This patient's pallor, jaundice, splenomegaly, and laboratory findings are consistent with hemolytic anemia.  The most likely diagnosis is autoimmune hemolytic anemia (AIHA), which is due to autoantibodies to red blood cells (RBCs).

Hemolysis can occur intra- or extravascularly.  Intravascular hemolysis is due to significant RBC structural damage resulting in RBC destruction within the intravascular space (eg, paroxysmal nocturnal hemoglobinuria, disseminated intravascular coagulation).  The hemoglobin released from hemolyzed RBCs binds to haptoglobin, and the hemoglobin-haptoglobin complex is cleared by the liver.  This leads to markedly reduced serum haptoglobin (to undetectable levels).  RBC hemolysis also results in elevated indirect bilirubin levels (from heme breakdown) and raised serum lactate dehydrogenase (LDH) levels (released from RBCs).

In extravascular hemolysis, the RBCs are predominantly destroyed by phagocytes in the reticuloendothelial system (eg, lymph nodes, spleen).  As a result, there is less hemoglobin release than in intravascular hemolysis, so laboratory results usually show normal to slightly low haptoglobin, slightly elevated LDH, and elevated indirect bilirubin.  Extravascular hemolysis can be due to causes such as antibody-mediated RBC destruction (eg, most cases of AIHA) or intrinsic RBC enzyme (eg, glucose-6-phosphate dehydrogenase deficiency) or membrane (eg, hereditary spherocytosis) defects.

This patient's laboratory findings (anemia, indirect hyperbilirubinemia, low-normal haptoglobin, and slightly elevated LDH) all suggest extravascular hemolysis; her peripheral smear shows spherocytes without central pallor.  These findings can be seen in AIHA as well as in hereditary spherocytosis.  AIHA usually has a negative family history and positive Coombs test.  Hereditary spherocytosis usually has a strong family history and a negative Coombs test.  If the Coombs test is negative and there is still a high index of suspicion for AIHA, a micro-Coombs test can be performed to confirm the diagnosis.  This patient most likely has warm-agglutinin (IgG autoantibody mediated-) AIHA from an autoimmune cause.  AIHA usually causes extravascular hemolysis, although some degree of intravascular hemolysis can occur, especially with IgM-mediated AIHA.

(Choice B)  Glucose-6-phosphate dehydrogenase deficiency is an X-linked hereditary cause of hemolytic anemia in which hemolytic episodes may be triggered by medications (eg, sulfa drugs).  Peripheral blood smear may show cells with Heinz bodies.

(Choice C)  Hereditary spherocytosis usually has a strong family history (most cases are autosomal dominant), positive eosin-5-maleimide (and osmotic fragility) test, and a negative Coombs test.

(Choice D)  Paroxysmal nocturnal hemoglobinuria is caused by a defect in the cell membrane anchor that leads to complement-mediated hemolysis with a negative Coombs test but evidence of venous thrombosis and sometimes episodic intravascular hemolysis.

(Choice E)  Sickle cell anemia is usually associated with a strong family history and sickle-shaped cells on peripheral blood smear.  Splenomegaly may be seen in childhood, but autosplenectomy is a more common finding by adulthood.

Educational objective:
Autoimmune hemolytic anemia (AIHA) and hereditary spherocytosis (HS) can cause extravascular hemolytic anemia.  A negative family history and positive Coombs test suggest AIHA; a positive family history and negative Coombs test suggest HS.  The peripheral blood smear in both conditions may show spherocytes without central pallor.