Why are haptoglobin levels low in immune-mediated thrombotic thrombocytopenic purpura (iTTP)?

Why Haptoglobin Levels Are Low in Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP)

Haptoglobin levels are low in iTTP due to ongoing microangiopathic hemolytic anemia, where red blood cells are mechanically sheared as they pass through microvascular thrombi, leading to intravascular hemolysis and rapid consumption of haptoglobin as it binds to free hemoglobin released from lysed red blood cells. 1

Pathophysiological Mechanism

The low haptoglobin levels in iTTP can be explained by the following sequential process:

1. Primary pathophysiology: iTTP is caused by autoantibodies against ADAMTS13, the enzyme that cleaves von Willebrand factor (vWF) 2

   • When ADAMTS13 activity is severely reduced (<10%), large multimers of vWF accumulate
   • These large vWF multimers bind platelets, forming microthrombi in small vessels

2. Mechanical hemolysis:

   • Red blood cells passing through these partially occluded vessels become fragmented
   • This mechanical destruction causes intravascular hemolysis
   • Free hemoglobin is released into the circulation

3. Haptoglobin consumption:

   • Haptoglobin binds to free hemoglobin with high affinity
   • The haptoglobin-hemoglobin complexes are rapidly cleared by the reticuloendothelial system
   • This clearance depletes circulating haptoglobin levels

Diagnostic Significance

Low haptoglobin is a key laboratory marker in iTTP diagnosis:

• Haptoglobin levels in iTTP are typically extremely low (median 0.39 mg/dL) compared to other conditions like septic DIC (median 54.20 mg/dL) 1
• A cutoff level of <2.868 mg/dL haptoglobin has been identified as useful in distinguishing iTTP from septic DIC 1
• The combination of low haptoglobin with normal Factor XIII activity (which remains preserved in iTTP but decreases in DIC) forms the basis of the TTP/DIC index, which has 94.3% sensitivity and 86.7% specificity for differentiating iTTP from septic DIC 1

Clinical Implications

The low haptoglobin level in iTTP has important clinical implications:

• It serves as an early marker of hemolysis, often detectable before schistocytes appear on peripheral smear
• The presentation of anemia plus thrombocytopenia should always prompt determination of haptoglobin, indirect bilirubin, and LDH levels 3
• Persistently low haptoglobin despite treatment may indicate ongoing hemolysis and incomplete disease control
• Normalization of haptoglobin can be used as one indicator of treatment response

Diagnostic Algorithm for Suspected iTTP

When evaluating a patient with thrombocytopenia and anemia:

1. Check haptoglobin, LDH, and indirect bilirubin levels immediately
2. If haptoglobin is low (<2.868 mg/dL), LDH is elevated, and there is evidence of non-immune hemolytic anemia (negative direct Coombs test)
3. Urgently measure ADAMTS13 activity (severely deficient if <10% in iTTP)
4. Assess for schistocytes on peripheral blood smear (though absence doesn't exclude diagnosis) 3
5. Rule out other causes of thrombotic microangiopathy (TMA)

The combination of severe ADAMTS13 deficiency and extremely low haptoglobin is highly suggestive of iTTP and should prompt immediate initiation of therapy with plasma exchange, corticosteroids, and rituximab to improve survival 4.