What is the initial workup for a patient presenting with hemolytic anemia?

Initial Workup for Hemolytic Anemia

The initial workup for a patient presenting with hemolytic anemia should include complete blood count with red cell indices, reticulocyte count, peripheral blood smear, markers of hemolysis (lactate dehydrogenase, haptoglobin, unconjugated bilirubin), and direct antiglobulin test. 1

Step 1: Confirm Hemolysis

First, establish the presence of hemolysis with these essential tests:

• Complete blood count (CBC) with red cell indices

  • Hemoglobin/hematocrit (degree of anemia)
  • Mean corpuscular volume (MCV) - can be normal, microcytic, or macrocytic
  • Red cell distribution width (RDW) - typically elevated

• Reticulocyte count

  • Elevated in hemolysis (compensatory response)
  • Exception: may be inappropriately normal/low with concurrent bone marrow suppression

• Markers of hemolysis

  • Lactate dehydrogenase (LDH) - elevated
  • Haptoglobin - decreased or absent
  • Unconjugated (indirect) bilirubin - elevated
  • Urinalysis for hemoglobinuria/hemosiderinuria (in intravascular hemolysis)

• Peripheral blood smear

  • Critical for identifying abnormal red cell morphologies
  • Can suggest specific diagnoses (spherocytes, schistocytes, etc.)

Step 2: Determine Immune vs. Non-immune Cause

• Direct antiglobulin test (DAT/Coombs test)
  • Positive in immune-mediated hemolysis
  • Negative in non-immune causes

Step 3: Further Testing Based on Initial Results

For Immune Hemolytic Anemia (Positive DAT)

• Cold agglutinin titers
• Evaluation for underlying conditions:
  • Autoimmune disorders (ANA, RF)
  • Lymphoproliferative disorders
  • Infections (Mycoplasma, EBV, etc.)
  • Medication history (drug-induced hemolysis)

For Non-immune Hemolytic Anemia (Negative DAT)

Based on peripheral smear findings and clinical context:

• Membranopathies (if spherocytes present)

  • Osmotic fragility test
  • Ektacytometry
  • Genetic testing for hereditary spherocytosis

• Enzymopathies

  • G6PD activity
  • Pyruvate kinase (PK) activity 1
  • Other enzyme assays as indicated

• Hemoglobinopathies

  • Hemoglobin electrophoresis
  • Genetic testing

• Microangiopathic Hemolytic Anemia (if schistocytes present)

  • Coagulation studies (PT, PTT, fibrinogen)
  • Platelet count
  • ADAMTS13 activity (TTP)
  • Evaluation for DIC, HUS, malignant hypertension

• Mechanical Hemolysis

  • Cardiac evaluation if prosthetic valve
  • Evaluation for march hemoglobinuria

• Infectious causes

  • Blood cultures
  • Specific testing for malaria, babesiosis, etc.

Step 4: Evaluate for Secondary Complications

• Iron studies (ferritin, transferrin saturation)
• Renal function tests
• Liver function tests
• Coagulation profile if indicated

Special Considerations

1. Transfusion history - Recent transfusions can complicate interpretation of test results

2. Timing of sample collection - Ideally before any transfusions

3. Inadequate reticulocytosis may occur in:

   • Concurrent bone marrow suppression
   • Nutritional deficiencies (iron, folate, B12)
   • Infections
   • Autoimmune reaction against erythroid precursors 2

4. Intravascular vs. extravascular hemolysis

   • Intravascular: marked LDH elevation, hemoglobinuria, hemosiderinuria
   • Extravascular: more prominent hyperbilirubinemia, splenomegaly

Common Pitfalls to Avoid

1. Overlooking drug-induced hemolysis - Always obtain detailed medication history

2. Missing concurrent nutritional deficiencies - Iron, B12, or folate deficiency can mask expected reticulocytosis

3. Incomplete evaluation - Failure to perform peripheral smear examination can miss critical diagnostic clues

4. Premature closure - Assuming common diagnosis without excluding important alternatives

5. Delayed diagnosis of rapidly progressive forms - Some hemolytic anemias (TTP, DIC) require immediate intervention

By following this systematic approach, the underlying cause of hemolytic anemia can be identified efficiently, allowing for appropriate management and treatment.