What is autoimmune hemolytic anemia?

What is Autoimmune Hemolytic Anemia?

Autoimmune hemolytic anemia (AIHA) is a condition in which autoantibodies target and destroy red blood cells, leading to premature erythrocyte destruction and anemia that ranges from asymptomatic to life-threatening hemolysis. 1, 2

Pathophysiology

AIHA results from a breakdown of immunologic tolerance, though the exact etiology remains incompletely understood. The key mechanisms include:

• Antibody-mediated destruction: In over 90% of cases, nonmalignant B lymphocytes produce polyclonal high-affinity IgG antibodies via T-cell-mediated mechanisms, which opsonize red blood cells and lead to their destruction through antibody-dependent cellular cytotoxicity 3

• Immune dysregulation: The pathogenesis involves T and B cell dysregulation, reduced CD4+ and CD25+ regulatory T cells, increased clonal expansions of CD8+ T cells, imbalance of Th17/Tregs and Tfh/Tfr ratios, and impaired lymphocyte apoptosis 4

• Cellular mechanisms: IgG-opsonized cells are destroyed via antibody-dependent cellular cytotoxicity, and changes in RBC membrane structures under mechanical or oxidative stress may promote autohemolysis 3, 4

Classification of AIHA

AIHA is classified into several distinct categories based on antibody characteristics and direct antiglobulin test (DAT) findings:

1. Warm Antibody AIHA (wAIHA)

• Most common type, accounting for approximately 97% of hospitalized AIHA patients 5
• Characterized by pan-reactive IgG autoantibodies recognizing portions of band 3 protein 1
• DAT is positive with IgG, C3d, or both 1

2. Cold Antibody AIHA

• Includes cold agglutinin syndrome (CAS) and cold agglutinin disease (CAD) 1
• Caused by IgM antibodies typically specific to the Ii blood group system 1
• CAS is polyclonal while CAD is monoclonal and more severe 1
• DAT is positive only with C3d 1

3. Mixed AIHA

• Also called combined cold and warm AIHA 1
• DAT positive for both IgG and C3d 1

4. Paroxysmal Cold Hemoglobinuria (PCH)

• Driven by biphasic cold-reactive IgG antibody recruiting complement 1
• DAT positive only for C3d 1
• Usually self-remitting 1

5. DAT-Negative AIHA

• IgG antibody levels below detection thresholds, or non-detected IgM or IgA antibodies 1

6. Drug-Induced Immune Hemolytic Anemia (DIIHA)

• Appears as wAIHA with DAT IgG and/or C3d positive 1
• Common causative drugs include ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, and fludarabine 6

Primary vs. Secondary AIHA

• Primary AIHA: Occurs with unknown cause, accounting for approximately 30% of cases 5
• Secondary AIHA: Associated with underlying diseases or infections, including chronic lymphocytic leukemia (CLL), systemic lupus erythematosus (SLE), and other autoimmune conditions 3

Clinical Presentation

The severity of anemia in AIHA varies considerably:

• Approximately 3% of hospitalized patients present with hemoglobin <30 g/L 5
• 34% present with hemoglobin between 30-59.9 g/L 5
• 46% present with hemoglobin ranging from 60-89.9 g/L 5
• Symptoms range from no symptoms to severe life-threatening hemolysis 5

Association with Other Conditions

CLL-Associated AIHA

• AIHA occurs in 5-7% of CLL patients, with autoimmune thrombocytopenia also occurring but less frequently 3
• Autoimmune disorders are particularly common in advanced phases of CLL 3
• Patients with anemia due to immune mechanisms have better outcomes than those with anemia from bone marrow infiltration 3

SLE-Associated AIHA

• Anemia is commonly observed in SLE patients, especially in advanced disease stages 3
• Results from iron deficiency or AIHA caused by increased eryptosis (programmed red cell death) 3
• SLE patients exhibit higher percentages of phosphatidylserine-exposing erythrocytes, elevated cytosolic Ca²⁺ levels, abundance of reactive oxygen species, and significant erythrocyte shrinkage 3

Diagnostic Approach

The direct antiglobulin test (DAT/Coombs test) is the hallmark diagnostic test and should be performed before initiating treatment. 6

Key diagnostic elements include:

• Monospecific DAT: Considered mandatory in the diagnostic workup to determine the specific type of antibody involved 7
• Hemolysis markers: Evaluate LDH, haptoglobin, bilirubin, and reticulocyte count 6
• Peripheral blood smear: Examine for evidence of hemolysis 6
• Autoantibody testing: Indirect immunofluorescence on freshly frozen rodent substrate (kidney, liver, stomach) is the preferable technique for routine autoantibody testing 3

Prognosis Considerations

• Autoimmune cytopenia is not necessarily associated with poor prognosis 3
• In CLL patients, those with anemia or thrombocytopenia due to immune mechanisms have better outcomes than those with bone marrow infiltration 3
• Primary AIHA patients with nadir hemoglobin of approximately 40-50 g/L during hospitalization have the highest rate of remission 5