acquired Thrombotic Thrombocytopenic Purpura (aTTP) is a rare blood-clotting disease that can be life threatening. It usually presents with an acute onset of symptoms, and it may have a severe disease course. Here we explore the characteristics of the condition; its underlying biology; the symptoms; who is affected; the risk factors and triggers; how a diagnosis is made; how the condition is treated and the long-term effects

What is aTTP?

aTTP is a rare blood disorder that causes blood clots in small blood vessels around your body. The name of the condition describes its four main characteristics:

acquired: Patients develop or “acquire” aTTP later in life, rather than having been born with it. The condition is not, therefore, passed onto any children. The condition’s newer name, immune-mediated TTP (iTTP), reflects how the condition is now known to be an autoimmune disorder. There is a hereditary form of the disease too, which is known as congenital TTP, inherited TTP or Upshaw-Schulman syndrome. However, the acquired form of the TTP accounts for 95% of TTP cases.

Thrombotic: this refers to microthrombi (small blood clots). Microscopically small, these form spontaneously inside blood vessels, blocking them and preventing blood circulation, putting the organs of the body at severe risk

Thrombocytopenic: this means the number of platelets in the blood has become low: they are being consumed during the formation of the microthrombi

Purpura: these are spots on the skin or in the mucous membranes, caused by bleeding from small blood vessels under the skin

aTTP was first described by Dr E Moschcowitz in 1924. The patient he described was a 16-year-old girl who had acute fever, severe anaemia, heart failure and stroke. She died after two weeks. A post-mortem found widespread microthrombi in her heart and kidney.

The underlying biology: the role of the enzyme ADAMTS13 in aTTP

When the body is cut or injured, platelets in the blood stick together to stop the bleeding. The platelets can do this because of a large protein called von Willebrand Factor (vWF). Normally, this large vWF protein is cut into smaller pieces by the enzyme ADAMTS13, but the immune systems of people with aTTP produce autoantibodies that block ADAMTS13 activity, preventing this process.

When ADAMTS13 is blocked, the vWF attracts platelets quickly so that microscopic blood clots (platelet microthrombi) form spontaneously, even though there is no bleeding. Furthermore, fewer platelets circulate in the blood due to platelet consumption in the microthrombi.

Haemolytic anaemia (a disorder where red blood cells are destroyed more quickly than they are made) can occur too. This is because red blood cells get damaged or fragmented when they are forced through blood vessels that are partially blocked by microthrombi. Blockages to the blood flow in the smallest vessels cause ischaemia (inadequate blood flow) to tissues, and this can result in organ damage.

What are the symptoms of aTTP?

aTTP has a highly variable set of symptoms, all caused by the extensive formation of microthrombi in the organs of the body, most commonly in the brain, the gastrointestinal system and the heart. 

General: tiredness, shortness of breath

Kidneys: dark urine

Skin: Red, purple or brownish-yellow bruises (purpura) from bleeding under the skin. Small red spots on the skin (petechiae) that may look like a rash, caused by blood leaking from blood vessels.

Nervous system: coma, stroke, seizure, confusion, disturbed vision

Heart: chest pain, heart attack

Digestive system: diarrhoea, stomach pain

Who is affected by aTTP?

aTTP is a rare condition with an incidence of two to six cases per million individuals.

• aTTP usually affects people who are 20–59 years old, but it can affect people of any age
• up to 75% of people affected by aTTP are women
• there is a seven-times greater incidence of aTTP in people with African heritage

Those living with a rare condition can find it difficult to access information and support. Support organisations and networks play a vital role in supporting individuals and families affected by aTTP.

What are the risk factors and triggers?

The risk factors for developing aTTP include obesity, African heritage and being female.

An aTTP episode may be caused by physiological triggers including inflammation, infections, pregnancy  or sepsis. It is important that women with aTTP who are pregnant or wish to become pregnant discuss this with their doctor as their health condition will need to be closely watched.

External triggers to an aTTP episode include surgery and certain medications (quinine, chemotherapy, cyclosporine A, clopidogrel and ticlopidine).

How is a diagnosis made?

aTTP usually presents with an acute onset of symptoms and may have a severe disease course. These symptoms can be caused by other conditions too, making a correct diagnosis difficult. This poses a significant challenge as aTTP is a life-threatening condition that must be treated urgently.

Patients may be affected by aTTP in many ways. The brain, gastrointestinal system and heart are the most commonly affected organs. Neurological symptoms can be present in 70–80% of cases: from paresis (muscular weakness), headache and confusion to stroke, coma and seizure.,

Clinical algorithms can be used to predict that there is a low level of ADAMTS13 activity. The most well-known algorithms are the Plasmic score and the French score. These are based on simple laboratory tests that can be performed in the emergency room, and they help the doctor decide to start treatment promptly.

Blood tests can support and confirm a diagnosis through:

• checking if the number of platelets and red blood cells in the blood is lower than it should be

• checking if organs are working properly, by checking the levels of certain chemicals in the blood (lactate dehydrogenase, creatinine, troponin)
• confirming the activity level of the ADAMTS13 enzyme

ADAMTS13 assays are necessary to confirm a diagnosis of aTTP, so a blood sample should be collected, ideally before treatment is started. Severe ADAMTS13 deficiency with activity levels below 10% and presence of anti-ADAMTS13 autoantibodies confirm a diagnosis. However, availability of ADAMTS13 assays is limited and turnaround times can be long. aTTP requires urgent management and it is not recommended to wait for ADAMTS13 assay results.

How is aTTP treated?

When people are first diagnosed with aTTP, they are typically treated in intensive care units within the first few days following aTTP diagnosis, or they may be highly dependent on specialist care for several weeks. The treatment will likely continue once the patient goes home. Currently the mainstay of treatment is ADAMTS13 replacement through plasma exchange (PEX) along with immunosuppression, but there is still a high mortality rate of 10–20%. 

Plasma exchange is the process of replacing the plasma in a patient’s blood with plasma donated by somebody else. Plasma exchange cleans the blood, removing components that patients have in excess (such as autoantibodies) and replacing components that are lacking, such as ADAMTS13 and platelets). The treatment usually takes a couple of hours each day and may need to be done for several consecutive days or weeks. In immunosuppression, medication is used to suppress the anti-ADAMTS13 antibodies.

What are the long-term effects of aTTP?

Unfortunately, an episode of aTTP can leave survivors with ongoing problems related to cognitive function, particularly impairment in learning, memory and attention. There is also the risk of renal insufficiency, stroke, severe headaches, depression, systemic lupus and obesity. Patients report that their health-related quality of life is lower after recovery from an episode of aTTP, and in particular, they report concerns with memory, concentration and physical endurance. The emotional impact of aTTP can be high and there is a high rate of post-traumatic stress disorder (PTSD) and depression in survivors.

aTTP is a lifelong condition: in one study that followed aTTP patients for up to 30 years, 84% experienced a recurrence. Regular check-ups are, therefore, vitally important. Testing may include monitoring the level of the ADAMTS13 enzyme and the number of platelets in the patient’s blood. Patients must contact their doctor if there are any new or reoccurring symptoms, so that treatment can start promptly.

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MAT-US-2205450-v1.0-09/2022

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