Autoimmune Hemolytic Anemia (AIHA) Resource Center

Autoimmune hemolytic anemia (AIHA) is an autoimmune disorder resulting in the production of antibodies directed against red blood cell antigens, causing shortened erythrocyte survival. The disorder is an acquired hemolysis and can be idiopathic or secondary to other autoimmune disorders, malignancies, or infections.

AIHA is classified according to the thermal range of the autoantibodies. The subtypes can be classified as either warm type (wAIHA) – the majority of AIHA cases, cold type (cold agglutinin disease (CAD)), or a rarer mixed warm and cold type.

• Warm Autoimmune Hemolytic Anemia (wAIHA) is the most common form of AIHA, representing 60-70% of all AIHA cases, and disproportionally affects women. It is most often characterized by having a gamma immunoglobulin (IgG) antibody that binds to red blood cell antigens independently of temperature.
• Cold Autoimmune Hemolytic Anemia, or cold agglutinin disease (CAD), is most commonly caused by immunoglobulin M (IgM), a cold-reactive autoantibody that binds to red blood cells at lower temperatures, leading to red cell agglutination in cooler areas of the body and activation of the complement system. CAD is reported to account for 20-25% of all AIHA cases.
• Mixed-type Autoimmune Hemolytic Anemia (mAIHA) is a rare and complex form of AIHA, accounting for fewer than 10% of AIHA cases. It is characterized by the presence of both warm (IgG) and cold (IgM) reactive autoantibodies.

AIHA can be further classified as either primary (idiopathic) or secondary. Primary AIHA occurs in the absence of an identifiable underlying disorder and accounts for the majority of cases, estimated at more than 60%. Secondary AIHA may occur due to many underlying medical disorders, including autoimmune illnesses, blood malignancies, and infections, including coronavirus disease 2019 (COVID-19).

Section Resources:

• Tranekær S, Hansen DL, Frederiksen H. Epidemiology of Secondary Warm Autoimmune Haemolytic Anaemia—A Systematic Review and Meta-Analysis. Journal of Clinical Medicine. 2021; 10(6):1244. https://doi.org/10.3390/jcm10061244
• Despotovic JM, Kim TO. Cold AIHA and the best treatment strategies. Hematology Am Soc Hematol Educ Program. 2022; 2022 (1):90-95. https://pmc.ncbi.nlm.nih.gov/articles/PMC9821124/
• Branch DR. Warm autoimmune hemolytic anemia: new insights and hypotheses. Curr Opin Hematol. 2023; 30(6):203-209. https://pmc.ncbi.nlm.nih.gov/articles/PMC10552839/
• Berentsen S. Diagnosis and management of cold agglutinin disease. Hematology Am Soc Hematol Educ Program. 2025; 2025 (1): 295–304. doi: https://doi.org/10.1182/hematology.2025000718
• Barcellini W, Fattizzo B. The Changing Landscape of Autoimmune Hemolytic Anemia. Front Immunol. 2020;11:946. https://pmc.ncbi.nlm.nih.gov/articles/PMC7325906/
• Versino F, Pedone GL, Bortolotti M, Barcellini W, Fattizzo B. Mixed Type Autoimmune Hemolytic Anemia: A Single Center Observational Study. Blood. 2024; 144 (Supplement 1): 3844. doi: https://doi.org/10.1182/blood-2024-194219
• Jacobs JW, Raza S, Clark LM, et al. Mixed Autoimmune Hemolytic Anemia: A Systematic Review of Epidemiology, Clinical Characteristics, Therapies, and Outcomes. Am J Hematol. 2025;100(8):1397-1407. https://pmc.ncbi.nlm.nih.gov/articles/PMC12232602/
• Loriamini M, Cserti-Gazdewich C, Branch DR. Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management. Int J Mol Sci. 2024; 25(8):4296. https://pmc.ncbi.nlm.nih.gov/articles/PMC11049952/

Other Tools:

• International Consensus Report on AIHA: Provider-driven medical summary on the treatment and management of AIHA, drawn from physicians worldwide
• New England Journal of Medicine Treatment Guide on AIHA: The NEJM has curated a set of resources for providers
• CDC’s NHLBI Autoimmune Hemolytic Anemia Resource Center: The CDC’s NHLBI collected resources of evergreen information for a good primer for providers
• Autoimmune Hemolytic Anemia in Emergency Medicine Questions & Answers: Medscape features a summary of ITP from diagnosis to treatment to ongoing management

AIHA can occur at any age, but its presentation, underlying causes, clinical course, and management considerations differ substantially from childhood through adulthood. Recognition of these age-related differences is essential to accurate diagnosis, appropriate treatment selection, and long-term care planning.

Pediatric AIHA
AIHA is rare in children but can occur at any age, and may present with variable degrees of severity. Warm autoimmune hemolytic anemia (wAIHA) is the most common subtype in pediatric patients. Children may present with pallor, fatigue, jaundice, dark urine, tachycardia, or severe anemia requiring treatment. Treatment is necessary, given that the condition is chronic. The rate of mortality is up to 4% in children due to the severity of their condition or the multiple types of treatment.

Adolescence and Menarche

For adolescent girls, AIHA may present unique challenges as menstruation begins. Fatigue and anemia related to hemolysis can be compounded by menstrual blood loss, particularly in those experiencing heavy menstrual bleeding. Clinicians should consider iron status, menstrual history, and overall quality of life when evaluating symptoms.

Adolescence may also be a time when underlying autoimmune conditions first emerge, increasing the potential for secondary AIHA. Collaboration between hematology, primary care, and reproductive health providers can help address both hematologic and gynecologic concerns during this important developmental stage.

Adults with AIHA
Also considered rare in adults, AIHA is most commonly diagnosed in adults above 40 years. Warm AIHA accounts for approximately 60-70% of all cases and is the predominant subtype in adults. Secondary AIHA is more common in adulthood and may occur in association with autoimmune diseases, infections, or certain medications. As comorbidities increase with age, older adults with wAHIA also face an increased risk of morbidity and mortality.

AIHA in Females
wAHIA disproportionately affects women in the adult population, with approximately two-thirds of diagnosed patients being female. This increased risk is largely driven by the higher prevalence of associated autoimmune conditions in women, particularly systemic lupus erythematosus (SLE), the most common cause of secondary wAIHA in adults. Among adult-only cohorts, women account for 61–71% of cases, a pattern that contrasts with pediatric populations, where males represent the majority of patients.

Although uncommon, AIHA may develop for the first time during pregnancy, worsen during pregnancy, or flare in the postpartum period. Disease activity can be difficult to distinguish from other causes of anemia during pregnancy, making close monitoring important. Collaboration among hematologists, maternal-fetal medicine specialists, obstetricians, and pediatric providers is often necessary to optimize outcomes for both mother and baby.

In women, wAIHA most often presents later in life, with peak incidence between 60 and 70 years of age. Older adults may experience greater disease-related morbidity due to the presence of comorbid conditions. Careful evaluation of anemia and hemolysis remains important in this population.

Section References

• Voulgaridou A, Kalfa TA. Autoimmune Hemolytic Anemia in the Pediatric Setting. J Clin Med. 2021; 10(2):216. https://pmc.ncbi.nlm.nih.gov/articles/PMC7828053/
• Jackson L, Zhdanava M, Pesa J, Boonmak P, Chen G, Liu D, Pilon D, Choudhry Z, Shah S. Mortality associated with warm autoimmune hemolytic anemia among Medicare beneficiaries. Blood. 2025; 146 (Supplement 1): 2694. doi: https://doi.org/10.1182/blood-2025-2694
• Tranekær S, Hansen DL, Frederiksen H. Epidemiology of Secondary Warm Autoimmune Haemolytic Anaemia—A Systematic Review and Meta-Analysis. Journal of Clinical Medicine. 2021; 10(6):1244. https://doi.org/10.3390/jcm10061244

Diagnosing autoimmune hemolytic anemia (AIHA) can be challenging, particularly for clinicians who do not routinely manage hemolytic disorders. AIHA should be suspected in patients with evidence of hemolytic anemia, including fatigue, pallor, jaundice, dark urine, shortness of breath, tachycardia, or an unexplained decline in hemoglobin.

The diagnosis of AIHA is based on a set of highly specific biological changes and a positive direct Coombs test. Because the course of the disorder varies across populations and may be chronic or idiopathic, the treatment protocols may also vary, but primarily involve immune modulation with corticosteroids and other agents, including a growing focus on complement inhibitors.

Diagnostic Tests

• Complete Blood Count
• Haptoglobin
• Lactate Dehydrogenase
• Reticulocyte Count (not a percent)
• Bilirubin
• Peripheral Smear
• Direct Antiglobulin Testing (DAT), also known as the Coombs test

Direct Antiglobulin Testing (DAT)
The DAT is a laboratory procedure used to detect the presence of antibodies against circulating red blood cells that induce hemolysis.

In wAIHA, the DAT is most commonly positive for IgG, with or without complement (C3). In contrast, cold agglutinin disease is typically associated with complement-positive testing. It should be noted that while a positive DAT supports the diagnosis, it does not independently establish AIHA. Likewise, a negative DAT does not completely exclude AIHA.

Diagnostic Challenges
Diagnosis of AIHA may be difficult in certain clinical settings, as the DAT is neither fully sensitive nor specific. Initial polyspecific DAT testing, which is commonly performed in transfusion services, may fail to detect some cases of AIHA, does not reliably distinguish wAIHA from CAD, and may be confounded by prior treatments such as transfusion or immunosuppression.

Additionally, the presence of concomitant hemolytic conditions may complicate or obscure the diagnosis of AIHA. Overlapping disorders, such as paroxysmal nocturnal hemoglobinuria (PNH), inborn errors of immunity, and bone marrow failure syndromes, can affect diagnostic interpretation and should be considered during evaluation.

Given the complexity of diagnosis and treatment, individuals with suspected AIHA should generally be referred to or managed in consultation with a hematologist. Early recognition and accurate classification of AIHA are important because treatment strategies, prognosis, and monitoring requirements differ substantially among AIHA subtypes.

Section References

• Tripathi AK, Chuda R. Laboratory Evaluation of Immune Hemolytic Anemias. [Updated 2024 Jul 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK606096/
• Theis SR, Hashmi MF. Coombs Test. [Updated 2022 Sep 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547707/

Management of AIHA is guided by disease severity, etiology, comorbidities, patient preferences, and response to prior therapy. Treatment goals include controlling hemolysis, improving anemia and symptoms, preventing complications, minimizing treatment-related toxicity, and maintaining long-term quality of life and daily functioning.

First-line Therapy
Corticosteroids remain the cornerstone of initial therapy for wAIHA. Prednisone (or equivalent) is effective in rapidly controlling hemolysis in the majority of patients and is typically initiated at diagnosis.

Red blood cell transfusion may be required in cases of severe or life-threatening anemia, with careful compatibility testing. Identification and management of underlying or secondary causes—such as autoimmune disease, infection, or malignancy—are essential components of first-line care.

Close collaboration among hematologists, transfusion medicine specialists, and blood banks is often required.

Supportive Care
Supportive management is an important competent of care and may include:

• Supplements: folic acid, vitamin B12, and iron replacement (when iron deficiency is documented)
• Monitoring for treatment-related complications
• Assessment of fatigue, functional status, and quality of life

Second-line Therapies
Rituximab – has become an important treatment option for those who relapse, fail to reposed adequately to corticosteroids, or require a steroid-sparing approach

Immunosuppressive Therapies – additional immunosuppressive agents may be considered in selected patients with relapsed or refractory disease

Third-line Therapy
Splenectomy – may be considered for selected patients, particularly when other treatment options have failed or are not tolerated; decisions regarding surgery should be individualized and made in consultation with an experienced hematology team

Additional Therapies
The treatment landscape for AIHA continues to evolve rapidly. Additional information on emerging therapies and clinical trials can be found in the Research & Clinical Trials section.

Section Resources

• Kuter DJ. Warm autoimmune hemolytic anemia and the best treatment strategies. Hematology Am Soc Hematol Educ Program. 2022; (1):105-113. https://pmc.ncbi.nlm.nih.gov/articles/PMC9821065/

Clinical trials are prospective studies in human participants designed to evaluate the safety, efficacy, and clinical utility of medical, surgical, or behavioral interventions. They are the primary mechanism for assessing new therapies, including drugs, devices, and lifestyle interventions. Trials may compare investigational approaches to the standard of care or evaluate strategies for early detection, prevention, and risk reduction. Some also focus on quality of life and patient-reported outcomes in chronic or life-threatening conditions.

ClinicalTrials.gov is a publicly accessible registry and results database of clinical studies conducted around the world, maintained by the U.S. National Library of Medicine.

Clinical Trials on AIHA Clinical Trials on wAIHA

Actively Recruiting Studies in the US:

• A Study to Investigate the Efficacy, Safety, and Pharmacokinetics of Oral Rilzabrutinib Compared With Placebo in Participants 18 Years of Age and Older With Warm Autoimmune Hemolytic Anemia (LUMINA 3)
• Cold Agglutinin Disease Real World Evidence Registry (CADENCE)
• Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT (HSCT+RIC)

A diagnosis of AIHA can be overwhelming for patients and families. Since AIHA is a rare and often complex condition, many patients have questions about their diagnosis, treatment options, long-term outlook, and how the disease may impact their daily life.

Providing patients with reliable, easy-to-understand educational materials can improve understanding, support shared decision-making, and help patients feel more confident managing their condition. These curated resources offer information on AIHA, treatment options, symptom management, and patient support. They may serve as a starting point for education and empowerment throughout the AIHA journey.

Patient Education and Disease Information

• Educational Resources for Patients with AIHA – St. Jude’s Research Hospital has created patient-friendly materials to help navigate ongoing treatment and management, including discussion points to ask providers.
• Understanding AIHA and Its Treatment – Indiana Hemophilia & Thrombosis Center
• Resources to Help Patients Live with Autoimmune Hemolytic Anemia – Johns Hopkins University
• Educational Resources for Patients with AIHA St. Jude’s Research Hospital has created patient-friendly materials to help navigate ongoing treatment and management, including discussion points to ask providers.

Living Well with AIHA

• Living with Autoimmune Hemolytic Anemia – Resources focused on day-to-day disease management, treatment adherence, coping with fatigue, and maintaining quality of life

Patient Support and Advocacy

• wAIHA Warriors – A patient support and advocacy organization dedicated to individuals living with warm autoimmune hemolytic anemia (wAIHA). The organization provides educational resources, peer support opportunities, patient stories, and community connections for patients, caregivers, and healthcare professionals
• Platelet Disorder Support Association (PDSA) – AIHA resources including educational materials, webinars, patient stories, and support resources