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What does good care look like during an acute episode of aTTP?

Dr Chaturvedi is an associate professor of medicine at Johns Hopkins University. She specialises in the care of adults with thrombotic microangiopathy, particularly aTTP. Her research is focused on improving long-term outcomes of people living with aTTP. Here, Dr Chaturvedi gives an overview of the challenges around diagnosing and treating people during an acute episode of aTTP. She gives her insights into best practice in terms of treatment and discusses the current unmet needs

acute episode of aTTP

The challenges around diagnosing an acute episode of aTTP

Dr Chaturvedi is quick to highlight the exceptionally high stakes involved in diagnosing aTTP quickly: “Diagnosing promptly is critical: if aTTP is untreated, over 90% of people with it may die. Even if it is not fatal, a delay in diagnosis and starting treatment can increase the chance of long-term consequences such as a stroke.”

Unfortunately, there are many challenges that can lead to a delay in diagnosis. Not least is the fact that aTTP is a rare disease that only affects about two to six in a million people, so many doctors have never seen it before.

A second challenge is that aTTP was originally thought to be associated with a group (or pentad) of five signs and symptoms, but not many patients have all five. The pentad consists of low platelets, microangiopathic haemolytic anaemia (anaemia with red cell fragments on the blood smear), kidney problems, fever and neurologic problems. Most patients present with other symptoms, perhaps a headache, abdominal discomfort or great tiredness. Because they are non-specific, such symptoms can slow the diagnostic process.

A third challenge is that older patients present with less typical symptoms, delaying diagnosis in a group already at risk of more negative outcome.

The confirmatory test for aTTP is testing the patient’s blood to see if ADAMTS13 activity level is below 10%. Few hospitals can do this test in their own labs but sending blood samples out to a central lab can slow a diagnosis down by several days.

If ADAMTS13 testing is not immediately available, there are tools to support doctors in deciding whether a patient should have plasma exchange. The French score and the PLASMIC score are the most used of these tools and they can be used in the emergency room on the day of admission. The French score looks at platelet counts and serum creatinine counts to help doctors decide whether to begin treatment for aTTP. The PLASMIC score has additional parameters including excluding conditions such as cancer, chemotherapy and stem cell transplant that can cause a TTP-like disorder (that is not the same as aTTP and is treated differently).

There are also rapid tests to measure ADAMTS13 activity that have recently been developed that require the use of specific analytical platforms. These may be set up at the point of care, potentially giving hospitals another useful diagnostic tool. These may improve time to diagnosis, although they are not yet widely available.

acute episode of aTTP

The challenges in starting treatment for an acute episode of aTTP

Because aTTP is so serious, delaying treatment until diagnosis is confirmed can be extremely dangerous. If aTTP is suspected, treatment must be started immediately.

“For a patient who’s presenting with low platelets, which is otherwise unexplained; has anaemia, or a haemoglobin level of approximately 10 grams/decilitre or less; and if the blood smear shows schistocytes (red cell fragments) for which there is no other obvious cause, you can suspect aTTP and start treating the patient as if they have aTTP—with therapies to reduce or stop excessive blood clot formation and suppress or remove the harmful antibodies. Early treatment with these therapies can prevent organ damage that is caused by blockages in the small blood vessels and may avoid death and other complications.”

There are three major challenges in terms of starting treatment, once a diagnosis is either made or suspected.

First a therapy called plasma exchange which replaces the liquid part of the blood in an effort to control excessive clotting, requires a blood bank and trained nurses or technicians on site. Therefore the patient may need to be sent elsewhere before treatment can start. “At some centres in the United States, this service may be contracted out to a third party, which may add to the delay,” Dr Chaturvedi adds.

The second problem with starting treatment is that plasma exchange requires placement of a central line or catheter (a tube placed into a large vein). “Someone with aTTP comes in with really low platelets, so a lot of doctors are worried about placing a catheter because of the potential risk of bleeding due to the procedure. In truth, the risk of bleeding with aTTP is much lower than in other conditions with very low platelets and the risk of bleeding is quite low with an experienced operator,” Dr Chaturvedi explains.

Finally, if doctors are not familiar with the diagnosis and treatment of aTTP, they may be reluctant to start treatment for it. In particular, they may be cautious about starting the patient on newer treatments, such as targeted therapies to potentially stop excessive  clotting in the small blood vessels and/or targeted immunosuppression.

acute episode of aTTP

Best practice when treatment for an acute episode begins

Targeted immunosuppression

As well as starting treatments  to supress excessive  clot formation along with steroids for immunosuppression, as soon as aTTP is suspected, the ISTH guidelines suggest that doctors should consider treating the patient with targeted immunosuppression treatment that suppresses B cells (a type of white blood cell) that produce antibodies that may cause aTTP  “By giving it during the first episode, we reduce the risk of relapse. In my experience, it can also reduce the duration of steroid therapy, which comes with significant side effects, and helps to get them off other treatments faster,” Dr Chaturvedi says.

Other treatment considerations

There are some other things that doctors should remember when treating patients with aTTP, Dr Chaturvedi explains.

Doctors should start patients on preventative doses of blood thinners to prevent blood clots once the patient’s platelet count starts to recover: “Patients with aTTP present with low platelets, but there is still a fairly high risk that there might be blood clots. This is something that is often forgotten.”

Furthermore, people on high-dose steroids for long periods may need an antacid to protect their stomachs, and an antibiotic to prevent pneumocystis pneumonia, a fungal infection of the lungs that can be a side effect of high-dose steroids. Steroids may also affect blood pressure and blood sugar, so it is important that someone monitors those and for treatment to be given if needed.

acute episode of aTTP

Current unmet needs in the management of acute episodes of aTTP

Unmet needs: therapies

Some patients are either unwilling or unable to receive plasma. Jehovah’s Witnesses, for example, have religious reasons for not wanting plasma exchange. Dr Chaturvedi has also seen a few patients who cannot tolerate donor plasma at all because it contains components that could cause patient’s immune system to react: “they have severe allergic reactions regardless of what we do”. Although plasma-free treatment to supress clotting has been done and may become more widely used in the future, it is currently considered experimental.

Refractoriness is when a patient’s body does not respond to treatment as expected, and this can also be a problem when treating aTTP. Dr Chaturvedi explains: “The most common type of refractoriness is during an acute aTTP episode when the platelet count does not come up or comes up a little bit and does not recover fully because platelets are being consumed in persistent  clotting.  Targeted therapies can potentially address this, however they are not yet universally available/accessible.

On the other hand, Dr Chaturvedi explains that some people do not respond well to the usual immunosuppressive medications used for aTTP— and the ADAMTS13 activity does not improve, even if the platelet count has recovered. This is a problem because the risk of relapse and other complications is much higher for patients who do not achieve ADAMTS13 remission: “We have no standard treatment for them. We try one immunosuppressive medication after the other and hope something will work. Finding the best second- or third-line immunosuppression is important, particularly in people who have already had relapses.”

Dr Chaturvedi says various immunosuppressive drugs are used to treat aTTP but, apart from anti-CD20 therapies, there is no robust evidence for how well they work. Gathering such evidence is, therefore, another unmet need.

Unmet needs: predicting relapse

A further unmet need is for there to be better tools to predict relapse in patients when they present for the first time:

There are things that doctors can look at to help predict relapse: patients who are younger, male, or have African heritage, for example, and above all ADAMTS13 activity during remission. The lower that is, the higher the risk of relapse—to the point that if it is in the range of 20% or lower, doctors will consider preventative immunosuppression to bring that number up and prevent a relapse.

“We don’t have great tools for identifying someone in the hospital and saying your risk of relapse is close to zero or your risk of relapse is more than 10 to 20%, for instance. If we had that information, we might potentially tailor treatments, such as giving more intensive immunosuppression only to someone who’s at higher risk of relapse.

Right now, we may be treating some patients with additional  immunosuppression drugs needlessly, because they will never go into relapse. The risk of these treatments is low, and the potential benefit in terms of preventing an episode is high enough that we take that risk. But in a perfect world, we would only treat the patients who needed it.”

Dr Chaturvedi hopes that research may uncover biomarkers (a substance in the body that doctors can measure) that could help clarify which patients are most likely to relapse, so resolving this important unmet need. Such research needs to be collaborative, so that researchers can have access to larger cohorts of patients than is normally the case.


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