Warm Autoimmune Hemolytic Anemia

Risk factors

• Autoimmune disease: SLE (most common), rheumatoid arthritis, Evans syndrome (AIHA + ITP)
• Lymphoproliferative: CLL, non-Hodgkin lymphoma, Hodgkin lymphoma
• Solid tumors (ovarian teratoma, others)
• Drugs: alpha-methyldopa, penicillins (high-dose IV), cephalosporins, fludarabine, NSAIDs, interferon, checkpoint inhibitors (nivolumab, pembrolizumab)
• Infection: mycoplasma (typically cold AIHA), EBV, HIV, CMV
• Post-transplant (solid organ or HSCT)

Pathophysiology

IgG (sometimes IgG + complement) autoantibodies bind Rh-related red cell antigens at 37°C. Fc receptors on splenic macrophages recognize IgG-coated cells, leading to partial membrane removal (producing spherocytes) and eventual phagocytic destruction in the spleen — extravascular hemolysis. Complement activation contributes in some cases, occasionally causing intravascular hemolysis.

Clinical presentation

Differential diagnosis

• Cold agglutinin disease — IgM antibody, optimum binding at 4°C, peripheral cyanosis on cold exposure, DAT positive for complement only (C3d), often post-Mycoplasma or with lymphoma
• Paroxysmal cold hemoglobinuria — Donath-Landsteiner antibody (IgG biphasic), post-viral in children; cold-induced hemoglobinuria
• Drug-induced immune hemolysis — Temporal relation to drug; DAT may be positive; resolves on drug discontinuation
• Hereditary spherocytosis — Chronic mild hemolysis, family history, negative DAT, positive osmotic fragility/EMA binding
• G6PD deficiency / oxidative hemolysis — Bite cells, Heinz bodies, negative DAT, drug trigger
• Microangiopathic hemolytic anemia (TTP/HUS/DIC) — Schistocytes, thrombocytopenia, end-organ dysfunction; negative DAT
• Mechanical hemolysis (prosthetic valve) — Schistocytes, history of valve replacement; negative DAT

Diagnostic workup

Diagnostic algorithm

Treatment

Complications

• Venous thromboembolism — increased risk during active hemolysis (consider VTE prophylaxis)
• Cardiovascular events from severe anemia
• Cholelithiasis (pigment stones)
• Steroid-related: hyperglycemia, osteoporosis, infection, weight gain, mood changes, avascular necrosis
• Rituximab-related: infusion reactions, hepatitis B reactivation, infection
• Post-splenectomy sepsis from encapsulated organisms
• Relapse common; many patients require long-term immunosuppression

PANCE pearls

• Positive direct Coombs (DAT) is the diagnostic hallmark — distinguishes immune from non-immune hemolysis.
• Spherocytes on smear can be seen in BOTH hereditary spherocytosis AND warm AIHA — DAT differentiates (positive in AIHA, negative in HS).
• Up to 10% of warm AIHA have negative DAT ('Coombs-negative AIHA') — diagnosis requires high clinical suspicion and exclusion of alternatives.
• Always screen for underlying lymphoma or CLL in adults with new warm AIHA; consider age-appropriate cancer screening.
• Methyldopa is the classic drug cause of warm AIHA — historical importance in board questions despite uncommon use today.
• Evans syndrome = warm AIHA + immune thrombocytopenia (± immune neutropenia); higher relapse rates and often associated with underlying autoimmune disease.
• Cross-matching is difficult because autoantibody reacts with all RBCs — laboratory must identify any alloantibodies separately; 'least incompatible' units used if transfusion necessary.

References

• First International Consensus Meeting 2020 — Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting (Jäger et al., Blood Reviews 2020)
• BSH 2017 — Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia (Hill et al., Br J Haematol)
• Barcellini & Fattizzo — Clinical applications of hemolytic markers in the differential diagnosis and management of hemolytic anemia (Dis Markers 2015)
• Berentsen & Barcellini — Autoimmune Hemolytic Anemias (NEJM 2021)