Congenital TTP (inherited thrombotic thrombocytopenic purpura): symptoms, diagnosis and treatment

Thrombotic thrombocytopenic purpura, usually shortened to TTP, is a rare blood disorder. The name describes three of its features: thrombotic means clots forming inside blood vessels, thrombocytopenic means a lower than normal number of platelets, and purpura means purple bruising caused by bleeding under the skin.

The TTP Network, a patient-led UK charity, explains that the underlying problem is the ADAMTS13 enzyme. This enzyme normally breaks down von Willebrand factor, a protein that works with platelets to prevent bleeding. When the enzyme is missing or not working properly, platelets become sticky and form clots in small vessels, which can affect any organ. Platelets are used up, and red blood cells are damaged as they pass through the partly blocked vessels.

There are two main forms. In acquired TTP, which the TTP Network says accounts for around 95% of cases, the immune system makes antibodies that stop ADAMTS13 working. In congenital TTP, sometimes called Upshaw-Schulman syndrome, the body never makes a working enzyme because of an inherited gene change. That difference matters because the treatment is not the same.

The TTP Network lists the signs of congenital TTP in a baby or small child as jaundice, a low platelet count, anaemia, tummy upset, fever and a red pinprick rash (petechiae) or purpura. An exchange transfusion using whole blood may be needed for jaundice in a newborn.

Not everyone is affected at birth. The charity says that some people show signs and symptoms at birth while others do not show them until adulthood, and that factors such as pregnancy or infection seem to play a role in triggering inherited TTP in some people. Between episodes a person may feel well, which is one reason the diagnosis can be delayed.

For TTP in general, the TTP Network says symptoms can be very variable. They may look like a common complaint, such as flu-like tiredness, and can include the following.

• Headaches and confusion.

• Anxiety and stomach upset.

• Fever.

• Disturbed vision.

• Stroke-like symptoms such as trouble speaking or loss of balance.

• Bruises or small red or purple dots on the skin.

A flare of TTP is an emergency because small clots can damage the brain, kidneys and heart. Sudden stroke-like symptoms, new confusion, severe headache, fits or collapse need a 999 call, whether or not a person has a known diagnosis.

Someone already known to have congenital TTP should follow the plan agreed with their specialist centre. In practice that normally means contacting the haematology team promptly if headache, unusual tiredness, fever, dark urine, new bruising or a pinprick rash appear, rather than waiting to see whether things settle. If you cannot reach the team, NHS 111 or A&E can help, and carrying a letter that explains the diagnosis is sensible.

The TTP Network says whole platelets should not be given to a person with TTP because this can effectively feed the disease. This is a reason to make sure any emergency team knows the diagnosis early.

Congenital TTP is caused by changes in the gene that carries the instructions for making ADAMTS13. The condition is recessive: a child is affected when they inherit a non-working copy from each parent. The TTP Network explains that each parent has half of the non-working gene and does not have the condition themselves, so there is often no family history.

Because the condition is inherited, there is nothing a person or parent did to cause it, and it cannot be caught from someone else. Families may be offered genetic counselling through the NHS genetics service so that the implications for relatives and future pregnancies can be explained.

The TTP Network lists the tests done as a matter of routine when TTP is suspected: a full blood count for platelets and haemoglobin, an ADAMTS13 test that measures the level and activity of the enzyme, a reticulocyte count, a clotting screen, kidney and liver function, LDH (a marker of tissue breakdown), a viral screen, blood group and a pregnancy test.

The ADAMTS13 result is the key test. It is usually very low in TTP. To tell congenital from acquired TTP, specialists look for antibodies against the enzyme and consider the pattern of the illness, the age at which it began and the family history. Genetic testing can then confirm the gene change. The TTP Network says the diagnosis is made and managed through specialist centres: since 2022 NHS England has commissioned 9 regional specialist centres for TTP, across 11 hospital sites, and every patient with a diagnosis should be linked to one.

In congenital TTP the body does not make enough enzyme, so treatment replaces it. The TTP Network describes plasma infusions given every 1 to 2 weeks. In the UK the plasma product used is Octaplas, which is similar to fresh frozen plasma but processed to prevent infections and reduce reactions. A needle is placed in a vein and 600 to 1000 ml of plasma is given over one to two hours, with the volume and frequency decided by weight and symptoms.

Plasma infusion is not the same as plasma exchange, which is used in acute acquired TTP. Allergic reactions to plasma can happen, most often a mild rash, and are very rarely severe; antihistamines can be given or the infusion paused.

The charity also describes recombinant ADAMTS13, which is the missing enzyme produced as a pure protein rather than from blood donations. It is given as a powder mixed with a small volume of water and injected over 3 to 5 minutes into a vein. The TTP Network describes it as being developed for congenital TTP. NICE technology appraisal TA667 on caplacizumab, by contrast, covers acute acquired TTP, so it is not a standard treatment for the congenital form.

Congenital TTP is lifelong, and care is built around keeping enzyme levels high enough to prevent flares and being ready to treat quickly if one starts. The TTP Network says that pregnancy is a known trigger for TTP and the TTP Network lists research papers on TTP in pregnancy among its resources. Anyone planning a pregnancy should speak to their specialist team early so that a joint plan can be made.

Practical steps include keeping a written summary of the diagnosis, the specialist centre contact and the usual plasma dose; telling dentists and surgeons; and being aware that infection can act as a trigger. The TTP Network offers a travel letter explaining the diagnosis that has been translated into many languages, and runs peer support and psychological practitioner networks.

Because congenital TTP is so rare, treatment in the UK is concentrated in a small number of NHS specialist haematology centres, and plasma products are normally given through those services. Private haematology consultations may be used for a second opinion or for local follow-up, but anyone with TTP should remain linked to an NHS specialist centre so that emergency access and enzyme monitoring are not interrupted.