Hemolytic anemia differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

Overview

The differential diagnosis for hemolytic anemia is broad and includes a variety of conditions that affect red blood cells. Nutritional deficiencies and thalassemias are important components of the differentiation. Certain laboratory tests and physical exam features can help to distinguish these conditions. The treatment of these conditions are quite different, so it is important to distinguish hemolytic anemia from other causes of anemia or other conditions that present similarly.

Differentiating Hemolytic anemia from other Diseases

Characteristic/Parameter	Hemolytic anemia	Sideroblastic anemia	Anemia of chronic disease	Thalassemia	Iron-deficiency anemia	Erythropoietin deficiency	Vitamin B12 or folate deficiency
Etiology	Drug-induced, immune-mediated, non-immune-mediated, infections, rheumatologic disease	Alcoholism, lead poisoning, vitamin B6 deficiency, isoniazid, chloramphenicol	Chronic kidney disease, rheumatologic disease, cancer, HIV, chronic infection; excess release of IL-1 and IL-6	Genetic defect with alpha- or beta-globin production	Loss of iron from gastrointestinal blood loss or menstrual blood loss	Chronic kidney disease or other renal dysfunction	Pernicious anemia, Diphyllobothrium latum infection, nutritional deficiency, Crohn's disease of terminal ileum
Mean corpuscular volume	Normocytic (80-100 femtoliter)	Microcytic (<80 femtoliter) or normocytic (80-100 femtoliter)	Normocytic (80-100 femtoliter)	Microcytic (<80 femtoliter)	Microcytic (<80 femtoliter)	Normocytic (80-100 femtoliter)	Macrocytic (>100 femtoliter)
Laboratory abnormalities	Indirect hyperbilirubinemia, reticulocytosis, low haptoglobin, elevated LDH	Ringed sideroblasts in bone marrow; low vitamin B6 level, high lead level	Elevated ESR and CRP, elevated hepcidin, low serum iron, low transferrin, elevated ferritin	Abnormal hemoglobin electrophoresis (in beta-thalassemia)	Low serum iron, elevated transferrin, low transferrin saturation, low ferritin	Low erythropoietin level	Low vitamin B12 or folate level, megaloblastic anemia and hypersegmented neutrophils
Physical exam	Pallor, jaundice	Pallor, weakness	Pallor, weakness	Irritability, growth retardation, jaundice, hepatomegaly, splenomegaly	Pallor, weakness, positive occult blood testing (if GI bleeding)	Pallor, weakness, signs of chronic kidney disease	Numbness, weakness, tingling, paresthesias
Treatment	Removal of offending agent, steroids, alternative immunosuppression	Removal of offending medication, high-dose vitamin B6 (up to 200mg daily), avoidance of splenectomy, symptomatic transfusion support with iron chelation as needed	Treatment of the underlying cause; erythropoiesis-stimulating agents, supportive red blood cell transfusions	Transfusion support, iron chelation, gene therapy if available	Intravenous or oral iron supplementation	Epoetin alfa 50-100 units/kg 3 times weekly, darbepoietin 0.45 mcg/kg weekly or 0.75 mcg/kg every 2 weeks	Vitamin B12 1000mcg daily, folate 1mg daily
Other associated abnormalities	HELLP syndrome, TTP, CLL	Myelodysplastic syndrome, myeloproliferative neoplasm, iron overload	Inflammatory bowel disease	Extramedullary hematopoiesis	Chronic blood loss	Dialysis dependence, myelodysplastic syndrome	Neuropathy

Characterisitc/Parameter	Etiology	Mean corpuscular volume	Laboratory abnormalities	Physical examination	Treatment	Other associated abnormalities
Hemolytic anemia	Drug-induced Immune-mediated Non-immune-mediated Infections Rheumatologic disease	Normocytic (80-100 femtoliter)	Indirect hyperbilirubinemia Reticulocytosis Low haptoglobin Elevated LDH	Pallor Jaundice	Removal of offending agent Steroids Alternative immunosuppression	HELLP syndrome TTP CLL
Sideroblastic anemia	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
Anemia of chronic disease	Chronic kidney disease Rheumatologic disease Cancer HIV Chronic infection; excess release of IL-1 and IL-6	Normocytic (80-100 femtoliter)	Elevated ESR and CRP Elevated hepcidin Low serum iron Low transferrin Elevated ferritin	Pallor Weakness	Treatment of the underlying cause; erythropoiesis-stimulating agents Supportive red blood cell transfusions	Inflammatory bowel disease
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
Erythropoietin deficiency	Chronic kidney disease or other renal dysfunction	Normocytic (80-100 femtoliter)	Low erythropoietin level	Pallor Weakness Signs of chronic kidney disease	Epoetin alfa 50-100 units/kg 3 times weekly Darbepoietin 0.45 mcg/kg weekly or 0.75 mcg/kg every 2 weeks	Dialysis dependence Myelodysplastic syndrome
Vitamin B12 or folate deficiency	Pernicious anemia Diphyllobothrium latum infection Nutritional deficiency Crohn's disease of terminal ileum	Macrocytic (>100 femtoliter)	Low vitamin B12 or folate level Megaloblastic anemia with hypersegmented neutrophils	Numbness Weakness Tingling Paresthesias	Vitamin B12 1000mcg daily Folate 1mg daily	Neuropathy

Table legend: HELLP, hemolysis/elevated liver enzymes/low platelets; TTP, thrombotic thrombocytopenia purpura; CLL, chronic lymphocytic leukemia