What are the signs, symptoms, and management of Thrombotic Thrombocytopenic Purpura (TTP)?

Thrombotic Thrombocytopenic Purpura (TTP): Signs, Symptoms, and Management

Thrombotic Thrombocytopenic Purpura requires immediate therapeutic plasma exchange (TPE) along with immunosuppression, with the addition of caplacizumab for acquired TTP to reduce mortality and morbidity. 1, 2

Clinical Presentation

Signs and Symptoms

• Classic pentad (only present in ~5% of cases):

  1. Microangiopathic hemolytic anemia
  2. Severe thrombocytopenia (typically <30 × 10^9/L)
  3. Neurological abnormalities (39-80% of cases)
  4. Fever
  5. Renal dysfunction

• Common presenting features:

  • Neurological manifestations: headache, confusion, seizures, focal deficits
  • Abdominal pain (35-39%)
  • Purpura, petechiae, or mucosal bleeding
  • Evidence of microangiopathy: schistocytes on peripheral smear
  • Laboratory evidence of hemolysis (elevated LDH, decreased haptoglobin)

Diagnostic Workup

• Essential laboratory tests:

  • Complete blood count with peripheral smear (look for schistocytes)
  • ADAMTS13 activity level and inhibitor titer (diagnostic when <10%)
  • LDH, haptoglobin, reticulocyte count, bilirubin
  • Coagulation studies (PT, aPTT, fibrinogen)
  • Renal function tests
  • Direct antiglobulin test (Coombs)

• Additional evaluations:

  • Brain imaging (CT/MRI) if neurological symptoms present
  • Echocardiogram if cardiac involvement suspected
  • Blood group and antibody screen
  • CMV serology
  • Rule out other causes of thrombotic microangiopathy

Management Algorithm

First-Line Treatment (Initiate Immediately)

1. Therapeutic Plasma Exchange (TPE):

   • Begin immediately upon clinical suspicion, don't wait for ADAMTS13 results
   • First session: 1-1.5× plasma volume replacement with FFP
   • Continue daily until platelet count >150 × 10^9/L and LDH normalizes for 2-3 consecutive days
   • For refractory cases, consider twice-daily TPE 3

2. Corticosteroids:

   • Methylprednisolone 1g IV daily for 3 days, with first dose after first TPE
   • Then transition to prednisone 1-2 mg/kg/day

3. Caplacizumab (for acquired TTP):

   • 11 mg IV bolus before first TPE, then 11 mg SC daily during and 30 days after TPE
   • Reduces time to platelet normalization and early recurrence risk 4, 2
   • May extend for additional 28 days if persistent disease (suppressed ADAMTS13)

4. Rituximab:

   • Consider early addition (375 mg/m² weekly for 4 weeks)
   • Particularly for severe cases or inadequate response to TPE and steroids

Management Based on Severity

• Life-threatening TTP (G4):

  • Permanently discontinue any causative agent (e.g., immune checkpoint inhibitors)
  • Immediate hospital admission
  • Urgent hematology consultation
  • Implement full treatment protocol as above
  • Consider additional immunosuppression if no improvement (cyclophosphamide, IVIG)

• Severe TTP (G3):

  • Hold causative medications
  • Consider hospital admission
  • Prednisone 1-2 mg/kg/day
  • RBC transfusion as needed (target Hgb 7-8 g/dL)
  • Folic acid supplementation (1 mg daily)

Special Considerations

• Platelet transfusions: Generally contraindicated unless life-threatening bleeding or required for invasive procedures
• Antiplatelet/anticoagulant medications: Avoid during acute TTP
• Monitoring during remission: Regular ADAMTS13 activity testing; consider preemptive rituximab when <20% to prevent relapse 2
• Pregnancy: Requires specialized multidisciplinary management

Prognosis and Follow-up

• With prompt TPE and immunosuppression, survival rates exceed 90% 2
• Without treatment, mortality approaches 90%
• Approximately 16% of patients experience at least one relapse
• Long-term follow-up is essential to monitor for:
  • ADAMTS13 activity levels
  • Development of other autoimmune diseases
  • Neurological or cognitive sequelae

Common Pitfalls to Avoid

1. Delayed diagnosis: Waiting for the full pentad to appear before initiating treatment
2. Delayed TPE: Not starting TPE immediately upon clinical suspicion
3. Premature discontinuation: Stopping TPE too early before sustained platelet recovery
4. Platelet transfusion: Administering platelets can worsen microvascular thrombosis
5. Inadequate immunosuppression: Not adding rituximab early in severe cases
6. Insufficient monitoring: Not following ADAMTS13 levels during remission

The management of TTP requires rapid recognition and immediate intervention. The introduction of TPE has dramatically improved survival, and newer therapies like caplacizumab and rituximab have further enhanced outcomes by addressing the underlying pathophysiology of the disease.