Autoimmune Hemolytic Anemia (AIHA)

AIHA is a group of immune-mediated hemolytic anemias in which antibodies target red blood cells and, in some cases, activate the complement system, causing shortened red blood cell survival.

AIHA is classified according to the temperature at which the antibodies react most strongly and the underlying immune mechanism.

Warm autoimmune hemolytic anemia (wAIHA) is the most common form and is usually mediated by IgG antibodies that react near normal body temperature.

Cold agglutinin disease (CAD) is mainly mediated by cold-reactive IgM antibodies and complement activation. CAD has a distinct disease mechanism and treatment approach.

Paroxysmal cold hemoglobinuria (PCH) is another cold-reactive form of AIHA with a different mechanism and is more commonly seen in children following infections.

Mixed AIHA has features of both clinically significant warm and cold-reactive antibodies.

AIHA may be primary or secondary.

Primary AIHA means that no clear underlying condition is identified after evaluation. Secondary AIHA may be associated with:

• Autoimmune diseases such as systemic lupus erythematosus

• Lymphoid disorders such as lymphoma or chronic lymphocytic leukemia

• Certain infections

• Immunodeficiency

• Immune complications after hematopoietic stem cell transplantation

• Certain medications, including some antibiotics and other drugs

The associated conditions also vary by subtype.

For example, CAD is often associated with a clonal B-cell disorder in the bone marrow, while secondary cold agglutinin syndromes may occur in association with infections or other diseases.

Symptoms of AIHA result mainly from anemia and increased destruction of red blood cells and can range from mild to life-threatening.

Possible symptoms include:

• Fatigue and weakness

• Dizziness

• Rapid heartbeat or shortness of breath with activity

• Pale skin

• Yellowing of the skin or eyes

• Dark urine

• An enlarged spleen

• Chest pain, breathing difficulty, or circulatory instability in severe anemia

wAIHA may develop gradually or present with rapid hemolysis. Some patients also develop immune thrombocytopenia, a combination known as Evans syndrome.

In CAD, patients may also have cold-induced circulation symptoms such as bluish discoloration, pain, or numbness of the fingers, toes, ears, or nose. These symptoms often worsen with cold exposure.

PCH may cause sudden intravascular hemolysis after cold exposure, sometimes accompanied by fever, chills, back pain, and hemoglobinuria.

Patients with active AIHA may also have an increased risk of thrombosis, particularly when hemolysis is severe.

Diagnosis of AIHA requires evidence of both hemolysis and an immune cause.

Blood tests commonly include a complete blood count, reticulocyte count, bilirubin, lactate dehydrogenase (LDH), and haptoglobin.

Typical laboratory findings may include:

• Low hemoglobin

• Increased reticulocytes

• Increased indirect bilirubin

• Elevated LDH

• Reduced haptoglobin

However, not every patient meets the same fixed laboratory thresholds.

The direct antiglobulin test (DAT) is a key diagnostic test. It detects IgG and/or complement components attached to red blood cells.

DAT patterns can also help classify AIHA. wAIHA commonly shows IgG positivity, sometimes with complement, while CAD typically shows complement positivity.

Additional testing may include cold agglutinin titers for suspected CAD or Donath-Landsteiner antibody testing for suspected PCH.

After AIHA is confirmed, further evaluation may be needed to look for an underlying autoimmune disease, infection, lymphoid disorder, medication trigger, or other cause.

Bone marrow testing is not required for every patient and is generally reserved for selected cases with unexplained cytopenias, suspected lymphoid disease, or diagnostic uncertainty.

Treatment depends strongly on the type of AIHA because wAIHA and CAD have different underlying mechanisms.

When AIHA is secondary to another condition or medication, treatment of the underlying disorder or withdrawal of the suspected drug is also important.

Warm AIHA

Corticosteroids remain the standard first-line treatment for wAIHA. Many patients respond initially, but relapse during or after steroid tapering is common, so reducing prolonged steroid exposure is an important treatment goal.

For patients who do not respond adequately, become steroid-dependent, or relapse, rituximab is now an important preferred second-line option.

Other immunosuppressive therapies may be considered in selected patients. Splenectomy is still an option but is generally used later than in the past because other effective therapies are now available.

Cold Agglutinin Disease

Treatment of CAD differs substantially from treatment of wAIHA.

Avoiding significant cold exposure remains helpful, but patients with symptomatic anemia, significant fatigue, or bothersome circulation symptoms may require drug therapy.

Corticosteroids are usually ineffective in CAD and are not routinely recommended.

Treatment may target the abnormal B-cell clone with therapies such as rituximab, or target complement-mediated hemolysis.

Sutimlimab, a monoclonal antibody targeting complement C1s, can rapidly reduce complement-mediated hemolysis and is approved for adults with CAD in several countries.

Transfusion and Supportive Care

Red blood cell transfusion may be given when anemia is clinically significant.

The decision to transfuse depends on symptoms, hemoglobin level and rate of decline, age, cardiovascular status, and overall clinical condition.

Additional supportive care may include folate supplementation, prevention or treatment of thrombosis, and management of infections or other complications.