Pathophysiology/Etiology
- Type II hypersensitivity reaction causing premature destruction of RBCs due to autoantibodies.
- Can be primary (idiopathic) or secondary to other conditions or drugs.
- Classified based on the optimal temperature at which the autoantibodies react.
  - If it’s cold → stay inside
  - If it’s warm → go outside & play

Feature	Warm AIHA	Cold AIHA
Antibody	IgG	IgM
Temp	Core Body Temp (~37°C)	Cold Temps (<37°C)
Hemolysis	Extravascular (spleen)	Intra- & Extravascular (complement)
Presentation	Anemia sx, jaundice, splenomegaly	Anemia sx, acrocyanosis
Smear	Spherocytes	Agglutination
DAT (Coombs)	+ for IgG (± C3)	+ for C3 only
Associations	SLE, CLL, Drugs	Mycoplasma, EBV, Lymphoid Malignancy
1st Line Tx	Corticosteroids	Cold Avoidance, Rituximab
Splenectomy	Effective	Not Effective

Warm AIHA

Pathophysiology/Etiology
- Most common type of AIHA (80-90% of cases).
- Mediated by IgG antibodies that bind to RBCs at core body temperature (~37°C).
- Leads to extravascular hemolysis, where splenic macrophages recognize the Fc portion of IgG on RBCs and phagocytose them.
- Associated with: Systemic lupus erythematosus (SLE), chronic lymphocytic leukemia (CLL), and drugs (e.g., alpha-methyldopa, penicillin).
Clinical Presentation
- Classic signs of anemia: fatigue, dyspnea, pallor.
- Jaundice (due to increased unconjugated bilirubin from hemolysis), splenomegaly.
Diagnosis
- Labs: ↓ Hgb, ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, ↑ reticulocyte count.
- Peripheral smear: Spherocytes are common due to partial phagocytosis of the RBC membrane.
- Direct Coombs Test (Direct Antiglobulin Test - DAT): Positive for IgG with or without complement (C3).
Management
- First-line: Corticosteroids (e.g., prednisone).
- Second-line/Refractory cases: Rituximab (anti-CD20 antibody), splenectomy, or other immunosuppressants (e.g., azathioprine).
- In severe cases, IVIG can be used as a temporary measure to “distract” macrophages.

Cold AIHA (Cold Agglutinin Disease)

Pathophysiology/Etiology
- Mediated by IgM antibodies that bind to RBCs at colder temperatures (<37°C), typically in the extremities.
- IgM binding activates the complement system, leading to both intravascular (via MAC complex) and extravascular hemolysis.
- Associated with: Infections (e.g., Mycoplasma pneumoniae, Epstein-Barr virus [EBV]), and lymphoid malignancies (e.g., Waldenström’s macroglobulinemia).
Clinical Presentation
- Symptoms of anemia.
- Cold-induced symptoms like acrocyanosis (painful, blue fingers and toes) and livedo reticularis.
Diagnosis
- Labs: Similar to warm AIHA, showing signs of hemolysis.
- Peripheral smear: May show RBC agglutination.
- Direct Coombs Test (DAT): Positive for complement (C3) only, as the IgM antibody often detaches from the RBC at warmer lab temperatures.
- High titers of cold agglutinins (IgM) may be detected.
Management
- Supportive care: Avoidance of cold exposure is crucial.
- First-line for symptomatic patients: Rituximab.
- Corticosteroids and splenectomy are generally not effective.

Hereditary Spherocytosis: Inherited defect in RBC membrane proteins. Also presents with spherocytes and extravascular hemolysis, but the Coombs test is negative.
Drug-Induced Hemolytic Anemia: Can mimic AIHA; a thorough medication history is essential. Cessation of the offending drug often resolves the hemolysis.
Alloimmune Hemolysis: E.g., hemolytic transfusion reaction or hemolytic disease of the newborn. History and specific antibody testing can differentiate.
Paroxysmal Nocturnal Hemoglobinuria (PNH): Intravascular hemolysis due to complement activation from a lack of CD55/CD59. Presents with hemoglobinuria (often at night/morning) and thrombosis.

Warm AIHA: IgG, spherocytes, associated with SLE and CLL, positive Coombs for IgG.
Cold AIHA: IgM, complement activation, acrocyanosis, associated with Mycoplasma and EBV (infectious mononucleosis), positive Coombs for C3.