What is Thrombotic Thrombocytopenic Purpura (TTP)?

What is Thrombotic Thrombocytopenic Purpura (TTP)?

TTP is a life-threatening thrombotic microangiopathy caused by severe deficiency of ADAMTS13 enzyme, resulting in microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia from disseminated microvascular platelet-rich thrombi. 1, 2

Pathophysiology

TTP occurs when ADAMTS13 activity falls below 10%, preventing the cleavage of ultra-large von Willebrand factor (VWF) multimers. 3, 1 These unfolded VWF multimers cause spontaneous platelet activation and aggregation in arterioles and capillaries throughout the microcirculation, forming microthrombi that consume platelets and shatter red blood cells as they pass through. 2, 4

The ADAMTS13 deficiency can be:

• Acquired (immune-mediated iTTP): Caused by autoantibodies against ADAMTS13, accounting for most adult cases and occurring twice as frequently in women 1, 5
• Congenital (cTTP): Caused by biallelic mutations in the ADAMTS13 gene, typically presenting in childhood or during pregnancy 6, 5

Clinical Manifestations

The classic pentad includes microangiopathic hemolytic anemia, thrombocytopenia, neurological abnormalities, renal dysfunction, and fever—though not all five features need be present. 3

Specific Clinical Features:

• Neurological symptoms: Confusion, headache, visual disturbances (blurred vision, visual field defects), seizures, or stroke from CNS microthrombi 3, 2
• Thrombocytopenia: Moderate to severe, typically from platelet consumption in microthrombi 3, 2
• Renal dysfunction: Elevated creatinine, though typically less severe than in hemolytic uremic syndrome 3
• Fever: Present in some cases 3

Laboratory Findings:

• Microangiopathic hemolytic anemia: Schistocytes on peripheral smear, elevated LDH, indirect hyperbilirubinemia, reticulocytosis 3, 2
• Negative direct antiglobulin test (Coombs): Distinguishes TTP from autoimmune hemolytic anemia 3
• Severe thrombocytopenia: From platelet consumption 2, 6
• ADAMTS13 activity <10%: Diagnostic confirmation 3, 1

Diagnostic Approach

When TTP is suspected based on thrombocytopenia and hemolysis, treatment must be initiated immediately—do not wait for ADAMTS13 results, as untreated TTP has extremely high mortality. 2, 6

Diagnostic Algorithm:

1. Identify thrombocytopenia and microangiopathic hemolytic anemia on CBC and peripheral smear (schistocytes present) 2
2. Calculate PLASMIC score to determine probability of severe ADAMTS13 deficiency in hospitalized patients with thrombocytopenia and hemolysis 2
3. Send ADAMTS13 activity level (results take several days) 2, 6
4. Initiate plasma exchange immediately if high clinical suspicion, pending confirmatory testing 2, 6

Differentiation from Other Conditions:

• Malignant hypertension-associated TMA: Coexistence of severe blood pressure elevation with advanced retinopathy; ADAMTS13 activity is not severely reduced 3
• ITP: Isolated thrombocytopenia without hemolysis or schistocytes; normal ADAMTS13 activity 7
• Hemolytic uremic syndrome: More severe renal dysfunction, often diarrhea-associated; ADAMTS13 activity typically normal 3

Critical Pitfalls to Avoid

Delaying plasma exchange while awaiting ADAMTS13 results is the most dangerous error—TTP is rapidly fatal without treatment. 2, 6 Start therapeutic plasma exchange immediately when clinical suspicion is high based on thrombocytopenia, hemolysis with schistocytes, and organ dysfunction (especially neurological symptoms). 2, 6

Overlooking neurological symptoms as the presenting feature can delay diagnosis, as these manifestations may initially be attributed to other causes. 3 Any patient with unexplained neurological symptoms plus thrombocytopenia and hemolysis requires immediate TTP evaluation. 3, 2

Misdiagnosing TTP as ITP is catastrophic, as ITP treatment (observation or corticosteroids alone) is inadequate for TTP. 7, 1 The presence of hemolysis with schistocytes immediately excludes isolated ITP and mandates consideration of thrombotic microangiopathy. 2, 6