warm autoimmune hemolytic anemia

**Pathophysiology** - Autoantibodies are mostly IgG and react at 37°C. They are directed against RBC membrane antigens, often Rh proteins. - IgG-coated RBCs are bound by Fc receptors on splenic macrophages. The macrophages remove part of the membrane, which produces spherocytes, and they phagocytose the cells. The result is extravascular hemolysis. - Complement (C3b) may also coat the cells. Hemolysis is mostly extravascular, though it can be partly intravascular if complement activation is strong.

**Etiology** - Idiopathic or primary: about 50%. - Secondary causes: - Autoimmune disease: SLE (the classic association), other connective tissue diseases, and ulcerative colitis. - Lymphoproliferative disorders: CLL, non-Hodgkin lymphoma. - Drugs: methyldopa (true autoantibody), penicillins and cephalosporins (hapten mechanism), and others such as fludarabine. - Immunodeficiency, and rarely other malignancies or infections. - Evans syndrome is AIHA plus immune thrombocytopenia (ITP).

**Clinical features** - Fatigue, pallor, dyspnea, jaundice, and dark urine. - Splenomegaly. - Symptoms can develop gradually or abruptly.

**Labs** - Normocytic or macrocytic anemia. Macrocytosis reflects reticulocytosis. - Reticulocytosis. - Increased indirect (unconjugated) bilirubin and LDH. - Decreased haptoglobin. - Peripheral smear: spherocytes (loss of central pallor) and polychromasia. - Direct antiglobulin (Coombs) test is positive for IgG ± C3. The DAT detects antibody or complement already on the patient's RBCs. The indirect Coombs test detects free antibodies in serum and is used in transfusion and prenatal screening. - Increased MCHC and a negative osmotic fragility pattern are not diagnostic. Spherocytes are also seen in hereditary spherocytosis, but that condition has a negative DAT.

**Treatment** - First line: glucocorticoids (prednisone). About 70-80% respond. - Second line: - Rituximab (anti-CD20), which is increasingly used early. - Splenectomy for refractory or relapsing disease. Give pneumococcal, meningococcal, and H. influenzae vaccines first. - Immunosuppressants such as azathioprine and cyclophosphamide. - Treat the underlying cause. For drug-induced disease, stop the offending drug. - Give folate supplementation because of increased RBC turnover. - Transfuse only if the anemia is severe or symptomatic. Cross-match can be difficult because of the autoantibody.

**Compare with cold agglutinin disease (cold AIHA)** - Antibody: IgM, which binds at less than 37°C, in the cooler extremities. - Complement: fixes complement, causing mostly intravascular and some extravascular (hepatic Kupffer cell) hemolysis. - DAT: positive for C3 only. - Associations: Mycoplasma pneumoniae, EBV/infectious mononucleosis, and lymphoproliferative disorders. Anti-I (Mycoplasma) and anti-i (EBV) specificities. - Features: acrocyanosis and Raynaud-like symptoms. - Treatment: avoid cold, and consider rituximab. Steroids and splenectomy are less effective.

**Paroxysmal cold hemoglobinuria:** biphasic IgG (Donath-Landsteiner) antibody, associated with viral infections or syphilis.

**High-yield pearls** - Warm = IgG = extravascular = spleen = steroids and splenectomy. - Cold = IgM = C3 = intravascular = Mycoplasma and EBV. - Spherocytes with a positive Coombs test point to warm AIHA. Spherocytes with a negative Coombs test point to hereditary spherocytosis. - Methyldopa is a classic drug cause. A positive DAT in a patient taking methyldopa does not always mean hemolysis is occurring. - Complications include thrombosis and, with massive hemolysis, folate deficiency and aplastic crisis (parvovirus B19).