Causes are listed in Table 62-3.

1. Intracellular RBC abnormalities: most are inherited enzyme defects [glucose-6-phosphate dehydrogenase (G6PD) deficiency > pyruvate kinase deficiency], hemoglobinopathies, sickle cell anemia and variants, thalassemia, unstable hemoglobin variants.
2. G6PD deficiency: leads to episodes of hemolysis precipitated by ingestion of drugs that induce oxidant stress on RBCs. These include antimalarials (chloroquine), sulfonamides, analgesics (phenacetin), and other miscellaneous drugs (Table 62-4).
3. Sickle cell anemia: characterized by a single-amino-acid change in β globin (valine for glutamic acid in the 6th residue) that produces a molecule of decreased solubility, especially in the absence of O₂. Although anemia and chronic hemolysis are present, the major disease manifestations relate to vasoocclusion from misshapen sickled RBCs. Infarcts in lung, bone, spleen, retina, brain, and other organs lead to symptoms and dysfunction (Fig. 62-2).
4. Membrane abnormalities (rare): spur cell anemia (cirrhosis, anorexia nervosa), paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis (increased RBC osmotic fragility, spherocytes), hereditary elliptocytosis (causes mild hemolytic anemia).
5. Immunohemolytic anemia (positive Coombs' test, spherocytes). Two types: (a) warm antibody (usually IgG): idiopathic, lymphoma, chronic lymphocytic leukemia, systemic lupus erythematosus, drugs (e.g., methyldopa, penicillins, quinine, quinidine, isoniazid, sulfonamides); and (b) cold antibody—cold agglutinin disease (IgM) due to Mycoplasma infection, infectious mononucleosis, lymphoma, idiopathic; paroxysmal cold hemoglobinuria (IgG) due to syphilis, viral infections.
6. Mechanical trauma (macro- and microangiopathic hemolytic anemias; schistocytes): prosthetic heart valves, vasculitis, malignant hypertension, eclampsia, renal graft rejection, giant hemangioma, scleroderma, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, disseminated intravascular coagulation, march hemoglobinuria (e.g., marathon runners, bongo drummers).
7. Direct toxic effect: infections (e.g., malaria, Clostridium perfringens toxin, toxoplasmosis).
8. Hypersplenism (pancytopenia may be present).