Autoimmune hemolytic anemia differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2]

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Differentiating Autoimmune hemolytic anemia from other Diseases

Diagnosis is made by first ruling out other causes of hemolytic anemia, such as G6PD, thalassemia, sickle-cell disease, etc.

Characteristic	Causes	Pathophysiology	Laboratory abnormalities	Physical examination	Therapy	Other associations
Autoimmune hemolytic anemia	Abnormal immune activation Failure of self vs. non-self recognition Infections Chronic lymphocytic leukemia non-Hodgkin's lymphoma Rheumatologic disease	Polyclonal antibody production that binds to and targets red blood cells for destruction intravascurly or extravascularly	Positive Coombs' test for IgG Indirect hyperbilirubinemia Reticulocytosis Low haptoglobin Elevated LDH	Pallor Jaundice Shortness of breath Tachypnea	Removal of offending agent Corticosteroids Cyclophosphamide Cyclosporine A Azathioprine Rituximab Splenectomy	Hemolysis can occur at warm or cold temperatures
Paroxysmal cold hemoglobinuria	Production of Donath-Landsteiner antibody, triggered by viral or bacterial infection	Biphasic hemolysin (IgG) that binds red blood cells and low temperatures and triggers complement-mediated intravascular hemolysis at warm temperatures	Positive Donath-Landsteiner antibody Microscopic hematuria Negative Coombs' test for IgG or C3d Negative cold agglutinin titer Indirect hyperbilirubinemia Reticulocytosis Low haptoglobin Elevated LDH	Hematuria in the presence of cold weather Jaundice	Removal of offending agent Steroids Alternative immunosuppression	Associated with syphilis Maternal IgG can cross the placenta and affect the fetus
Hereditary spherocytosis	Alcoholism Lead poisoning Vitamin B6 deficiency Isoniazid Chloramphenicol	Microcytic (<80 femtoliter) Or Normocytic (80-100 femtoliter)	Ringed sideroblasts in bone marrow Low vitamin B6 level High lead level	Pallor Weakness	Removal of offending medication High-dose vitamin B6 (up to 200mg daily) Avoidance of splenectomy Symptomatic transfusion support with iron chelation as needed	Myelodysplastic syndrome Myeloproliferative neoplasm Iron overload
Thalassemia	Genetic defect with alpha- or beta-globin production	Microcytic (<80 femtoliter)	Abnormal hemoglobin electrophoresis (in beta-thalassemia)	Irritability Growth retardation Jaundice Hepatomegaly Splenomegaly	Transfusion support Iron chelation Gene therapy if available	Extramedullary hematopoiesis
Iron deficiency anemia	Loss of iron from gastrointestinal blood loss or menstrual blood loss	Microcytic (<80 femtoliter)	Low serum iron Elevated transferrin Low transferrin saturation Low ferritin	Pallor Weakness Positive occult blood testing (if GI bleeding)	Intravenous or oral iron supplementation	Chronic blood loss
Pernicious anemia	Vitamin B12 deficiency	Macrocytic (>100 femtoliter)	Low vitamin B12 level Presence of anti-intrinsic factor or anti-parietal cell antibody	Numbness Weakness Tingling Paresthesias	Vitamin B12 1000mcg daily	Autoimmune disorders
Chronic lymphocytic leukemia	Mutations in hematopoietic stem cells and B lymphocytes	Clonal proliferation of malignant B lymphocytes	Elevated absolute lymphocyte count Anemia (Rai stage III) and thrombocytopenia (Rai stage IV)	Numbness Weakness Tingling Paresthesias	Vitamin B12 1000mcg daily	Secondary autoimmune hemolytic anemia occurs in advanced CLL; treatment with corticosteroids or anti-leukemic therapy will correct the underlying anemia

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