What is the difference between plasma free hemoglobin and haptoglobin?

Plasma Free Hemoglobin vs. Haptoglobin: Key Differences and Clinical Significance

Plasma free hemoglobin (pfHb) is a marker of hemolysis, while haptoglobin is an acute phase protein that binds and clears free hemoglobin from circulation to prevent its toxic effects. These two laboratory parameters have opposite relationships during hemolysis and serve complementary diagnostic purposes.

Definitions and Basic Functions

Plasma Free Hemoglobin

• Released into circulation when red blood cells rupture (hemolysis)
• Toxic molecule that can cause tissue and organ damage
• Elevated levels indicate ongoing hemolysis
• Normal range: typically <5 mg/dL

Haptoglobin

• Glycoprotein primarily produced by the liver
• Acts as a scavenger by binding free hemoglobin
• Becomes depleted during hemolysis
• Normal range: typically 30-200 mg/dL

Key Differences

Characteristic	Plasma Free Hemoglobin	Haptoglobin
Origin	Released from lysed RBCs	Produced by the liver
During hemolysis	Increases	Decreases
Function	None (toxic byproduct)	Binds and clears free hemoglobin
Clinical significance	Marker of active hemolysis	Marker of hemolysis when decreased

Relationship During Hemolysis

During hemolytic processes:

1. Red blood cells rupture, releasing hemoglobin into plasma
2. Free hemoglobin binds to available haptoglobin molecules
3. These hemoglobin-haptoglobin complexes are rapidly cleared by the reticuloendothelial system
4. Haptoglobin levels decrease as it's consumed in this process
5. When hemolysis exceeds haptoglobin's binding capacity, plasma free hemoglobin increases

Clinical Utility

Plasma Free Hemoglobin

• Direct marker of intravascular hemolysis
• Particularly useful in mechanical hemolysis (e.g., mechanical circulatory support devices)
• Elevation indicates active, ongoing hemolysis
• Used to monitor for pump thrombosis in patients with ventricular assist devices 1

Haptoglobin

• Indirect marker of hemolysis (decreases with hemolysis)
• More sensitive for detecting low-grade hemolysis
• Remains low until hemolysis resolves and liver production catches up
• Used in diagnosis of hemolytic anemias and monitoring response to treatment 1

Clinical Interpretation Considerations

False Positives/Negatives for Haptoglobin

• False low haptoglobin (suggesting hemolysis when none exists):

  • Liver cirrhosis (decreased production)
  • Hemodilution
  • Congenital ahaptoglobinemia

• False normal/high haptoglobin (masking hemolysis):

  • Acute inflammatory states (as an acute phase reactant)
  • Medications (androgens, corticosteroids)
  • Recent transfusion 2, 3

Monitoring Hemolysis in Transfused Patients

• Serum haptoglobin can still be used to evaluate hemolysis in recently transfused patients, as transfusion does not significantly affect haptoglobin levels 4

Clinical Applications

1. Diagnosis of hemolytic conditions:

   • Both markers should be measured together for comprehensive assessment
   • Low haptoglobin with elevated pfHb strongly suggests active hemolysis

2. Monitoring mechanical circulatory support:

   • Baseline and serial measurements help detect complications
   • Elevation of lactate dehydrogenase above baseline or 2.5 times normal requires evaluation 1

3. Atypical hemolytic uremic syndrome (aHUS):

   • The presentation of anemia plus thrombocytopenia should prompt determination of haptoglobin, indirect bilirubin, and LDH levels 1

4. Therapeutic applications:

   • Exogenous haptoglobin administration may enhance pfHb clearance during hemolysis and reduce end-organ damage 5

Practical Approach to Laboratory Testing

When hemolysis is suspected:

1. Order both plasma free hemoglobin and haptoglobin
2. Include other hemolysis markers: LDH, indirect bilirubin, reticulocyte count
3. Interpret results in context of patient's clinical condition and other laboratory findings
4. Consider potential confounding factors (liver disease, inflammation)

Remember that haptoglobin depletion is a reliable marker for accelerated red cell destruction regardless of the site of hemolysis (intravascular vs. extravascular) or the presence of inflammation 3.