drug-induced hemolytic anemia

**Overview** Drug-induced hemolytic anemia (DIHA) is premature RBC destruction caused by a drug. Mechanisms are immune-mediated (direct antiglobulin/Coombs test usually positive) or non-immune (oxidative injury, usually Coombs negative).

**1. Immune-mediated (Type II hypersensitivity, mostly)** - **Hapten/drug-adsorption type**: The drug binds the RBC membrane, and IgG antibodies form against the drug-RBC complex. Splenic macrophages remove the cells (extravascular hemolysis). Classic drugs: high-dose penicillin and some cephalosporins. Coombs: DAT positive for IgG. - **Autoantibody type**: The drug induces true anti-RBC autoantibodies (often against Rh antigens). This looks like warm autoimmune hemolytic anemia (IgG, extravascular). Classic drug: **methyldopa**. Hemolysis can persist for weeks after stopping the drug. - **Immune complex ("innocent bystander") type**: Drug-antibody complexes deposit on RBCs and activate complement, causing intravascular hemolysis. This can be severe, with acute renal failure. Drugs: ceftriaxone, piperacillin, quinine/quinidine, and others. DAT is positive for complement (C3) only. - Other associated drugs: fludarabine and other purine analogs, and checkpoint inhibitors.

**2. Non-immune: oxidant-induced hemolysis** - **G6PD deficiency** (X-linked recessive) impairs NADPH production, so glutathione cannot neutralize H₂O₂. Hemoglobin denatures into **Heinz bodies**. Splenic macrophages then remove the damaged cells, producing **bite cells**, and some hemolysis is intravascular. - Triggers: **primaquine, dapsone, sulfonamides (sulfamethoxazole), nitrofurantoin, rasburicase, methylene blue, chloroquine/quinine (less so)**, plus infections and fava beans. - Presentation: Acute hemolysis 1–3 days after exposure, with dark urine, jaundice, and back pain. Patients are often African American or Mediterranean. It is self-limited, and the drug should be stopped. - Methemoglobinemia is a related oxidant effect of dapsone, nitrites, and benzocaine. Treat with methylene blue (contraindicated in G6PD deficiency).

**3. Other mechanisms** - Microangiopathic hemolysis (drug-induced TMA): quinine, gemcitabine, mitomycin C, calcineurin inhibitors (cyclosporine, tacrolimus), clopidogrel. Findings include schistocytes, thrombocytopenia, and a negative Coombs test. - Ribavirin: direct RBC toxicity.

**Lab findings** - ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, ↑ reticulocytes - Peripheral smear: spherocytes (immune), bite cells and Heinz bodies (G6PD), schistocytes (TMA) - Intravascular hemolysis: hemoglobinuria, hemosiderinuria, very low haptoglobin - DAT (Coombs) positive in immune forms, negative in oxidative and TMA forms

**Management** - Stop the offending drug (this is the most important step). - Give supportive care, with transfusion if needed. - Use steroids for severe immune cases (benefit is uncertain in drug-dependent types). - Screen for G6PD deficiency in at-risk patients before giving oxidant drugs. Test for G6PD activity after the acute episode, because the assay can be falsely normal during hemolysis when older, deficient cells have been destroyed and reticulocytes with higher enzyme activity predominate.

**Boards pearls** - Methyldopa → warm IgG autoimmune hemolysis, DAT positive. - Penicillin → hapten model. - Dapsone/primaquine → G6PD deficiency, Heinz bodies, bite cells. - Ceftriaxone → intravascular immune hemolysis, especially in children. - Quinine → TMA or immune complex hemolysis.