Thrombotic Thrombocytopenic Purpura
Life-threatening thrombotic microangiopathy caused by severe ADAMTS13 deficiency (<10%), leading to accumulation of ultra-large von Willebrand factor multimers and widespread platelet-rich microthrombi. Mortality exceeds 90% without treatment but falls to <20% with plasma exchange.
Key Facts
TTP is caused by severe ADAMTS13 deficiency (<10%): either autoimmune (anti-ADAMTS13 antibodies, 95%) or congenital (Upshaw-Schulman syndrome, 5%) Classic pentad: MAHA, thrombocytopenia, neurological features, renal impairment, fever (full pentad in <10%) ADAMTS13 activity <10% is diagnostic and distinguishes TTP from HUS Plasma exchange (PEX) is the mainstay of treatment: started immediately on clinical suspicion (do not wait for ADAMTS13 result) Caplacizumab (anti-VWF nanobody): accelerates platelet recovery and reduces thrombotic events (HERCULES trial); NICE TA667 Rituximab 375mg/m² weekly × 4: for refractory/relapsing TTP or to reduce anti-ADAMTS13 antibodies Untreated mortality >90%; with PEX + caplacizumab + rituximab: mortality <5% DO NOT transfuse platelets – fuels thrombosis (unless life-threatening bleeding)
Overview
Key Facts
TTP is a haematological emergency. Early recognition and immediate initiation of plasma exchange saves lives. ADAMTS13 testing should not delay treatment.
Epidemiology
- Incidence: ~4 per million/year
- Peak age: 30-50 years; F:M 2-3:1
- More common in Afro-Caribbean populations
- Pregnancy-associated TTP: increased risk in third trimester
Aetiology
- Acquired (95%): IgG autoantibodies against ADAMTS13
- Congenital (5%): ADAMTS13 gene mutations (Upshaw-Schulman syndrome)
- Triggers: infection, pregnancy, surgery, autoimmune conditions, drugs (ticlopidine, clopidogrel, quinine)
Pathophysiology
- ADAMTS13 normally cleaves ultra-large VWF multimers (ULVWF) released from endothelium
- Deficiency → accumulation of ULVWF → spontaneous platelet adhesion and aggregation
- Platelet-rich microthrombi in arterioles and capillaries → organ ischaemia
- Red cell fragmentation through occluded microvasculature → schistocytes (MAHA)
- Platelet consumption → thrombocytopenia
- Brain and kidneys most commonly affected
Clinical Presentation
Presentation
- MAHA: pallor, jaundice, fatigue, dark urine
- Thrombocytopenia: petechiae, purpura, mucosal bleeding
- Neurological features (60-70%): headache, confusion, visual changes, seizures, stroke, coma
- Renal impairment: usually mild-moderate (distinguishes from HUS where renal is predominant)
- Fever: variable
Classic Pentad (Present in <10%)
- Microangiopathic haemolytic anaemia
- Thrombocytopenia
- Neurological abnormalities
- Renal impairment
- Fever
Red Flags
- MAHA + thrombocytopenia + any neurological symptom → treat as TTP until proven otherwise
- Fluctuating neurological signs: characteristic of TTP
- Do not delay plasma exchange waiting for ADAMTS13 result
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| HUS | Renal predominant, diarrhoeal prodrome, ADAMTS13 >10% | ADAMTS13, stool culture |
| DIC | Prolonged PT/APTT, low fibrinogen, bleeding | Coagulation screen |
| HELLP syndrome | Pregnancy, liver dysfunction | LFTs, pregnancy test |
| Evans syndrome | AIHA + ITP, Coombs positive | Direct Coombs test |
| SLE with TMA | Multi-system, ANA positive | Immunology |
Diagnosis / Investigation
Urgent Bloods
- FBC: anaemia, thrombocytopenia (often <30 × 10⁹/L)
- Blood film: schistocytes (fragmented RBCs) – >1% is significant
- LDH: markedly elevated
- Haptoglobin: undetectable
- Direct Coombs test: negative
- Reticulocyte count: raised
- U&Es: mild renal impairment (moderate in some)
- Coagulation: PT, APTT, fibrinogen usually NORMAL (distinguishes from DIC)
- ADAMTS13 activity: <10% is diagnostic (send BEFORE starting PEX but do NOT delay treatment)
- ADAMTS13 inhibitor/antibodies: confirms autoimmune aetiology
- Troponin: cardiac involvement in 25%
Other
- Pregnancy test: exclude HELLP
- HIV, hepatitis screen: potential triggers
- CT head: if neurological features (often normal or subtle changes)
Management
Emergency Treatment (Start on Clinical Suspicion)
1. Plasma exchange (PEX):
- Daily PEX with 1.5 plasma volume exchange using FFP replacement
- Continue daily until platelet count normalises (>150 × 10⁹/L) for ≥2 consecutive days
- Removes ULVWF multimers and anti-ADAMTS13 antibodies; replaces ADAMTS13
2. Caplacizumab:
- 11mg IV first dose, then 11mg SC daily until 30 days after last PEX
- Anti-VWF nanobody; prevents VWF-platelet interaction
- HERCULES trial: faster platelet normalisation, fewer thrombotic events, less PEX
- NICE TA667 approved
3. Immunosuppression:
- Corticosteroids: methylprednisolone 1g IV daily × 3, then prednisolone 1mg/kg
- Rituximab 375mg/m² weekly × 4: for refractory, relapsing, or high anti-ADAMTS13 antibody titre
- Rituximab increasingly used as early adjunct
4. Supportive:
- Folate supplementation (5mg OD)
- VTE prophylaxis (when platelets >50 × 10⁹/L)
- Do NOT transfuse platelets unless life-threatening haemorrhage
- Red cell transfusion: if symptomatic anaemia
Congenital TTP (Upshaw-Schulman)
- Regular FFP infusions (every 2-3 weeks) to replace ADAMTS13
- Recombinant ADAMTS13 (emerging therapy)
Monitoring
- Daily FBC, LDH, reticulocytes during PEX
- ADAMTS13 levels to guide treatment duration
- Relapse rate: 30-50% over lifetime; monitor ADAMTS13 regularly
Prognosis
- Untreated TTP: mortality >90% (one of the highest in medicine)
- With plasma exchange alone: mortality reduced to 10-20%
- With PEX + caplacizumab + rituximab: mortality <5%
- Relapse rate: 30-50% over lifetime; more common in first year
- ADAMTS13 monitoring: persistently low ADAMTS13 activity predicts relapse
- Pre-emptive rituximab: given when ADAMTS13 activity falls below 10% in remission, reduces clinical relapse
- Cardiac involvement: troponin elevation in 25%; cardiac events are a significant cause of death
Other Relevant Information
PLASMIC Score (Prediction of ADAMTS13 Deficiency)
| Criterion | Points |
|---|---|
| Platelet count <30 × 10⁹/L | 1 |
| Haemolysis (reticulocyte count >2.5%, undetectable haptoglobin, or indirect bilirubin >34 µmol/L) | 1 |
| No active cancer | 1 |
| No stem cell or solid organ transplant | 1 |
| MCV <90 fL | 1 |
| INR <1.5 | 1 |
| Creatinine <176 µmol/L | 1 |
Score ≥6: high probability of ADAMTS13 <10% → treat as TTP
TTP vs HUS vs DIC
| Feature | TTP | HUS | DIC |
|---|---|---|---|
| ADAMTS13 | <10% | >10% | Normal |
| Neurological | +++ | + | Variable |
| Renal | + | +++ | Variable |
| Coagulation | Normal | Normal | Abnormal |
| Fibrinogen | Normal | Normal | Low |