Thrombotic Thrombocytopenic Purpura

A rare, life-threatening thrombotic microangiopathy: severe deficiency of ADAMTS13 (the plasma enzyme that cleaves von Willebrand factor multimers) lets ultra-large vWF multimers form platelet-rich microthrombi in small vessels, causing thrombocytopenia, microangiopathic haemolytic anaemia, and ischaemic organ damage.

Epidemiology and cause:

• Annual incidence 1.5-6 per million adults; more common in women, and up to 8-fold more common in Black patients.

• 90% of cases are immune-mediated (an autoantibody against ADAMTS13), acquired in adulthood. Secondary causes include HIV, SLE, antiphospholipid syndrome, and drugs (ticlopidine is the classic culprit).

• Hereditary TTP (Upshaw-Schulman syndrome, recessively inherited ADAMTS13 mutation) is 3-5% of cases, usually presenting in childhood, sometimes first unmasked by pregnancy.

History and examination

Initial symptoms range from mild/gradual to acute/severe. Anaemia causes weakness and fatigue; thrombocytopenia causes purpura and mucosal bleeding. Ischaemic organ damage can affect any system — confusion, headache, seizures, abdominal pain, nausea, vomiting, diarrhoea, arrhythmia. A preceding infection is common. Fever is not a typical feature.

The classic pentad (fever, altered mental status, anaemia, thrombocytopenia, renal failure) now appears in fewer than 10% of cases — most patients present with just thrombocytopenia and microangiopathic haemolytic anaemia. TTP overlaps clinically with haemolytic-uraemic syndrome and other thrombotic microangiopathies.

Investigations

FBC and blood film (schistocytes), direct antiglobulin (Coombs) test — negative in TTP, which distinguishes it from immune haemolysis — LDH, PT, APTT, fibrinogen, haptoglobin, and ADAMTS13 activity/autoantibody.

The PLASMIC score estimates the pre-test probability of severe ADAMTS13 deficiency from routine results (platelet count, haemolysis markers, MCV, INR, creatinine, active malignancy/transplant) and helps decide whether to start plasma exchange before ADAMTS13 results return — treatment should not wait for confirmatory testing in a patient whose presentation fits.

Differential: hereditary/acquired ADAMTS13 deficiency (TTP) vs disseminated intravascular coagulation, HUS (especially with prominent renal failure), Evans syndrome, antiphospholipid syndrome, and — in pregnancy — HELLP syndrome or first-presentation Upshaw-Schulman syndrome.

Management

Untreated TTP is >90% fatal. Refer urgently to the ED for admission under haematology — this is a medical emergency.

• Plasma exchange — first-line, started urgently and continued daily until platelet count and LDH normalise. With current therapy (plasma exchange + glucocorticoids + rituximab), >95% of patients recover completely.
• Glucocorticoids — standard adjunct to plasma exchange; higher doses give higher remission rates.
• Rituximab — for refractory/relapsing disease (up to 50% of patients don’t respond to first-line therapy); also reduces relapse risk in patients with low ADAMTS13 activity.
• Caplacizumab (anti-vWF nanobody) — hastens platelet count recovery and may reduce plasma exchange requirements, but as monotherapy rarely induces durable remission and increases bleeding risk; its role alongside plasma exchange/immunosuppression is still debated (cost and bleeding risk vs faster platelet recovery). ISTH guidance supports its use as part of the treatment strategy.
• Hereditary TTP does not respond to plasma exchange/steroids/rituximab — managed with regular fresh-frozen plasma (or recombinant ADAMTS13) infusions instead.
• Avoid platelet transfusion unless there is overt bleeding or an invasive procedure is planned — it can worsen microthrombosis.

Relapse: occurs in up to 40% with autoantibody-mediated severe ADAMTS13 deficiency, usually within 1-2 years but reported up to 20 years later — patients need long-term follow-up and rapid reassessment for any relapse symptoms.