What is haptoglobin?

Haptoglobin: Function and Clinical Significance

Haptoglobin is a plasma glycoprotein primarily produced by the liver that binds free hemoglobin released during hemolysis, preventing oxidative damage and renal injury while serving as an important biomarker for hemolytic conditions. 1

Basic Properties and Function

Haptoglobin has several critical physiological roles:

• Primary function: Binds free hemoglobin released during red blood cell breakdown, forming a haptoglobin-hemoglobin complex that:

  • Prevents hemoglobin-induced oxidative damage to tissues
  • Prevents renal damage from hemoglobin filtration
  • Conserves iron by facilitating hemoglobin recycling 1, 2

• Secondary functions:

  • Acts as an acute phase protein that increases during inflammation
  • Has immunomodulatory properties, including lymphocyte function suppression
  • Demonstrates antibacterial activity 3

Genetic Polymorphism

Haptoglobin exists in three major phenotypes determined by genetic polymorphism:

• Hp 1-1: Homozygous form that is biologically most effective at binding free hemoglobin and suppressing inflammatory responses
• Hp 2-2: Homozygous form that is biologically least active
• Hp 2-1: Heterozygous form with moderate activity 3

These phenotypes have been associated with predisposition to various diseases, including cardiovascular disorders, autoimmune conditions, and malignancies 2, 4.

Clinical Significance and Diagnostic Value

Hemolysis Detection

Haptoglobin is a highly sensitive marker for hemolysis:

• Low or undetectable haptoglobin is a key indicator of hemolytic processes, as it becomes rapidly depleted when binding free hemoglobin 1
• When evaluating potential hemolysis, haptoglobin should be measured alongside:
  • Lactate dehydrogenase (LDH)
  • Indirect bilirubin
  • Reticulocyte count 1, 5

Diagnostic Algorithm for Hemolysis

1. Confirm hemolysis: Low haptoglobin + elevated LDH + elevated indirect bilirubin 1

2. Classify type of hemolysis:

   • Intravascular hemolysis: Very low/undetectable haptoglobin, hemoglobinuria, hemosiderinuria
   • Extravascular hemolysis: Low haptoglobin without hemoglobinuria 1

3. Determine if immune-mediated:

   • Perform direct Coombs test (direct antiglobulin test)
   • Consider cold agglutinin testing if suspected 1

Other Clinical Applications

• Inflammatory marker: Elevated haptoglobin indicates acute phase response in inflammatory conditions 1
• Thrombotic microangiopathy (TMA): Low haptoglobin with Coombs-negative hemolysis and thrombocytopenia suggests TMA 6
• Atypical hemolytic uremic syndrome (aHUS): Reduced haptoglobin levels are part of diagnostic criteria 6

Interpretation Pitfalls

Several factors can affect haptoglobin levels and interpretation:

• False negatives (normal haptoglobin despite hemolysis):

  • Concurrent inflammatory conditions may elevate baseline haptoglobin
  • Medications like androgens and corticosteroids can increase haptoglobin production
  • Hypersplenism can affect results 5

• False positives (low haptoglobin without hemolysis):

  • Liver disease (cirrhosis) may reduce haptoglobin production
  • Hemodilution
  • Improper specimen handling 5

Clinical Applications in Specific Conditions

• Methemoglobinemia: Haptoglobin levels help differentiate between hemolytic and non-hemolytic causes 6
• Pyruvate kinase deficiency: Haptoglobin is typically low due to chronic hemolysis 6
• Thrombotic microangiopathies: Unmeasurable haptoglobin with schistocytes suggests TMA 6

Conclusion

Haptoglobin measurement is a valuable tool in diagnosing hemolytic conditions, with low levels being a sensitive marker for hemolysis. However, interpretation should always consider other laboratory parameters and the patient's clinical context to avoid misdiagnosis due to the various factors that can influence haptoglobin levels.