Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is anemia caused by autoantibodies directed against a person's own red-cell antigens, leading to premature destruction of red cells. It is classified by the thermal characteristics of the antibody into warm AIHA, in which IgG antibodies react at body temperature, and cold agglutinin disease, in which IgM antibodies react at lower temperatures; the diagnosis rests on the direct antiglobulin (Coombs) test.

Definition

Autoimmune hemolytic anemia is a group of disorders in which autoantibodies against self red-cell antigens cause accelerated red-cell destruction and anemia, subclassified by the optimal reaction temperature of the antibody (warm or cold) and by whether it is primary or secondary to another condition.

Scope

This entry covers the definition and classification of AIHA (warm, cold, and mixed types, primary and secondary), the immune mechanisms of red-cell destruction, and the central role of the direct antiglobulin test in diagnosis. It is a reference topic in immunohematology and does not provide treatment regimens.

Core questions

• How do autoantibodies cause red-cell destruction in AIHA?
• What distinguishes warm AIHA from cold agglutinin disease?
• Why is the direct antiglobulin test central to diagnosis?
• What does it mean for AIHA to be primary versus secondary?

Key concepts

• Red-cell autoantibodies
• Warm AIHA (IgG, extravascular hemolysis)
• Cold agglutinin disease (IgM, complement-mediated)
• Direct antiglobulin (Coombs) test
• Extravascular vs intravascular hemolysis
• Primary vs secondary AIHA
• Reticulocytosis and markers of hemolysis

Mechanisms

In warm AIHA, IgG autoantibodies bind red cells at body temperature; the antibody-coated cells are recognized by Fc receptors on macrophages in the spleen and removed by extravascular hemolysis. In cold agglutinin disease, IgM autoantibodies bind red cells at lower temperatures and fix complement, leading to complement-mediated clearance and, at times, intravascular hemolysis. The direct antiglobulin test detects immunoglobulin and/or complement on the red-cell surface and is the defining laboratory feature; the pattern of reactivity helps distinguish warm from cold types. AIHA may be primary (idiopathic) or secondary to lymphoproliferative disorders, autoimmune disease, infection, or drugs.

Clinical relevance

AIHA is a principal cause of acquired immune hemolysis, and recognizing it depends on linking the clinical picture of hemolytic anemia to a positive direct antiglobulin test. This entry explains the mechanisms and classification that underpin diagnosis; it is educational and does not recommend specific therapies, which are individualized and beyond its scope.

Epidemiology

AIHA is uncommon, with warm AIHA the most frequent form; cold agglutinin disease is rarer and often associated with lymphoproliferative disorders or certain infections. A substantial proportion of cases are secondary to an identifiable underlying condition, which is why evaluation for associated disease is part of the diagnostic reasoning.

History

The recognition of AIHA as an antibody-mediated disorder followed the introduction of the antiglobulin test by Coombs, Mourant and Race in 1945, which allowed detection of antibody coating red cells in vivo. Subsequent work distinguished warm and cold forms by the thermal and immunoglobulin characteristics of the autoantibody and clarified the associations with lymphoproliferative and autoimmune disease.

Debates

How should warm AIHA be treated beyond first-line therapy?

The optimal sequence of therapies in relapsed or refractory warm AIHA remains an area of evolving evidence and clinical judgement, as reviewed in contemporary how-I-treat literature.

Key figures

• Robin Coombs
• Wendell Rosse
• Lawrence Petz
• Wilma Barcellini

Seminal works

• coombs-1945
• barcellini-2021

Frequently asked questions

What test confirms autoimmune hemolytic anemia?

The direct antiglobulin (direct Coombs) test, which detects antibody and/or complement bound to the patient's red cells, is the central confirmatory test, interpreted together with evidence of hemolysis.

What is the difference between warm and cold AIHA?

Warm AIHA involves IgG antibodies that react at body temperature and cause mainly spleen-mediated extravascular hemolysis, whereas cold agglutinin disease involves IgM antibodies that react in the cold and activate complement.