Thrombotic thrombocytopenic purpura (TTP)

Written by Dr Sarah Allford, research registrar and Professor Samuel Machin, professor of haematology



For a full description of platelets and the causes and effects of a low platelet count see the factsheet on thrombocytopenia.

What is thrombotic thrombocytopenic purpura?

Thrombotic thrombocytopenic purpura (TTP) is a rare blood condition characterised by the formation of small clots (thrombi) within the circulation, which results in the consumption of platelets and thus a low platelet count (thrombocytopenia).

What causes TTP?

Until recently the cause of TTP remained elusive. However, recent research points to the involvement of a protein in the plasma called von Willebrand factor (vWF).

vWF is a normal component of plasma, the straw-coloured fluid in which blood cells are suspended. It is required for effective blood clotting, and deficiency results in von Willebrand's disease, an inherited condition characterised by excessive bleeding.

Von Willebrand factor (vWF) is an extremely large molecule composed of identical subunits (multimers). Each multimer is able to bind to platelets or damaged endothelium (lining of blood vessels) at the site of an injury. The greater the number of multimers, the more effective is the binding.

Ultra-large molecules of the factor (ULvWF) are therefore especially sticky but are not usually found circulating in the blood. Instead, they are normally broken down to slightly smaller sizes, so vWF retains its adhesive properties without binding inappropriately to platelets and causing undesired clots.

In TTP, vWF is synthesised normally, initially as ULvWF but its subsequent break down (cleavage) is defective. This is due to a lack of enzyme activity, called vWF cleaving protease, that breaks down von Willebrand factor in the blood. This deficiency may be inherited (genetic), in which case it will be revealed in childhood or it can be acquired later in life.

Most adult-onset TTP appears to be secondary to the development of an antibody that inhibits this enzyme activity, whereas the childhood form is due to a simple reduction in enzyme activity. Both mechanisms result in the presence of ultra-large von Willebrand factor within the circulation.

Circulating ULvWF leads to the inappropriate formation of platelet clumps (thrombi) particularly within blood vessels supplying the brain and kidneys. These give rise to the typical symptoms of TTP.

Adult-onset TTP

TTP is an extremely rare condition. The adult form affects 1-3 per million per year while the inherited form is rarer still. Anyone can develop TTP but it is most common among 20-40 year olds. Women are also twice as likely as men to acquire the condition.

What triggers adult-onset TTP?

Most often, TTP seems to develop spontaneously. However, in a small number of cases (less than 20 per cent) there are factors present that are known to increase the risk of TTP.

Drugs Several drugs are linked to TTP. However, only a small percentage of patients taking these drugs actually develop TTP. The drugs implicated to date include the anti-platelet drug clopidogrel, oral contraceptive pills, quinine and ciclosporin. If you are taking any one of these drugs at the time of diagnosis it will be stopped.

Pregnancy

TTP can develop at any time during pregnancy but in one study was shown to be most likely during the second trimester. TTP does not affect the foetus. TTP can occur in late pregnancy or even after the birth and as it can also cause high blood pressure TTP can sometimes be hard to distinguish from eclampsia.

Infections

Patients may initially have symptoms suggestive of a viral infection - fever, malaise and diarrhoea - before florid TTP symptoms develop. Certain infections have been associated including HIV. Some strains of E.coli result in haemolytic uraemic syndrome but not TTP.

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