This patient received amoxicillin and subsequently developed symptomatic anemia (eg, fatigue, exertional dyspnea), splenomegaly, and jaundice, raising strong suspicion for drug-induced hemolytic anemia.  Penicillins (eg, amoxicillin) and cephalosporins are common triggers of drug-induced hemolytic anemia because these medications bind to the surface of erythrocytes, creating a hapten for IgG attachment.  IgG-coated erythrocytes are then partially or wholly phagocytized by splenic macrophages, leading to extravascular hemolysis.  Complement-mediated intravascular hemolysis may also occur.

Patients generally show signs of anemia (eg, fatigue, pallor, dyspnea) and hemolysis (eg, jaundice, dark urine) within 2-4 days of medication exposure.  Laboratory assessment typically reveals indirect hyperbilirubinemia, elevated lactate dehydrogenase, decreased haptoglobin, and reticulocytosis (due to the generation of new erythrocytes in response to anemia).  Most patients have normocytic anemia with a normal or slightly elevated mean corpuscular volume due to the presence of reticulocytes.  Splenomegaly can also occur due to increased red blood cell sequestration in the spleen.

The diagnosis is made with direct antiglobulin (Coombs) testing, which identifies IgG or C3 (a complement fragment) attached to the erythrocyte surface.  Because penicillin- and cephalosporin-induced hemolysis is primarily triggered by drug binding to the erythrocyte surface, withdrawal of the medication generally leads to resolution.  Therefore, amoxicillin should be discontinued in this patient; a different class of antibiotics could be started if needed.

(Choices B, C, and E)  Investigation for other causes of hemolytic anemia is not generally necessary when there is a clear inciting factor such as recent administration of a medication known to trigger hemolysis (eg, amoxicillin).  However, in patients who do not have resolution of hemolysis after medication cessation, additional workup may be required; this often includes antinuclear antibody testing for systemic lupus erythematosus, bone marrow biopsy for leukemia, and/or liver function testing for viral hepatitis.

(Choice D)  Hemoglobin electrophoresis can diagnose sickle cell disease, which causes hemolytic anemia and splenomegaly.  However, most cases present in early childhood with vasoocclusive pain crises.  This patient with no chronic medical history who developed hemolysis after taking amoxicillin is much more likely to have drug-induced hemolysis.

(Choice F)  Splenectomy can improve platelet count in recalcitrant idiopathic thrombocytopenia.  Splenectomy is not advised for drug-induced hemolysis because the hemolysis typically resolves rapidly with drug cessation.

Educational objective:
Drug-induced hemolytic anemia is often triggered by penicillin and cephalosporin medications.  It is marked by evidence of extravascular hemolytic anemia such as fatigue, weakness, splenomegaly, dark urine, and jaundice.  Discontinuation of the offending drug usually results in complete resolution of symptoms within days.  No additional workup is generally required.