Hemolytic Anemia – Differential Diagnosis

Alloimmune: Transfusion reactions, hemolytic disease of the fetus and newborn. Neonatal DAT is positive.
Autoimmune hemolytic anemia: Warm or cold autoimmune hemolytic anemia. DAT positive.
Drug-induced: Drug-induced thrombotic microangiopathy, drug-induced immune hemolytic anemia, oxidative hemolysis.
Envenomation: Insects, cobra, brown recluse spider
Enzymopathy: G6PD or pyruvate kinase deficiencies. Lab test = Enzyme activity measurement
Hemoglobinopathy: Sickle cell disease, thalassemias, hemoglobin defects. Lab test = Hemoglobin electrophoresis
Membranopathy: Hereditary spherocytosis, hereditary elliptocytosis, paroxysmal nocturnal hemoglobinuria
Microangiopathic hemolytic anemia (MAHA) /thrombotic microangiopathy: Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, disseminated intravascular coagulation, HELLP syndrome, drug-induced thrombotic microangiopathy
Infection: Malaria, Babesia, Bartonella, Clostridia, Rickettsia, Haemophilus influenzae, human immunodeficiency virus
Osmotic: Freshwater drowning
Systemic disease: Malignant hypertension, systemic lupus erythematosus, scleroderma, liver disease, vasculitides, hypersplenism
Trauma: Endovascular devices, aortic stenosis, extracorporeal membrane oxygenation, arteriovenous malformation, march hemoglobinuria, burns

Classifying Hemolytic Anemias with the DAT (Coombs test).

The direct antiglobulin test (DAT) differentiates immune causes of hemolytic anemia from nonimmune causes.

• DAT positive: autoimmune, drugs, infection, lymphoproliferative disease, Rh or ABO incompatibility
• DAT negative: intrinsic red cell disease
  1. Abnormal hemoglobin: sickle cell disease, thalassemia, methemoglobinemia
  2. Membrane defect: hereditary spherocytosis, hereditary elliptocytosis, paroxysmal nocturnal hemoglobinuria
  3. Enzyme defect: G6PD deficiency, pyruvate kinase deficiency
• DAT negative: extrinsic disease
  1. Microangiopathic hemolytic anemia, eg, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, prosthetic valve hemolysis
  2. Splenic sequestration
  3. Infection: malaria, Clostridium, Borrelia
  4. Burns

DAT = direct antiglobulin test = Direct Coombs test.

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