Key Facts

TTP is a thrombotic microangiopathy characterised by systemic platelet-rich microvascular thrombosis due to severe deficiency of the vWF-cleaving protease ADAMTS13. Without treatment it is almost universally fatal.

Epidemiology

• Rare: incidence approximately 4-6 per million/year in the UK
• Peak age: 30-50 years
• Female predominance (F:M 2-3:1)
• More common in Black African/Caribbean populations (3-fold increased risk)
• Pregnancy is a recognised trigger

Aetiology

• Acquired TTP (~95%): autoantibodies (IgG) against ADAMTS13 → severe deficiency (<10% activity)
• Congenital TTP (~5%): homozygous/compound heterozygous ADAMTS13 gene mutations (Upshaw-Schulman syndrome)
• Triggers: pregnancy, infection, autoimmune disease (SLE), drugs (quinine, ticlopidine)

Pathophysiology

• ADAMTS13 normally cleaves ultra-large vWF multimers (ULvWF) into smaller fragments
• Severe ADAMTS13 deficiency → accumulation of ULvWF multimers
• ULvWF causes spontaneous platelet adhesion and aggregation in the microcirculation
• Platelet-rich microthrombi → mechanical shearing of RBCs (schistocytes/MAHA)
• Microvascular occlusion → end-organ ischaemia (brain, kidneys, heart)
• Consumptive thrombocytopenia (platelets consumed in microthrombi)

Typical Presentation

• Fatigue and malaise (anaemia)
• Petechiae and purpura (thrombocytopenia)
• Neurological features (60-70%): confusion, headache, focal deficits, seizures, coma
• Jaundice (haemolysis)
• Dark urine (haemoglobinuria)
• Fever (less common than historically described)

Organ Involvement

• CNS: most common site of ischaemia – fluctuating neurological signs
• Renal: usually mild impairment (creatinine rarely >300 µmol/L; if severe, consider HUS)
• Cardiac: troponin elevation in ~50%, myocardial ischaemia
• GI: abdominal pain, pancreatitis

Red Flags

• Thrombocytopenia + schistocytes on blood film → assume TTP until proven otherwise
• NEVER transfuse platelets – potentially fatal
• Neurological deterioration → urgent PEX
• Raised troponin → cardiac involvement (poor prognostic sign)

Bedside

• Blood pressure: may be normal or mildly elevated (severe hypertension suggests alternative diagnosis)
• Neurological assessment: GCS, focal deficits
• Urine dipstick: haemoglobinuria

Bloods

• FBC: thrombocytopenia (often <30 × 10⁹/L), anaemia
• Blood film: schistocytes (fragmented red cells) – essential diagnostic finding
• LDH: markedly elevated (haemolysis + tissue ischaemia)
• Haptoglobin: undetectable (consumed in haemolysis)
• Reticulocyte count: elevated (appropriate response to haemolysis)
• Unconjugated bilirubin: raised
• DAT (Coombs test): negative (distinguishes from AIHA)
• Coagulation screen: normal PT and APTT (distinguishes from DIC)
• Fibrinogen: normal (low in DIC)
• ADAMTS13 activity: <10% confirms TTP (send BEFORE starting PEX)
• ADAMTS13 inhibitor/antibody: identifies acquired TTP
• Troponin: cardiac involvement assessment
• U&Es: usually mild renal impairment

Imaging

• CT head: if neurological symptoms (exclude intracranial haemorrhage)
• MRI brain: if focal neurological deficits

Special Tests

• PLASMIC score: clinical prediction tool (score ≥6 suggests TTP)
• Components: platelet count <30, haemolysis markers, no cancer, no transplant, MCV <90, INR <1.5, creatinine <177

Non-pharmacological

• Haematological emergency – do not delay treatment while awaiting ADAMTS13 result
• Daily plasma exchange (PEX): commence within hours of clinical suspicion
  • Removes autoantibodies and ULvWF; replaces ADAMTS13
  • 1.5 plasma volume exchanges daily until platelet count >150 × 10⁹/L for ≥2 consecutive days
  • Then taper (alternate day, then stop)

Pharmacological

Acute management:

• Methylprednisolone 1g IV daily for 3 days then prednisolone 1mg/kg/day (taper over weeks)
• Caplacizumab 11mg IV (first dose before PEX), then 11mg SC OD for 30 days after last PEX (HERCULES trial: faster platelet recovery, reduced exacerbations)

Refractory/relapsing:

• Rituximab 375mg/m² IV weekly × 4 – targets B-cells producing anti-ADAMTS13 antibodies
• Increasingly used as part of first-line in severe cases

Supportive:

• Folic acid 5mg OD (increased erythropoiesis)
• VTE prophylaxis once platelets >50 × 10⁹/L
• Red cell transfusion for symptomatic anaemia
• DO NOT transfuse platelets unless life-threatening haemorrhage

Referral Criteria

• Suspected TTP → immediate haematology and arrange PEX
• Refractory TTP → tertiary centre with TTP expertise
• All patients require long-term haematology follow-up (relapse risk 20-50%)

• Untreated mortality: >90%
• With plasma exchange: mortality ~10-20%
• With PEX + caplacizumab + rituximab: mortality <5%
• Relapse rate: 20-50% in acquired TTP (highest in first 2 years)
• Congenital TTP: requires regular plasma infusions, generally good prognosis
• Cardiac involvement (raised troponin) associated with worse outcomes
• Long-term neurocognitive sequelae in survivors

PLASMIC Score

Key Distinction: TTP vs HUS vs DIC