Autoimmune hemolytic anemias (AIHAs) are a collection of disorders characterized by the destruction of RBCs through antibody-mediated hemolysis (extravascular and/or intravascular). There are two broad types, categorized by the temperature at which the antigen-antibody reactions maximally occur: cold agglutinin hemolytic anemia (cold AIHA) and warm agglutinin hemolytic anemia (warm AIHA). AIHAs can be either idiopathic or secondary to another disease e.g., infectious, lymphoproliferative, or autoimmune diseases. Cold AIHA and warm AIHA share some characteristics, e.g., they can both present with clinical and , and produce symptomatic anemia severe enough to require blood transfusion. However, their pathophysiology, etiology, epidemiology, clinical and diagnostic features, and targeted treatments all have key differences. Careful clinical and diagnostic evaluation (including direct Coombs testing, antibody titers, and peripheral blood smear) can help distinguish between the types, however, occasionally patients may have a mixed-type AIHA or unusual clinical presentations and laboratory findings. Management depends on the clinical presentation, etiology, and subtype, and is typically performed in consultation with a hematologist. Treatments include stabilization with blood transfusion and temporizing measures (e.g., plasmapheresis, plasma exchange), systemic immunomodulators (e.g., glucocorticoids, rituximab), treatment of underlying conditions, supportive care, and in warm AIHA, splenectomy.
- Both and :
- Patients may occasionally exhibit a mixed-type AIHA or have atypical clinical presentations and initial diagnostic results. 
- Hematology consultation is advised if the diagnosis is uncertain.
|Typical distinguishing features of autoimmune hemolytic anemias |
|Cold AIHA||Warm AIHA|
|Clinical features|| |
Typical biochemical findings in hemolysis include ↓ haptoglobin, ↑ LDH concentration, ↑ indirect bilirubin concentration, peripheral blood smear abnormalities (e.g., ↑ reticulocytes, schistocytes, spherocytes, polychromasia), and urinalysis abnormalities (e.g., hemoglobinuria, hemosiderinuria, and urobilinogen).
Definitions: Cold agglutinin hemolytic anemia (cold AIHA) refers to a group of autoimmune disorders characterized by hemolysis that is caused by the binding of cold-sensitive autoantibodies to RBCs 
- Cold agglutinin disease (CAD): a primary (idiopathic) form of cold AIHA in which hemolysis is mediated by monoclonal cold-sensitive IgM autoantibodies produced by a low-grade clonal B-cell lymphoproliferative disorder of the bone marrow
- Cold agglutinin syndrome (CAS): a rare form of cold AIHA in which cold-sensitive autoantibody-mediated hemolysis occurs secondary to another condition (e.g., infection, lymphoma)
- Cold AIHAs comprise ∼ 10–25% of all AIHAs. 
- Most common in individuals > 50 years of age 
- Cold-sensitive antibodies (cold agglutinins): mostly IgM antibodies cause extravascular hemolysis and acute intravascular hemolysis and extravascular hemolysis
- The antigen-antibody reaction is triggered by low body temperature and/or cold ambient temperatures. 
- CAD: idiopathic
- CAS occurs secondary to other diseases, including:
- Classically associated with cold exposure
- Can occur as episodes of acute, severe symptoms 
- Pallor, fatigue, weakness
- Painful cyanosis of the extremities (acrocyanosis)
- Livedo reticularis
- Raynaud phenomenon
- Skin ulcerations
- Indications for testing: typical cold-induced symptoms (e.g., acrocyanosis, livedo reticularis) or unexplained anemia
- Initial investigations: CBC, reticulocyte count, , DAT, and cold agglutinin titer
- Additional investigations are indicated to identify secondary causes (i.e., to confirm CAS), for example:
- Diagnostics of cold AIHA can be established in patients with all of the following:
- Other potential diagnostic findings (nonspecific)
- Compensated hemolysis and mild or absent circulatory symptoms : close surveillance
- Significant clinical manifestations: Start acute therapy.
- CAD: Consider chronic therapy (systemic immunomodulatory).
- CAS: Treat the underlying condition
- Advise all patients to avoid exposure to the cold.
- Consider folic acid supplementation in all patients.
- Manage disease complications: Venous thromboembolism (VTE) 
- Indications: Severe symptoms of anemia or Hb < 7 mg/dL
- Indications: CAD with either symptomatic anemia or significant cold-induced symptoms
- Treatment: Systemic immunomodulators
- Definition: an autoimmune disease characterized by the binding of heat-sensitive autoantibodies to RBCs, which leads to the phagocytosis and destruction of RBCs in the reticuloendothelial system 
- Incidence: 1–3 cases/100,000 individuals
- Can occur at any age
- Heat-sensitive antibodies: Mostly polyclonal IgG antibodies; that first bind to multiple RBC antigens, then to Fc receptors on phagocytes
- Binding of the antibodies leads to ↑ extravascular hemolysis mediated by the reticuloendothelial system of the spleen and liver. 
- The antigen-antibody reaction is triggered by body temperatures of ≥ 37°C/98.6°F
“Warm weather is Great”: Warm AIHA is IgG mediated.
- Mostly idiopathic
- Secondary causes
- Order CBC, reticulocyte count, hemolysis workup, DAT, and PBS.
- Consider warm AIHA in patients with:
- Additional investigations: to rule out secondary causes (see “ .”)
- Manage severe disease acutely.
- Address potential secondary causes (see “Etiology”). 
- Hold any potentially causative medications.
- Identify and manage underlying conditions.
- Consider the need for chronic .
- Observation without immunosuppressive interventions may be appropriate for patients with mild asymptomatic anemia.
- Manage disease complications: e.g., VTE
- Monitor for relapses and consider repeated therapeutic intervention.
- Indications: Severe symptoms of anemia or Hb < 6–7 mg/dL
- Provide hemodynamic and respiratory support as needed.
- Alert the blood bank early about the need for a transfusion in a patient with warm agglutinin hemolytic anemia. 
- Consider an RBC transfusion under specialist guidance. 
- Consider temporizing measures.
- Consider VTE prophylaxis in patients with acute exacerbations of hemolysis. 
Do not delay a potentially life-saving blood transfusion in unstable patients with severe anemia, even if crossmatched blood is unavailable. Use type-specific uncrossmatched blood in close consultation with the blood bank. 
- Indications: Consider in most patients to reduce autoantibody production.
- Treatment: typically involves