Haematology - Thrombotic thrombocytopenic purpura

The early recognition and referral of patients with TTP is essential, says Professor David Roberts.

Microangiopathic haemolytic anaemia with red cell fragments and irregularly shaped red blood cells (Image: David Roberts and John Burthem)
Microangiopathic haemolytic anaemia with red cell fragments and irregularly shaped red blood cells (Image: David Roberts and John Burthem)

Thrombotic thrombocytopenic purpura (TTP) is an uncommon condition in general medical practice but is a medical emergency. Untreated it is fatal but the classical features of microangiopathic haemolytic anaemia, confusion or coma and renal failure frequently respond rapidly to plasma exchange and immunosuppression - early recognition and referral of patients with TTP is crucial.

Pathogenesis
The pathogenesis of TTP was unclear until recently. The long descriptive name reflects the previously uncertain aetiology and is misleading because purpura is an uncommon feature of the disease.

People develop this condition usually after developing auto-antibodies against a circulating protease, ADAMTS-13. This protease normally removes small peptide from the adhesion protein, von Willebrand factor (vWF), so preventing the formation of large multimers that promote adhesion of platelets to the endothelium, platelet activation, formation of fibrin strands and small thrombi.

In TTP reduced levels of this protease allow large vWF multimers to form and the resulting platelet activation and fibrin formation cause end-organ damage and the hallmark haemolysis and red cell fragmentation (microangiopathic haemolytic anaemia).

The disease may also be precipitated by bacterial or viral infection, including hepatitis or HIV, and pregnancy, or it can be drug-induced. It is rarely caused by a congenital insufficiency of the ADAMTS-13 protease. It must be distinguished from disseminated intravascular coagulation and systemic lupus erythematosus, and in pregnancy from haemolysis with elevated liver enzymes and low platelets (HELLP) or pre-eclampsia.

The toxin from a specific Escherichia coli serotype causes endothelial damage and haemolytic anaemia and renal impairment but not cerebral symptoms.

Autoimmune TTP is more common in young women, during pregnancy and in people of African descent but may occur at any age, with an overall incidence of 1:300,000 per year.

Diagnosis
TTP presents as a micro-angiopathic haemolytic anaemia with no obvious cause. The location of thrombotic damage to cells and tissues leads to the cardinal features of TTP.

Typically there is a sudden onset of anaemia causing fatigue, malaise, tiredness and dizziness. The cerebral symptoms include headache, confusion and loss of orientation, visual disturbance, weakness and seizures, and may progress rapidly to unconsciousness and coma. Thrombi in renal glomeruli may lead to renal failure and less commonly the coronary circulation may be affected, with arrhythmias or infarction.

A blood count and biochemical screen will reveal anaemia, thrombocytopenia, reticulocytosis with red cell fragmentation and irregularly shaped damaged red cells. Coagulation tests are normal. Urea and creatinine are often raised and elevated unconjugated bilirubin and lactate dehydrogenase (LDH) and lowered haptoglobin reflect intravascular haemolysis.

Diagnostic difficulty occurs in atypical cases where not all features are present and if fragmentation is limited and difficult to see on the blood film. Blood cultures, anticardiolipin antibodies, rheumatoid factor, ANA, pregnancy test and stool for culture for E coli can identify specific causes of TTP or similar syndromes.

Treatment should be instituted as soon as a diagnosis of TTP is suspected and specialist laboratories can assay ADAMTS-13 protease activity and for the presence of anti-ADAMTS-13 antibodies. Continuous clinical observation and ECG are required to monitor the development and progression of cerebral and cardiac disease. As with many uncommon conditions, thinking of the possibility of the disease is vital to making a swift and accurate diagnosis.

Management
Management of TTP relies on plasma exchange and immunosuppression. Patients can deteriorate rapidly and frequently need intensive care. Neurological symptoms are of particular concern because cerebral disease can progress rapidly and become life-threatening. Plasma exchange should be instituted as soon as possible.

The efficacy of plasma exchange relies on not only replacing normal vWF but also removing pathogenic antibodies and high molecular weight multimers of vWF. If there are neurological symptoms, daily plasma exchange is given until the platelet count is stable and the exchanges can be gradually withdrawn.

Therapy is often delayed because finding a facility able to exchange at the weekend is sometimes problematic. If exchange is delayed, infusion of fresh frozen plasma can provide adequate interim treatment.

Immunosuppressive therapy can reduce synthesis of the abnormal antibodies and high-dose prednisone (1mg/kg) or IV methylprednisolone 1g is started as soon as possible, giving the first dose after plasma exchange. Red cell transfusion may be required if haemolysis has been marked.

A response to therapy is seen by symptomatic improvement, a rise in the platelet count and haemoglobin and a fall in markers of haemolysis (enzyme levels of the red cell enzyme LDH).

If the disease does not respond to therapy within a few days, the immunosuppression may be augmented by vincristine and, if necessary, rituximab. Parenteral therapy should clearly be timed to avoid immediate plasma exchange.

Prognosis and continuing care
TTP can be fatal but up to 80% of patients may survive with intensive treatment. Recovery can take a few days to many weeks of daily exchange, which is tapered as the disease activity is brought under control.

Patients require close follow-up after the initial treatment, including clinical review and FBCs to check for early signs of relapse. Late relapses after weeks, months or years are not uncommon.

A poor response may occur with aggressive autoimmune TTP but is more likely when TTP is associated with malignancy or post bone marrow transplantation.

Patient support
The disease places stress on patients and their family. Good communication and support are required to help the patient and family cope with the dramatic appearance of severe symptoms, the life-threatening disease, uncertainty surrounding response and the possibility of a relapse. A good network exists to support patients and their families.

  • Professor Roberts is a consultant haematologist at NHS Blood and Transplant and University of Oxford

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