The patient should be given prednisone. She has warm autoimmune hemolytic anemia (WAIHA), indicated by the high reticulocyte count, elevated bilirubin and lactate dehydrogenase (LDH) levels, the positive direct antiglobulin (Coombs) test, and spherocytes seen on peripheral blood smear. In WAIHA, IgG antibodies are directed against erythrocyte surface membrane molecules, which leads to phagocytosis by macrophages that cause erythrocytes to become progressively more spherocytic. These abnormal erythrocytes are then destroyed in the spleen. WAIHA can manifest as a primary disorder or as a complication of another disorder, including autoimmune conditions (systemic lupus erythematosus) or lymphoproliferative disorders (chronic lymphocytic leukemia). Treatment is immunosuppression to halt the immune-mediated erythrocyte destruction and allow the patient's own bone marrow to regenerate the erythrocytes, if possible. The best initial treatment for this condition is a glucocorticoid such as prednisone.

Transfusion in patients with WAIHA is a topic of debate. Although this patient has severe anemia, she has no organ dysfunction, is not hypoxic, and has no signs or symptoms of heart failure or angina. Additionally, her bone marrow is able to respond to her hemolysis, and her hemoglobin level would be expected to recover with treatment of her hemolytic condition. Additionally, erythrocyte transfusions are complicated in patients with WAIHA, because the antibodies causing hemolysis may crossreact with transfused erythrocytes, making crossmatch-compatible blood difficult to find. Therefore, transfusion in patients with WAIHA should be approached carefully, and if necessary, should be performed with type-specific, crossmatch-incompatible blood. Consultation with a hematologist and transfusion medicine specialist is recommended.

Rituximab and splenectomy are typically reserved to treat patients in whom first-line therapy for WAIHA has failed; they are not used in the acute setting. An inadequate response to glucocorticoids may indicate the need for splenectomy or alternative immunosuppression.

Although the mean corpuscular volume is elevated, this patient's clinical picture is inconsistent with vitamin B₁₂ deficiency, which typically includes a low reticulocyte count (although the LDH and total bilirubin levels can be quite elevated because of intramedullary hemolysis). Additionally, no hypersegmented neutrophils are seen, and she has no abnormal neurologic findings.