What are the causes of warm autoimmune hemolytic anemia (AIHA)?

Causes of Warm Autoimmune Hemolytic Anemia (AIHA)

Warm AIHA can be classified as either primary (idiopathic, accounting for approximately 50% of cases) or secondary to underlying disorders including lymphoproliferative neoplasms, autoimmune diseases, infections, immunodeficiencies, drugs, and solid tumors. 1, 2

Primary (Idiopathic) Warm AIHA

• Approximately 50% of warm AIHA cases are primary, meaning no specific underlying etiology can be identified despite thorough investigation 2
• These cases represent a breakdown of immunologic tolerance through mechanisms that remain incompletely understood 3
• The pathophysiology involves production of IgG autoantibodies against RBC antigens (particularly band 3 protein) through polyclonal B-cell activation and T-cell-mediated mechanisms 4, 3

Secondary Warm AIHA

Lymphoproliferative Disorders

• Chronic lymphocytic leukemia (CLL) is a major cause of secondary warm AIHA 5
• More than 90% of autoimmune disorders in CLL are caused by nonmalignant B lymphocytes producing polyclonal high-affinity IgG via T-cell-mediated mechanisms 5
• CLL tumor cells act as antigen-presenting cells, inducing formation of autoreactive T-helper cells and nonfunctional T-regulatory cells 5
• Waldenström macroglobulinemia can cause cold agglutinin-mediated hemolytic anemia in fewer than 10% of patients 5
• Other lymphomas including diffuse large B-cell lymphoma and follicular lymphoma 5

Autoimmune Diseases

• Systemic lupus erythematosus and other connective tissue disorders are well-recognized causes 2
• Autoimmune hepatitis may be associated with autoimmune cytopenias, though this is less common 5
• Primary immunodeficiency syndromes, particularly those with immune dysregulation 2

Drug-Induced Immune Hemolytic Anemia (DIIHA)

• Common causative drugs include ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, and fludarabine 6
• Immune checkpoint inhibitors can cause hemolytic anemia as an immune-related adverse event 6
• Drug-induced cases present with DAT positive for IgG and/or C3d, appearing clinically as warm AIHA 4
• Some cases resolve after discontinuation of the offending drug 4

Infectious Causes

• Various infections can trigger warm AIHA, though specific pathogens are not consistently identified 2
• The mechanism involves molecular mimicry or polyclonal lymphocyte activation 3

Solid Tumors

• Malignancies can be associated with warm AIHA as a paraneoplastic phenomenon 1, 2

Post-Transplantation

• Passenger lymphocyte syndrome occurs after transplantation when donor B-cells produce antibodies against recipient RBC antigens 4
• This represents a unique form of alloimmune hemolysis in the transplant setting 4

Pathophysiologic Mechanisms

• The breakdown of immunologic tolerance involves multiple factors: defective antigen presentation, functional abnormalities of B and T cells causing polyclonal activation, altered cytokine production, and dysfunction of immunoregulatory T cells 3
• IgG-opsonized RBCs are destroyed via antibody-dependent cellular cytotoxicity, primarily through macrophage-mediated phagocytosis in the spleen and lymphoid organs (extravascular hemolysis) 5, 7
• Complement activation may contribute to hemolysis in some cases 7

Important Clinical Considerations

• In CLL-associated AIHA, the autoimmune cytopenia may precede clinically apparent CLL and can be detected in monoclonal B-cell lymphocytosis 5
• Patients with autoimmune cytopenia due to immune mechanisms in CLL have better outcomes than those with cytopenias from bone marrow infiltration 5
• The incidence of autoimmune cytopenia in CLL patients treated with chemoimmunotherapy is lower than with chemotherapy alone 5