Thrombotic thrombocytopenic purpura (TTP)

Background

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening form of thrombotic microangiopathy characterised by microangiopathic hemolytic anaemia, thrombocytopenia, and end-organ damage. TTP represents a medical emergency with untreated mortality approaching 90%, though this can be dramatically reduced to 10-20% with prompt treatment.

Epidemiology

TTP is a rare condition with an estimated incidence of 6 per 1,000,000 per year in the UK, though recognition is increasing. The disease predominantly affects adults with peak incidence in the fourth decade of life, showing a female predominance with a 3:2 female-to-male ratio. While very rare in children, when it does occur, approximately 35% present with neurological symptoms such as hemiparesis, hemiplegia, or seizure.

Pathophysiology

TTP results from a deficiency of ADAMTS13 (a disintegrin and metalloproteinase), a plasma von Willebrand factor-cleaving protease. This deficiency leads to the accumulation of ultra-large von Willebrand factor multimers, which have tremendous avidity for binding platelets and initiating spontaneous thrombus formation.

The condition can be:

• Congenital: Due to mutations in the ADAMTS13 gene
• Acquired: More common, caused by autoantibodies targeting ADAMTS13

ADAMTS13 activity levels below 10% are diagnostic for TTP. The resulting microthrombi formation leads to end-organ ischaemia and damage, with the central nervous system and kidneys being the most commonly affected organs.

Clinical presentation

TTP was historically characterised by a classic pentad of fever, thrombocytopenia, hemolytic anaemia, renal dysfunction, and neurological dysfunction. However, this complete pentad is present in fewer than 5% of cases. Modern understanding recognises that patients can present with varying combinations of these features.

Common presenting features:

• Gastrointestinal symptoms: 69%
• Weakness: 63%
• Bleeding or purpura: 54%
• Major neurological findings (coma, stroke, seizure, focal abnormalities): 41%
• Minor neurological findings (headache, confusion): 26%
• Fever and chills: 10%

Physical examination findings:

• Fever
• Purpura and petechiae (non-palpable, associated with platelet count <50 × 10⁹/L)
• Jaundice (secondary to haemolysis)
• Severe hypertension
• Neurological abnormalities
• Splenomegaly

Investigations and diagnosis

Laboratory Tests:

• Blood smear: Presence of schistocytes (fragmented erythrocytes) - hallmark finding
• Complete blood count: Anaemia and thrombocytopenia
• Haemolysis markers: Elevated LDH (extremely high), elevated indirect bilirubin, elevated reticulocyte count, decreased haptoglobin
• Renal function: Creatinine mildly elevated in about half of patients
• Urinalysis: Proteinuria and microscopic haematuria
• ADAMTS13 activity and antibody levels: Activity <10% confirms diagnosis

Additional Tests:

• HIV, hepatitis B and C serology
• Autoantibody screen
• Pregnancy test (when appropriate)
• Cardiac troponin (elevated levels indicate poor prognosis)

Management
TTP is a haematological emergency requiring immediate intervention, ideally within 4-8 hours of presentation.

First-Line Treatments:
Plasma Exchange (Plasmapheresis): Gold standard treatment

• Removes inhibitory antibodies and replaces deficient ADAMTS13
• Daily treatments of one plasma volume (40 mL/kg)
• Continued until platelet count >150,000/μL for >48 hours
• If plasma exchange unavailable include fresh frozen plasma infusion may be used

Corticosteroids:

• Prednisone 1 mg/kg/day for neurologically intact patients
• IV methylprednisolone 1000 mg daily for 3 days or 125 mg 2-4 times daily for severely ill patients
• Continue throughout plasma exchange course

Adjunctive and Second-Line Treatments:
Rituximab: Anti-CD20 monoclonal antibody

• Recommended for refractory/relapsing cases
• Consider early in acute cases with neurological/cardiac involvement
• May prevent relapses

Caplacizumab: Novel humanised monoclonal antibody fragment

• Blocks platelet adhesion to von Willebrand factor
• Rapid onset, significantly reduces mortality
• Given IV initially, then subcutaneous for 30 days post-plasma exchange

Supportive care:

• Red cell transfusion as clinically indicated
• Folate supplementation during active hemolysis
• Thromboprophylaxis with LMWH when platelets >50 × 10⁹/L
• Contraindication: Platelet transfusion (risk of thrombotic events unless life-threatening haemorrhage)

Prognosis:

• Untreated mortality: 90%
• Treated mortality: 10-20%
• Approximately one-third of survivors experience relapse within 10 years
• Early treatment significantly improves outcomes

Complications:

• End-organ damage (neurological, renal, cardiac)
• Complications of plasma exchange (central line infections, TRALI)
• Bleeding complications with anticoagulation
• Long-term neurological sequelae