relevant in vitro findings, early clinical data and future perspectives are reviewed.

View all citing articles on Scopus

^☆: This work was supported by research funding from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, grant no. RC 2014, and by Ministry of Health, grant no. RF 2010 convention no. 141/RF-2010-2303934.

^☆☆: The author has no conflicts of interest or disclosures.

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Immune Hemolysis: Diagnosis and Treatment Recommendations☆,☆☆

Section snippets

Diagnostic Aspects of AIHA

Clinical Aspects

Treatment of Warm AIHA

Treatment of CAD

Supportive Therapy

Blood

Blood

Blood

Blood

Transf Med Rev

Blood

J Infect

Clin MIcrobiol Infect

Am J Med

Eur J Intern Med

Autoimmun Rev

Rev Med Interne

Blood

Blood Reviews

Blood

Rev Med Intern

Blood

Blood

Blood

Blood

Blood

Ann Thorac Surg

Transl Res

Immune hemolytic anemias

Pitfalls in the diagnosis of autoimmune haemolytic anaemia

Blood Transfus

Immune hemolytic anemia-selected topics

Hematology Am Soc Hematol Educ Program

A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia

Br J Haematol

Sustained response to low-dose rituximab in idiopathic autoimmune hemolytic anemia

Eur J Haematol

Serologic findings in autoimmune hemolytic anemia associated with immunoglobulin M warm autoantibodies

Transfusion

A dual antiglobulin test for the detection of weak or nonagglutinating immunoglobulin M warm autoantibodies

Transfusion

New insights into childhood autoimmune hemolytic anemia: a French national observational study of 265 children

Haematologica

In vitro quantification of anti-red blood cell antibody production in idiopathic autoimmune haemolytic anaemia: effect of mitogen and cytokine stimulation

Br J Haematol

Clinical application of a flow cytometric direct antiglobulin test

Transfusion

Role of gel test and flow cytometry in diagnosis of Coombs׳ negative autoimmune haemolytic anaemia

Int J Lab Hematol

Primary chronic cold agglutinin disease: a population based clinical study of 86 patients

Haematologica