What does good care look like during aTTP remission?
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. The survival rates for patients with aTTP have radically improved over the last three decades. Here, Dr Chaturvedi gives an overview of the emerging challenges around long-term care for people who are in remission after an acute episode of the disease
The prognosis of patients with aTTP was transformed in 1991 when clinical trials of plasma exchange for patients showed that this treatment improves survival rates to over 90% from 10%. So, from being considered an acute and fatal condition, aTTP is now thought of as a chronic relapsing disorder.
Different papers give different figures for the risk of a patient relapsing: “anything between 30% and 50% depending on which you read; I think it’s more likely closer to 50%”, Dr Chaturvedi says. Most relapses occur within the first two years or so but can happen at any time. “The more intensive immunosuppression has probably pushed relapses further back, but in some patients there’s a wearing-off effect of these medications and relapses can occur more than a few years from the first episode.”
Monitoring people after an acute episode is critical in trying to prevent relapses. A patient is in clinical remission if 30 days have passed since stopping therapy and the platelet count has not dropped and there are no new symptoms of aTTP. If the ADAMTS13 activity has also recovered, the patient is in clinical and ADAMTS13 remission, “which is really where you want to be”, Dr Chaturvedi says.
Immunosuppressive therapies to prevent relapse
“Once a patient is in remission, we have clinical visits roughly every three months as well as doing blood work, which includes a blood count to look at the platelet count, and testing ADAMTS13 activity levels. Most people also recommend testing LDH levels (higher levels of the LDH enzyme are found in the blood when tissues in the body are damaged). I like to look at a blood smear, but not every treating physician does them all the time.”
If ADAMTS13 activity is tested regularly, trends can be monitored so that doctors can intervene before an acute episode. “If levels start approaching 20% or lower, our practice is to have a discussion with the patient to offer immunosuppressive medications, explaining that they give a good chance of preventing relapse. Most patients prefer to prevent relapse and avoid dealing with a relapse, even though there is a slightly increased risk of infection associated with the immunosuppressive medications.”
Despite current standard of care with immunosuppression and plasma exchange, 10-20% of patients develop refractoriness to treatment. When the ADAMTS13 levels have fallen in people who are refractory, that creates a more challenging situation in terms of treatment options. Low levels suggest a high risk of relapse but there is no guarantee that a relapse will happen, so the benefits of preventive treatment have to be weighed against the risks.
If somebody has already had one relapse, this person is at a risk for additional relapses. “In those situations, we will often use other immunosuppressive medications, trying to minimise toxicity and maximise benefit.
For people who have relapse after relapse, for whom nothing is working, there is the option to remove the spleen. “This is actually quite effective, but it is a very significant surgery with long-term consequences, so that decision is not taken lightly,” Dr Chaturvedi says.
The adverse consequences that may arise after an acute episode of aTTP
In addition to relapse, people with aTTP are at risk of multiple adverse consequences after an acute episode, including issues with mental health and cardiovascular disease.
An acute episode of aTTP is a life-threatening and traumatic experience: “Conceivably, someone may show up in the emergency room with vague symptoms—maybe a mini stroke—and be told ‘You have a life-threatening disorder, and if I don’t place a large line in your neck right now and exchange your entire body plasma for several days, you will die’.
“Among aTTP survivors, there is a high rate of anxiety, depressive symptoms and symptoms similar to post-traumatic stress disorder. An admission to an intensive care unit is quite traumatic, and it takes a while for people to recover from that.”
Coping with that experience may be a considerable challenge for people and symptoms of anxiety and depression can be compounded by the health issues associated with aTTP and by a feeling of isolation. “Because it’s such a rare disease, the person’s friends and family, and sometimes even their physicians won’t really understand what they’re going through.”
People with aTTP report trouble getting back to their previous level of functioning, not only because of symptoms such as fatigue, but also because of what they call “brain fog”. “Up to 45 to 50% of patients with aTTP report difficulties in terms of concentration. For example, they say ‘I have to try twice as hard to focus on schoolwork’, ‘I don’t know where I leave my keys’ or ‘I forget a phone number I heard just a few moments ago.’” (This data comes from a long-term study of neuropsychological consequences of aTTP in Italy of 35 patients.)
Testing has confirmed that aTTP survivors have cognitive deficits, particularly in terms of processing speed, working memory and executive function—the abilities that help us go about day-to-day life. So, doctors now realise this is a problem but do not yet fully understand why it happens. “Ongoing research suggests it may be because of strokes that occur during an aTTP episode, or even during remission if ADAMTS13 very low.”
Dr Chaturvedi says that occupational therapy can help people overcome some of these issues, and “some people with aTTP develop workarounds to overcome these issues themselves, such as writing things down or working in short blocks of time that work for them”.
People who have survived aTTP may also face cardiovascular health issues. There is a higher risk of stroke in someone who has survived aTTP and a higher risk of events such as heart attacks as well. “There is something about having aTTP that lead to earlier events of this type—up to one or two decades earlier than for someone without the condition. So, we’re talking about strokes and heart attacks in people in their 40s, 50s and early 60s, whereas in the general population, these tend to mostly occur in the 60s and 70s.”
There are probably many risk factors for cardiovascular disease (heart attack, stroke and aging of the blood vessels) for people living with aTTP. Among these are the following:
Cardiovascular health is, therefore, a significant problem for the aTTP community. Researchers are beginning to work out the best interventions to protect people with aTTP from cardiovascular disease, but Dr Chaturvedi emphasises the importance of simple strategies in the meantime. “At the very least, I think standard cardiovascular prevention is advisable, which means screening for high cholesterol and high blood pressure. And if these things are present, then it is important to treat them well”
”The challenge facing aTTP doctors and researchers is that having recognised this very large problem, do we wait to do a study where we give half the people aspirin and half not? Or do we just do what seems to be right and give everyone that treatment because the risk of side effects is low?”
Guidelines for the diagnosis and treatment of aTTP for somebody in remission
Although there are guidelines for diagnosis and treatment during an episode of aTTP, there are no formal guidelines about what to do for somebody who is in remission.
“The truth is that we do not have great evidence to guide us in terms of what to do if we find these problems. There is certainly guidance, if not guidelines, in terms of how to monitor to prevent relapse, but we’re not at the point where we have formal guidelines about how frequently to monitor people for these longer-term effects related to cognition and cardiovascular disease, and what to do if there are signs of these problems.”
There has recently been an update in the response criteria from the International Working Group (IWG) for TTP, Dr Chaturvedi explains. The IWG criteria now state that having an ADAMTS13 activity level that is lower than 20% is considered an “ADAMTS13 relapse”, and clinicians may consider immunosuppression to reduce the risk of clinical relapse.
Dr Chaturvedi looks forward to more research over the new few years that gives doctors a better understanding of managing other risks for aTTP patients in remission while preventing relapse.
aTTP is most common in females and it affects females of childbearing age who may have pregnancies after the diagnosis. Since pregnancy may trigger episodes of aTTP, women with a history of aTTP are at high risk for recurrence. They also have higher rates of other complications, such as preeclampsia.
The risk of relapse for a woman whose ADAMTS13 level has been normalised before pregnancy is quite low. But if the pregnancy is unplanned and ADAMTS13 levels fall below 25%, there is a higher risk of relapse and miscarriage, so regular monitoring of ADAMTS13 level is advisable.
Women may be monitored by a multidisciplinary team that includes a high-risk obstetrician as well as a haematologist.
“This doesn’t mean that women with aTTP can never have babies; it just means that they need closer monitoring and optimisation before they get pregnant.”
MAT-XU-2205561 – MAT-US-2205832-v2.0-11/2022
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