Thrombotic thrombocytopenic purpura (TTP)

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Thrombotic thrombocytopenic purpura (TTP)

Written by Dr Allford, research registrar and Professor

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 anti-platelet drugs (ticlopidine and

clopidogrel), oral contraceptive pill, 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.

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 (see Figure 1).

A blood film from a patient with TTP showing relatively minor

changes. Platelets are severely reduced and there are occasional red

cell fragments (arrowed).

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 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 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, cyclophosphamide and

ciclosporin.

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.

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.

Alternative names:

Moschcowitz's disease; TTP

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Definition:

A disorder of the blood characterized by low platelets, low red blood

cell count (caused by premature breakdown of the cells), and

neurological abnormalities.

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Causes, incidence, and risk factors:

This disease is seen most commonly in adults from 20 to 50 years old,

with women affected slightly more often than men. Purpura refers to

the characteristic bleeding that occurs beneath the skin, or in mucus

membranes, which produces bruises, or a red rash-like appearance. A

similar condition in children is hemolytic-uremic syndrome.

The disease may be precipitated by the use of estrogen or by

pregnancy. It is frequently preceded by a viral infection. It is also

associated with HIV infection. The neurological symptoms associated

with this disease may vary over several minutes and include

headaches, confusion, speech changes, and alterations in

consciousness, which vary from lethargy to coma. People may be very

ill with this disorder, and kidney abnormalities may develop. The

cause of the disease is unknown, but it is thought to be caused by

the development of antibodies. Risk factors are being between 20 and

50 years old, recent estrogen use or pregnancy, and HIV infection.

The incidence is 4 out of 100,000 people.

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Prevention:

Because the specific cause is unknown, specific prevention is also

unknown.

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Symptoms:

fever

weakness

easy fatigue

pallor

shortness of breath on exertion

heart rate over 100 per minute

bleeding into the skin or mucus membranes, purpura

headache

confusion

speech changes

alterations in consciousness

yellowish color to the skin (jaundice)

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Signs and tests:

platelet count, decreased

CBC showing anemia

bilirubin, elevated

peripheral blood smear showing schistocytes and fragmented blood

cells

gum biopsy revealing thrombotic thrombocytopenic purpura

urinalysis showing protein or microscopic blood

CHEM 20 showing elevated creatinine level

mucus membrane biopsy revealing platelet thrombi in small blood

vessels

This disease may also alter the results of platelet associated

antibodies test.

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Treatment:

Plasmapheresis, or plasma exchange, is used to remove unwanted

substances from the blood (antigen antibody complexes). Blood is

withdrawn from the patient as for a blood donation. Then the plasma

portion of the blood is passed through a cell separator. The

remaining portion of the blood is saved, reconstituted with a plasma

substitute, and returned to the patient as a blood transfusion. In

thrombotic thrombocytopenic purpura, this treatment is repeated daily

until blood tests show improvement. People who do not respond to this

treatment, or have frequent recurrences, may require the removal of

the spleen.

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Expectations (prognosis):

Plasmapheresis has improved the outcome of this disease so that 80 to

90% of patients now recover completely; however, fatalities still

occur. With relapses, the remaining cases become chronic.

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Complications:

renal impairment (renal failure)

hemorrhage

stroke