In this section you can find information about Aquired TTP and Congentital TTP.
Thrombotic Thrombocytopenic Purpura (TTP) is a rare blood disorder, that affects between 6 to 10 people in every million.
It is more common in women than men although it can affect people of all ages. Black African and Caribbean people are over-represented in TTP. The average age of diagnosis is 40 years.
TTP was first described in 1924 by Dr Eli Moschcowitz who had been treating a 16 year old female patient who was in a coma and had kidney failure. She died within 2 weeks. Moschcowitz described the characteristics of TTP based on his patient’s post mortem results. Survival rates have improved greatly since 1924. With accurate diagnosis and prompt treatment, current survival rates are approximately 80%.
TTP episodes are serious and life-threatening. It is considered a medical emergency and it is estimated that 10-20% of acute patients die from TTP, despite currently available treatments. TTP is a lifelong condition, as after their initial diagnosis many patients will experience further episodes of TTP (called relapses).
People with TTP have a deficiency of the enzyme that should break down the von Willebrand Factor, which, with platelets, normally prevents bleeding. This enzyme stops working properly and the platelets become sticky and form blood clots in small vessels that can affect any organ.
Thrombotic Thrombocytopenic Purpura (TTP) is known, in the majority of patients, as an autoimmune condition.
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The name thrombotic thrombocytopenic purpura actually describes three of the main features of the condition:
However, these three features only tell part of the story of TTP.
To fully understand how TTP affects the body, we first need to look in more detail at some of the components of blood. With TTP, we are interested in three components in particular:
Doctors will look for low platelet and low haemoglobin count.
The following tests are done as a matter of routine when treating a TTP Patient:
Symptoms can be very variable and may be a common complaint such as flu-like, tiredness; but patients may report having some of the following symptoms prior to diagnosis:
A patient with Acquired TTP will have a trigger that sets off the TTP episode. If you have acquired TTP you will have been susceptible for some (as yet unknown) reason to getting the condition, and the trigger will have brought on the episode of TTP. Here are some known triggers:
However, in most patients with acquired TTP, they have no obvious triggering factor. TTP affects both male and females, 2/3rds of patients are females and all age groups although it is most commonly seen in the 3rd and 4th decade. The best-known treatment for TTP is plasma exchange therapy. Whole platelets should not be given to a TTP patient as this effectively feeds the disease.
More commonly, people aren’t born with faulty genes but instead develop TTP at some point later in their lives.This is called Acquired TTP or immune-mediated TTP. In Acquired TTP, the body’s immune system starts producing antibodies that stop ADAMTS13 from working. Acquired TTP accounts for around 95% of all cases of TTP.
*image with thanks to https://thewaitingroom.karger.com/tell-me-about/types-and-symptoms-of-thrombotic-thrombocytopenic-purpura-ttp/
People with congenital (also called Inherited) TTP are born with the condition. It remains with them throughout their life. There is a mistake in the gene that tells the body how to make the enzyme ADAMST13, therefore, the ADAMST13 is missing. It affects males and females equally, and the condition is inherited from parents where each parent has half of the nonworking gene. The parents will not have the condition themselves as they only have half of the nonworking gene.
Congenital TTP is even rarer than the acquired form. As of 2007, there are approximately 15 cases in the UK. Symptoms of a patient (baby or small child) with congenital TTP include:
Like Acquired TTP, it is not clear what triggers congenital TTP in all patients – some patients show the signs and symptoms at birth while others do not show them until adulthood. As with Acquired TTP, there are certain factors, such as pregnancy or infection, that seem to play a role in triggering inherited TTP.
*image with thanks to https://thewaitingroom.karger.com/tell-me-about/types-and-symptoms-of-thrombotic-thrombocytopenic-purpura-ttp/
In this section we talk about different treatments for TTP.
To the right you can see a button which will take you to the British Society for Haematology Guidelines for treating TTP.
Plasma exchange is started when TTP is suspected and will be done by a specially trained apheresis nurse. A small thin tube is inserted into a large vein in the leg or neck by a doctor. This allows blood to flow into the plasma exchange (apheresis) machine. The blood is then separated into liquid plasma and blood cells and the plasma is replaced with healthy donated plasma. The donated plasma is screened and treated to minimise risk of any infection. The donated plasma will have Adamts13 which will replace the enzyme missing in TTP.Plasma exchanges are performed daily until the platelet count is back to normal, and each exchange takes around 3-5 hours.Sometimes people can have an allergic reaction to the plasma, this can be mild e.g a rash or very rarely a more severe reaction which medications can be given to reverse. There can also be a sensitivity to the anticoagulant used which can lower calcium. Calcium is given throughout the procedure to reduce the risk of this and if it occurs more can be given to reverse the effects. It can also cause low blood pressure leading to dizziness which is why plasma exchange is performed at the bedside.By replacing the missing Adamts13 and washing out the antibody attacking it this is a fast way of preventing the little clots forming (microthrombi) which are causing the damage in TTP
Caplacizumab is a small injection into the fatty layer just under the skin (sub cutaneous) given once per day. It is started as soon as acute TTP is confirmed, the first dose may be given through a cannula into a vein.
Capla stops the little clots that happen in acute TTP from forming by stopping platelets clumping together. Because the platelets are unable to clump it helps the platelet count normalise much faster than if capla was not used. This reduces the number of days plasma exchange is needed.
Because capla interferes with one of the clotting factors (von Willebrand) there is an increased risk of bleeding and heavy periods. Very rarely there may be a rash at the injection site, so dose may be changed or antihistamine can be given.
While in hospital the nurses will give the injection, however it is continued for a few weeks post episode so it is normally self-administered or administered by a family member or friend. If this is not an option a district nurse will be arranged to attend daily to administer the capla injection.
Steroids can be given as a tablet or intravenously (through a cannula into the vein) and are started when acute TTP is diagnosed. They are used in the short term as they suppress the immune system quickly, as other medications that suppress the immune system can take longer. The aim is to stop the steroids within a few weeks however this as always will depend on response to treatment.
Side effects are relatively common and can include changes in mood, sleep disruption, indigestion and stomach pains. Medication will be given to protect the stomach while on steroids. Being on steroids long term can cause osteoporosis (thinning of the bones) and weight gain. Blood sugar can also be affected, these will be monitored. Diabetic medication may need to be adjusted during this time.
However blood sugars usually settle once stopping the medication.
Steroids work quickly to suppress the immune system to prevent the making of the antibody attacking the ADAMTS 13.
Rituximab is a long infusion (a drip that goes through a cannula inserted into a vein). It is used during acute TTP episodes when someone is diagnosed or has relapsed TTP and is also used as elective treatment to prevent a relapse.
During an acute episode between, 4 to 6 rituximab infusions are given, with doses given closer together during acute admission if plasma exchanges are ongoing (as this can wash some of the medication out). The initial infusions will be given as an inpatient in hospital, however the course can be completed as an outpatient and Rituximab is given in an infusion bay, normally where chemotherapy is given, although Rituximab is not a chemotherapy, but an antibody therapy.
TTP is monitored lifelong, and around 50% of people will require treatment at some point again. If the ADAMTS 13 level goes down, this will be picked up in clinic and Rituximab will be given electively. This will happen as a planned, non emergency treatment and will be given weekly for four weeks in the outpatient department.
Rituximab binds to a type of white blood cell called a B cell to stop it producing antibodies that cause TTP.
The most common side effects of Rituximab are usually during the first infusion. These can be flu like symptoms including raised temperature, skin rashes or itching, aches and chills. This is why the first dose is given very slowly, and medication is given before the infusion is started to prevent side effects. If they still occur more can be given, normally steroids and antihistamines. Less commonly people experience joint pains in between infusions, a reduction in neutrophils (white cells) that can increase the risk of infection. There is a very rare side effect, called PML (progressive multifocal leukoencephalopathy). There is no cure for this and it occurs because the immune system is low and reactivates a virus in the brain. It has been rarely associated with other immune conditions but not TTP.
Obinutuzumab is an alternative to Rituximab if for some reason Rituximab is not an appropriate option. It is used electively, to prevent acute TTP, if a good response has not been achieved or if you are allergic to Rituximab.
It is given in an outpatient setting once a week, up to 4 doses. It is also a long infusion, given through the vein, the first dose is split over two days very slowly, the subsequent doses are given in one infusion.
The side effects are similar to Rituximab.
MMF is in tablet form and taken daily, the dose is adjusted depending on weight and response. It would be prescribed when ADAMTS 13 levels stay persistently low after having a full course of rituximab.
Once started it can take up to 4-6 weeks to see a response and if effective can be prescribed indefinitely.
MMF is an immunosuppressive medication, which works by reducing white blood cells called B and T cells, and used to further dampen down the immune system to prevent the antibody attacking Adamts13.
Side effects are more normal in the first few weeks of starting MMF and then tend to subside, but can include headaches, abdominal disturbances including nausea.
Velcade is occasionally used to help dampen down the immune system and reduce the antibodies against ADAMTS13. It is usually given as a weekly injection into the tummy just under the skin (subcutaneous). Usually up to four doses may be given. Most people do not experience any side effects of velcade during their TTP treatment as a small dose is used.
However side effects can include, low blood pressure causing dizziness, abdominal issues such as diarrhoea or constipation.
It works by reducing a specific type of white blood cells called a B cell which create the antibody causing the TTP. So by reducing the number of B cells the hope is fewer antibodies will be made to the ADAMTS 13 enzyme.
Plasma replacement therapy is used in congenital TTP (cTTP) , because the body does not make enough of the enzyme ADAMTS 13 (unlike in immune TTP where the body has created an antibody to it and is destroying it). In cTTP, no immunosuppression is used and instead patients will have plasma infusions every 1-2 weeks. In the UK we use Octaplas, which is similar to fresh frozen plasma, but has been processed to prevent infections and reduce reactions. Both are blood products.
Plasma infusion is not the same as a plasma exchange. A needle is inserted into the vein and 600-1000mls of plasma are given over one to two hours. Plasma infusion replaces the missing enzyme ADAMTS 13. The volume and frequency of plasma infusions will be decided on weight and symptoms.
Sometimes people can have an allergic reaction to the plasma, this can be a mild reaction like a rash or very rarely a more severe reaction which requires medications can be given to reverse. Depending on the severity of the reaction an antihistamine can be given or very rarely the infusion would need to be stopped.
Recombinant ADAMTS13 is the missing enzyme in TTP but made as a pure enzyme, not involving blood donations. It is being developed for congenital TTP.
It is a powder that is mixed with a small volume of water and given over 3-5 minutes into a vein. It increases the ADAMST13 levels to a higher lever than with plasma infusion.
The trial was looking for the two potential adverse reactions listed below, with really positive results for both so far:
1. Infusion reactions – none reported
2. Developing antibodies to the protein Adamst13 – none found
The benefit of this new treatment is to reduce acute TTP episode’s and also improve symptoms in cTTP.
