Information for Clinicians
Thrombotic Thrombocytopenic Purpura (TTP) is a rare disease with an incidence of approximately 6 per million of the population in the UK.
What Is TTP?
TTP is caused by severe deficiency of ADAMTS13, a metalloprotease enzyme which is essential for cleavage of von Willebrand Factor (vWF) multimers in the circulation. The majority of patients with TTP have an autoantibody which causes increased clearance and/or inhibition of ADAMTS13 (known as immune TTP, iTTP), but in some cases TTP can also be inherited via mutations in the ADAMTS13 gene (known as congenital TTP, cTTP).
Clinical features of TTP
TTP is one of a family of disorders known as thrombotic microangiopathes (TMAs) which share some characteristic features including the presence of a microangiopathic haemolytic anaemia (MAHA), thrombocytopenia and microvascular thrombosis. The presence of end organ damage is commonly seen in TTP, with the brain and heart being the main targets, although other organs can be affected.
While there are no specific symptoms for TTP, the majority (>70%) of patients present with neurological symptoms, which can range from headache and visual disturbance to more severe symptoms, including TIA or CVA. The haemolysis and resulting anaemia can cause progressive fatigue and SOB, as well as dark urine/haematuria. While bruising symptoms can occur, bleeding symptoms are not usually seen, despite severe thrombocytopenia. Cardiac involvement is not usually associated with symptoms other than in particularly severe cases, but usually detected via the finding of an elevated Troponin.
Diagnosis of TTP
Acute TTP is a life-threatening disorder, and it is essential that treatment is initiated as soon as TTP is suspected. The essential diagnostic features are the finding of a haemolytic anaemia with red cell fragments on the blood film (MAHA) in the presence of (usually severe) thrombocytopenia. Other features of haemolysis are usually present, including an elevated bilirubin and LDH and a red cell reticulocytosis, with a negative DAT and normal coagulation screen. Renal impairment is not uncommon in TTP, but this is not usually severe. TTP is confirmed through the finding of severe reduction in ADAMTS13 activity (typically <10 IU/dl) measured via a specialist assay. The detection of anti-ADAMTS13 antibodies via an ELISA assay are characteristic of immune TTP. Genetic testing is carried out where congenital TTP is suspected.
Treatment of acute TTP
Acute TTP is treated with the combination of plasma exchange, immunosuppression and the vWF nanobody Caplacizumab. Plasma exchange with Fresh Frozen Plasma (FFP, usually Octaplas) aims to temporarily correct the severe deficiency of ADAMTS13 levels as well as having some action of antibody removal. High doses of intravenous steroids and then oral steroids are given early in the acute treatment phase. Rituximab infusions are very effective at controlling immune TTP both acutely and longer-term. Caplacizumab injections are given acutely, to help speeden platelet recovery and reduce the microvascular thrombosis associated with acute TTP; this reduces the time plasma exchange is needed.
Congenital TTP is usually treated with FFP (Octaplas) infusion in the first instance (typically weekly) although patients are increasingly being treated with weekly rADAMTS13. This typically results in significant improvement in symptoms and markedly reduces the risk of potential complications associated with cTTP, including stroke.
Link to BCSH guidelines is available here:
Long-term follow up
It is essential that patients with immune and congenital TTP are followed-up long-term. Once patients with iTTP have gone into clinical remission, they are monitored in the clinic, typically every 3-6 months. All TTP patients should be seen in a TTP Specialist Regional Centre at least once a year. ADAMTS13 levels are monitored at each clinic visit, with the aim of giving further immunosuppressive treatment (usually with either rituximab, or in some cases alternative anti-CD20 therapy) if levels drop to <20 IU/dL, which indicates that patients are at high risk of an acute TTP relapse. Patients with cTTP are seen when attending for regular treatment (as above).
Prognosis of TTP and Useful Links
With early initiation of acute therapy, the majority of patients with acute TTP have an excellent prognosis, but the mortality of acute TTP is still around 5-10%. Monitoring of ADAMTS13 levels and initiation of elective (prophylactic) anti-CD 20 therapy is very effective in preventing further acute TTP episodes. Prognosis of cTTP is generally very good as long as long-term prophylactic treatment is initiated.
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