What it TTP?

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What is thrombotic thrombocytopenic purpura?
What Causes TTP?
Adult-onset TTP
What Triggers Adult-onset TTP?
What are the Symptoms?
How is it Diagnosed?
What Treatment is Available?
Poorly responding (refractory) disease
What is the Likely Outcome?

Congenital (inherited) TTP

Congenital TTP is even rarer than adult-onset TTP with only a few cases reported worldwide. The first episode of haemolysis (red cell breakdown) and thrombocytopenia usually occurs during infancy or early childhood. A child may be jaundiced and pale or complain of headache or abdominal pain. Nervous system symptoms, fever and kidney impairment can develop exactly like the adult forms.

Without preventive treatment, episodes typically recur every 21 to 28 days. However, milder cases are described in which symptoms only appear to develop in the context of a viral infection or after vaccination.

Congenital TTP may not be diagnosed immediately because at present, like adult-onset TTP, there is no single diagnostic test. However, the finding of ultra-large forms of vWF in the blood during periods of remission does support the diagnosis. Blood tests can also exclude other more common causes of haemolytic anaemia and thrombocytopenia.

Unlike the adult form of TTP, the congenital type appears to be secondary to an absolute deficiency of vWF-cleaving protease enzyme activity. There is no circulating inhibitory antibody, so plasma exchange is not required. A simple plasma infusion through an intravenous drip effectively averts symptomatic episodes. In severe cases these need to be administered in hospital every three to four weeks. Overnight admission is not required.

Milder cases may not require prophylaxis if episodes occur very infrequently. Instead, plasma infusions can be reserved for symptomatic episodes. However any symptomatic episode requires admission to hospital to ensure that that no additional treatment is required. Like the adult form, platelet transfusions should NOT be given.

All children with congenital TTP should receive hepatitis B vaccination due to their inevitable exposure to multiple donors.

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 (Plavix), oral contraceptive pills, quinine and ciclosporin (Neoral). 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.

Systemic lupus erythematosus (SLE)

A minority of patients with SLE (an inflammatory connective tissue disease) may also develop TTP. Usually the episode of TTP follows the diagnosis of SLE by some years but it can sometimes precede it. Screening tests for SLE may therefore be performed.

Malignancy

Cancer of any type may be complicated by TTP. TTP can also occur after bone marrow or peripheral stem cell transplantation. Total body irradiation and ciclosporin are recognised risk factors.

What are the symptoms?

The symptoms of TTP may at first be subtle - starting with malaise, fever, headache and sometimes diarrhoea. As the condition progresses clots (thrombi) form within blood vessels and platelets (clotting cells) are consumed. Bruising, and rarely bleeding, results and may be spontaneous. The bruising often takes the form of purpura while the most common site of bleeding, if it occurs, is from the nose or gums. Larger bruises (ecchymoses) may also develop.

Clots formed within the circulation can temporarily disrupt local blood supply. TTP preferentially affects the blood vessels of the brain and kidneys. Thus a patient may experience headache, confusion, difficulty speaking, transient paralysis, numbness or even fits whilst high blood pressure (hypertension) may be found on examination.

Fragmentation of circulating red blood cells accompanies the formation of platelet clots. These are evident if a blood sample is examined under a microscope. Such fragmented red cells have a much shorter life span than normal and are quickly removed from the circulation. This is known as microangiopathic haemolysis. If the rate of red cell destruction is greater than their rate of replacement, anaemia follows. Symptoms of anaemia include pallor, tiredness and shortness of breath. If red cell destruction (haemolysis) is severe, jaundice may develop and urine can turn red or brown.

Not all patients develop these symptoms. Some experience less common symptoms such as abdominal pain or sudden loss of vision due to detachment of the retina.

How is it diagnosed?

There is currently no specific routine test to confirm the diagnosis of TTP. Instead the diagnosis is made on the basis of symptoms and blood tests such as a blood count, blood film (see above), renal function and markers of haemolysis. Other more common causes of an acute illness with low platelets (thrombocytopenia) must also be excluded.

What treatment is available?

Treatment of TTP requires specialist care and may require transfer to a regional hospital.

Plasma exchange is the most important component of treatment for TTP. Plasma exchange involves the removal of a patient's plasma and its replacement by donor plasma. This removes circulating antibody against vWF cleaving protease and provides plasma with normal vWF-cleaving protease activity. The procedure usually needs to be performed daily for at least five days to be effective. Sometimes many more procedures are required.

Plasma exchange is not a surgical procedure. It requires only the placement of two intravenous lines (cannulae) into two separate veins. Blood is removed through one cannula, which is attached to a cell separator machine.

This contains a centrifuge, which separates the patient's blood cells from their own plasma. The patient's blood cells are then mixed with donor plasma and returned via the second cannula to the patient, while the patient's own plasma is discarded.

Although plasma exchange is not painful it may be slightly uncomfortable and is time consuming, lasting about three hours. There may be minor side effects, including:

• allergic reaction to donor plasma (rash or wheeze)

• tingling of fingers or around mouth caused by low calcium levels (due to the added anticoagulant in plasma).

Other initial treatment

• Corticosteroids (steroids) are used in combination with plasma exchange. Their immunosuppressive effects are thought to be important. Steroids may be given either intravenously or orally. They have a number of side effects (see thrombocytopenia).
  
  
• Red cell transfusion: regular blood transfusions will be given as required to treat anaemia.
  
  
• Folic acid is a vitamin required for healthy formation of red cells. The body cannot store large amounts of this vitamin and, in circumstances of excessive red cell production like TTP, folic acid deficiency can develop relatively quickly. Daily supplements are therefore given to prevent this.
  
  
• Platelet transfusions: the platelet count may fall extremely low in TTP. However, platelets are NOT usually replaced by transfusion, as this may actually increase the severity of TTP. However, if there is life threatening bleeding then platelets may be given.
  
  
• Hepatitis B vaccination. Plasma exchange requires multiple blood donors. Although UK blood is extremely safe because donors are carefully screened and tested for infection, there is still a small risk of acquiring disease. Hepatitis B vaccination should be given as soon as it is practical.
  
  
• Aspirin (eg Micropyrin) is an anti-platelet agent and may be commenced when the platelet count rises above a threshold of 50 x 109/L to minimise future relapse (see below).

Poorly responding (refractory) disease

The majority of people with TTP respond to the above first-line treatment. However, a minority remain refractory and increased treatment is required. At present there is no uniformly accepted second-line treatment and a number of different approaches may be used.

Alternative plasma replacement

The initial study demonstrating the effectiveness of plasma exchange in treating TTP used fresh frozen plasma for replacement and achieved remission rates of about 80 per cent. There have been reports of better results by using plasma from which large amounts of the clotting proteins factor VIII and fibrinogen have been removed or by using solvent-detergent treated plasma. However, this has not yet been fully confirmed.

Vincristine

Vincristine (eg Oncovin) is a chemotherapy drug that may be helpful in the treatment of TTP. It is thought to be effective either through a direct effect on platelets or by altering the way in which the lining cells of the blood vessels interact with the immune system. A small dose is given intravenously once every three to four days. Four doses are usually given in total. Although it is a chemotherapy agent, nausea and alopecia (hair loss) is extremely rare. Side effects include interference with the function of the nerves ('peripheral neuropathy'), which commonly presents as tingling or numbness of the fingertips and fades with time. If severe, withdrawal of treatment is required.

Splenectomy

Splenectomy (surgical removal of the spleen) has been proposed as treatment for refractory disease. However, the severity of TTP has sometimes worsened after surgery, so this operation should not be undertaken lightly. Splenectomy may have a role to play in those patients with frequently relapsing disease. Relapse rates have been reported to fall significantly when the operation is performed during haematological remission, but this data comes from only a small number of patients.

Immunosuppression

A variety of immunosuppressive drugs have been used in the treatment of refractrory TTP including azathioprine (eg Imuran), cyclophosphamide (eg Endoxana) and ciclosporin (Neoral).

Azathioprine

Azathioprine, which works by suppressing the body's immune response has occasionally been used in the treatment of refractory TTP. Once-daily oral dosage is required. Since the drug may have toxic effects on the bone marrow, weekly blood counts need to be taken in the first eight weeks of treatment. Patients are advised to seek medical advice if they develop symptoms of infection or recurrent bruising or bleeding. Other side effects include malaise and muscle and joint pains. Cyclophosphamide and, increasingly, ciclosporin are now often used in preference.

 

Cyclophosphamide

Like vincristine, cyclophosphamide is most commonly used in cancer treatment. It cannot therefore be used during pregnancy and may have a detrimental effect on fertility. However, it also has immunosuppressive effects and has been used in the treatment of refractory TTP - although it is more often used in cases of recurrent relapse. Both daily dosing and pulsed therapy have proved effective, although the reported numbers of cases are low. Its side effects include bone marrow suppression (which can lead to anaemia or an increased susceptibility to infection) so regular blood counts are necessary throughout treatment.

 

Ciclosporin

Although ciclosporin has been associated with a TTP-like illness following bone marrow transplant (see above), it has also been reported to be beneficial in the treatment of refractory TTP. This is thought to be secondary to its strong immunosuppressive actions. Ciclosporin may first be given intravenously but is later given orally twice daily as maintenance treatment. It requires careful monitoring to minimise side effects which include kidney impairment, high blood pressure, increased body hair, gum overgrowth and a burning sensation of the hands and feet which usually occurs only in the first week of treatment. Prolonged treatment (more than 12 months) may be required before the drug is gradually discontinued.

 

What is the likely outcome?

Until relatively recently the outlook of TTP was extremely grave with mortality rates in excess of 80 per cent. However with the advent of plasma exchange this has improved dramatically and survival rates are now approximately 80 per cent.

Although the majority of adult patients will only ever have one episode of TTP, a significant minority have further episodes. One study estimated that over a 10-year period from the initial presentation about a third of patients would have at least one relapse. This could occur up to eight years after the initial episode. At present there is no way to identify those at risk of relapse. Some doctors recommend long-term prophylaxis (preventative measures), with low dose aspirin (75mg once daily) once the platelet count rises above a threshold of 50 x 109/L. In one small study splenectomy was shown to reduce the risk of relapse, so this could be considered if a patient suffers multiple relapses.

Since TTP may recur it is important that all patients remain under the care of a haematologist. Medical attention should be sought immediately if symptoms or signs of TTP recur because prompt treatment may shorten the duration of a relapse.