Diagnosis of Thrombotic Thrombocytopenic Purpura (TTP)

PATHCHAT Edition No. 83
Published: 2023
Please contact your local Ampath pathologist for more information.

Author:

• Dr. PF Wessels

Key Messages

✅ Thrombotic Thrombocytopenic Purpura (TTP) is a rare but life-threatening disorder.

• Early recognition and communication with a haematologist improve outcomes.
• Diagnosis requires evidence of Coombs-negative microangiopathic haemolytic anaemia (MAHA), thrombocytopaenia, and organ involvement, with an ADAMTS13 activity level <10%.

✅ Acquired TTP (iTTP) and hereditary TTP (hTTP) differ in their pathogenesis.

• iTTP is associated with ADAMTS13 autoantibodies, while hTTP results from a genetic defect in ADAMTS13.
• A negative ADAMTS13 antibody test does not confirm hTTP, as other mechanisms may contribute to ADAMTS13 deficiency.

✅ Long-term monitoring is necessary.

• Distinguishing between hTTP and iTTP and monitoring disease activity are essential for appropriate management.

✅ Other conditions should be considered if ADAMTS13 activity is >10%.

📌 Timely diagnosis and appropriate treatment reduce TTP-related morbidity and mortality.

Introduction

✅ TTP belongs to the family of thrombotic microangiopathies (TMA).

• Characterized by occlusion of arterioles and capillaries, leading to organ dysfunction.
• Non-immune thrombocytopaenia and microangiopathic haemolytic anaemia (MAHA) are hallmark features.

✅ First Described in 1924

• Dr. Eli Moschcowitz described a 16-year-old girl who died from stroke and myocardial infarction 14 days after presenting with fever, weakness, and transient neurological symptoms.

✅ Modern Clinical Insights

• Mortality remains high (10–20%) despite advances in diagnosis and therapy.
• Long-term complications include neurocognitive impairment, hypertension, and depression.
• A relapsing course necessitates careful follow-up.

📌 Early recognition, diagnosis, and treatment initiation are critical for improving survival rates in TTP.

Pathophysiology of TTP

✅ Von Willebrand Factor (vWF) and ADAMTS13 in Normal Physiology

• vWF is released as large multimers that must be cleaved by ADAMTS13 to prevent excessive platelet aggregation.
• ADAMTS13 (a disintegrin and metalloprotease with thrombospondin Type 1 repeats, member 13) regulates vWF size.

✅ Mechanisms of TTP

• Deficiency of ADAMTS13 leads to the accumulation of ultra-large vWF multimers.
• Platelets bind excessively to vWF, forming microvascular thrombi.
• These thrombi obstruct small blood vessels, causing end-organ ischaemia.

📌 TTP is primarily caused by ADAMTS13 deficiency, leading to uncontrolled platelet aggregation and microvascular occlusion.

Types of TTP

1. Hereditary TTP (hTTP) - Upshaw-Schulman Syndrome

• Constitutes ~2% of TTP cases.
• Caused by recessively inherited ADAMTS13 gene mutations (>150 mutations identified).
• Clinical phenotype varies, with triggers (e.g., pregnancy, infection, trauma) often required for symptom onset.
• Incidence: 0.4–1 per million people.
• Diagnosis is confirmed by persistently low ADAMTS13 levels and absence of autoantibodies.
• ADAMTS13 gene sequencing is the gold standard for confirmation but is not yet available in South Africa.

2. Acquired TTP (iTTP)

• Immune-mediated TTP (iTTP):
  • Autoantibodies neutralize ADAMTS13 or accelerate its clearance.
  • Primary iTTP: No underlying associated disease.
• Unknown Mechanism TTP:
  • May result from vWF insensitivity to ADAMTS13 cleavage.
• Triggers include:
  • Inflammation, infection, and pregnancy.
  • Predisposing factors such as obesity and female sex (especially in African populations).
• Subcategories of acquired TTP include:
  • Drug-induced TTP (e.g., ticlopidine, Pfizer-BioNTech COVID-19 vaccine).
  • Obstetric TTP.
  • Autoimmune TTP (associated with SLE).
  • Cancer-associated TTP.
  • HIV-related TTP.

📌 Acquired TTP is primarily autoimmune, but various triggers and underlying diseases can contribute to its onset.

Clinical Presentation of TTP

✅ Classic TTP Pentad (Rarely Seen Today)

1. Thrombocytopaenia (<30 × 10⁹/L).
2. Microangiopathic haemolytic anaemia (MAHA) with schistocytes.
3. Neurological symptoms (headache, confusion, seizures, stroke, coma).
4. Renal insufficiency (proteinuria/haematuria).
5. Fever.

✅ Common Presentations

• Neurological symptoms: Headache, confusion, stroke, seizures.
• Gastrointestinal symptoms: Abdominal pain, diarrhoea (due to mesenteric ischaemia).
• Cardiac involvement: Myocardial infarction.
• Haematological findings: High D-dimer, normal or mildly elevated PT and aPTT.

📌 Most patients present with thrombocytopaenia, haemolytic anaemia, and neurological symptoms rather than the full pentad.

Diagnosis of TTP

✅ PLASMIC Score for TTP Prediction

• Scores >5 indicate likely TTP.
• Scores 6–7 correlate with ADAMTS13 activity <10%.

PLASMIC Score Components:

1. Platelet count <30 × 10⁹/L.
2. Haemolysis markers (e.g., high reticulocyte count, undetectable haptoglobin).
3. No active cancer in the last year.
4. No history of solid organ or stem cell transplantation.
5. MCV <90 fL.
6. INR <1.5.
7. Creatinine <176.8 µmol/L.

📌 The PLASMIC score aids in TTP diagnosis but does not replace clinical judgement.

Management of TTP

✅ Key Principles

• Immediate haematology consultation.
• ADAMTS13 activity testing.
• Peripheral blood smear evaluation for red cell fragmentation.
• Plasma exchange therapy (PEX) initiation.
• Immunosuppressive therapy (corticosteroids, rituximab) for iTTP.

✅ Practical Considerations for ADAMTS13 Testing

• ADAMTS13 antibody testing is only performed if ADAMTS13 activity <10%.
• Samples must be collected in citrate tubes (EDTA is unsuitable).
• High autoantibody levels may lead to false-positive or borderline results.

📌 Early treatment with plasma exchange and immunosuppression significantly improves survival in TTP patients.