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Immune TTP: Management following recovery from an acute episode and during remission

Immune TTP: Management following recovery from an acute episode and during remission
Authors:
James N George, MD
Adam Cuker, MD, MS
Section Editor:
Lawrence LK Leung, MD
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Dec 2022. | This topic last updated: Aug 23, 2022.

INTRODUCTION — Most patients (over 90 percent) with acquired autoimmune thrombotic thrombocytopenic purpura due to an autoantibody against ADAMTS13 (referred to as immune TTP) ultimately recover following treatment.

However, relapse remains an important concern. Therefore, all patients who have recovered from an episode of TTP require lifelong monitoring and rapid intervention at the first sign of a relapse, and some may benefit from prophylactic immunosuppressive treatment (rituximab) during remission. Additionally, patients require continued surveillance for a variety of important long-term health problems related to TTP.

This topic review discusses our approach to the management of a patient who has recovered from an acute episode of immune TTP, including routine monitoring, evaluation for symptoms of relapse, prophylaxis to prevent relapse, and management of long-term morbidities.

Separate topic reviews discuss other aspects of care for patients with immune TTP:

Diagnosis – (See "Diagnosis of immune TTP".)

Treatment of an acute episode – (See "Immune TTP: Initial treatment".)

Treatment of an acute episode during pregnancy – (See "Immune TTP: Initial treatment", section on 'Immune TTP during pregnancy'.)

Treatment of refractory or relapsed disease – (See "Immune TTP: Treatment of clinical relapse".)

Pathophysiology – (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)

Hereditary TTP (due to biallelic variants in the ADAMTS13 gene) is also discussed separately. (See "Hereditary thrombotic thrombocytopenic purpura (TTP)".)

TERMINOLOGY AND RESPONSE CRITERIA — We distinguish between acquired and hereditary TTP:

Immune TTP – Immune TTP is an acquired disorder due to autoantibodies directed against the von Willebrand factor-cleaving protease ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13). The diagnosis is confirmed by ADAMTS13 activity <10 percent with a demonstrable ADAMTS13 inhibitor and/or recovery of ADAMTS13 activity during remission. A few patients will have ADAMTS13 activity ≥10 percent at the time of their initial presentation. (See "Diagnosis of immune TTP".)

Hereditary TTP – Hereditary TTP is TTP due to biallelic pathogenic variants in the ADAMTS13 gene, associated with ADAMTS13 activity <10 percent without a demonstrable inhibitor (autoantibody) and the persistence of severe ADAMTS13 deficiency during remission. (See "Hereditary thrombotic thrombocytopenic purpura (TTP)".)

Other TMAs – Other thrombotic microangiopathies (TMAs) that are not associated with severe ADAMTS13 deficiency, such as drug-induced TMA, are not considered TTP, and the outcome definitions described below do not apply to them. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Overview of primary TMA syndromes'.)

We use the following definitions for outcomes following therapeutic plasma exchange (TPE) and other therapies [1]; these are summarized in the table (table 1) and described here:

Clinical response – Sustained platelet count ≥150,000/microL (eg, for at least two consecutive days), lactate dehydrogenase (LDH) <1.5 times the upper limit of normal for the assay, and no evidence of new or progressive ischemic organ injury. A plateau of the platelet count at a safe level (typically >100,000/microL) for two to three days may be considered as a response if the patient has another etiology for persistent mild thrombocytopenia.

Clinical remission – Sustained clinical response for ≥30 days after stopping TPE and/or caplacizumab -or- ADAMTS13 remission (partial or complete), whichever comes first.

ADAMTS13 remission

Partial ADAMTS13 remission – ADAMTS13 activity ≥20 percent but below the lower limit of normal for the assay.

Complete ADAMTS13 remission – ADAMTS13 activity above the lower limit of normal for the assay.

Clinical exacerbation – Decrease in the platelet count to <150,000/microL that occurs after a clinical response but within the first 30 days after stopping therapy (TPE or caplacizumab) and is not due to other causes of thrombocytopenia. Progressive or new organ injury may also occur but is not required to diagnose a clinical exacerbation. Exacerbations are expected to decrease with routine use of rituximab and incorporation of caplacizumab into initial therapy.

Clinical relapse – After a clinical remission, a platelet count decrease to <150,000/microL that is not due to another cause of thrombocytopenia. A clinical relapse must be confirmed by documentation of severe ADAMTS13 deficiency (activity <10 percent). Progressive or new organ injury may also occur but is not required to diagnose a clinical relapse.

ADAMTS13 relapse – After an ADAMTS13 remission (partial or complete), a decrease in ADAMTS13 activity to <20 percent.

Refractory disease – Clinical evidence of TTP (thrombocytopenia, high LDH, or progressive or new ischemic organ injury) that does not respond to initial treatment. This is becoming rare due to the routine incorporation of rituximab and in some cases us of caplacizumab as initial therapy. If a patient has persistent thrombocytopenia, high LDH, or progressive or new ischemic injury despite caplacizumab, it is important to confirm the initial diagnosis of TTP and to look for explanations other than TTP such as sepsis or drug-induced thrombocytopenia.

Any clinical exacerbation or relapse requires immediate hospitalization and initiation of treatment with TPE, glucocorticoids, and other medical therapy. (See "Immune TTP: Treatment of clinical relapse".)

MONITORING AND THERAPY AFTER RESPONSE TO TREATMENT

Overview of monitoring and risk of relapse — Once the patient has recovered from the acute episode of TTP, monitoring helps guide tapering of therapy and identification of biochemical and clinical relapses, as discussed below and illustrated in the figure (algorithm 1):

Monitoring for signs of clinical relapse – TTP is a rare condition. Patients, families, and caregivers must educate themselves about the possible symptoms of a relapse and the importance of seeking medical care immediately for a suspected relapse.

Symptoms and complete blood count (CBC) are evaluated frequently during the initial recovery period for the purpose of detecting a clinical exacerbation or relapse (table 2). For individuals receiving caplacizumab, a normal platelet count may suggest that TTP disease activity has declined when in fact it has not; if there is concern about relapse, other parameters including ADAMTS13 activity increase in importance.

Clinical relapse is suggested when the platelet count decreases to <150,000/microL or if symptoms suggestive of active TTP occur, such as any neurologic abnormalities. Symptoms heralding a relapse may be extremely variable and may include nonspecific symptoms (symptoms of anemia, gastrointestinal upset, neurologic changes ranging from headache or confusion to focal abnormalities). We expect that clinical relapse frequency will decrease over time with greater routine use of rituximab for treatment of initial episodes and preemptive rituximab for ADAMTS13 relapse during clinical remission.

Monitoring ADAMTS13 activity – ADAMTS13 activity is monitored after therapeutic plasma exchange (TPE) has been discontinued (table 2). An ADAMTS13 relapse (ADAMTS13 activity <20 percent) suggests an increased risk of clinical relapse, and we generally initiate preemptive rituximab if the ADAMTS13 activity decreases to <20 percent, as discussed below. (See 'Rituximab during remission to prevent relapse' below.)

Any patient with a history of immune TTP whose platelet count decreased to <100,000/microL requires immediate hospitalization, urgent additional diagnostic evaluation, and immediate initiation of TPE if the results of the evaluation are consistent with clinical relapse (algorithm 2). Management is generally similar to the initial episode. The diagnostic evaluation and management of relapse are discussed separately. (See "Immune TTP: Treatment of clinical relapse", section on 'Clinical relapse'.)

First week — Most exacerbations of TTP occur during the first week after stopping TPE or the week after stopping caplacizumab. We use the following sequence during the end of the hospitalization and initial days at home (table 2):

Stop TPE – When there is a clinical response, indicated by a normal platelet count for two days or a stable plateau platelet count in the normal or supranormal range for three days, TPE is stopped and immunosuppressive therapy is continued as outlined below. The patient usually can be discharged from the hospital. (See 'Rituximab during remission to prevent relapse' below.)

Daily CBC – We continue to obtain a CBC and monitor the platelet count. Initially this is done daily and gradually extended to every two to three days. We also check the lactate dehydrogenase (LDH) at the time of CBC. In some patients, the platelet count may exceed the baseline and then decrease or fluctuate before stabilizing in the patient's normal range. We do not check ADAMTS13 activity during the first week unless there are clinical or laboratory features suggesting clinical relapse.

Typically, exacerbation is characterized by a sharp decrease of the platelet count within the first week, which often occurs without any associated symptoms of TTP. If the platelet count decreases to <150,000/microL but not less than 100,000/microL and the patient has no TTP symptoms, daily monitoring alone may be appropriate, as some patients will subsequently have a spontaneous recovery of the platelet count back to the normal range.

Clinical status – We monitor the clinical status daily. We provide our patients with a wallet card (form 1) that explains the condition, provides our contact information, and emphasizes that any symptoms consistent with TTP call for an immediate CBC with platelet count and triage to a physician who can assess the possibility of relapse. (See 'Monitoring for clinical relapse' below.)

Central venous catheter - Previously, we would sometimes discharge the patient with the central venous catheter (CVC) in place for an additional two to three days to facilitate reinitiation of TPE if needed for a disease exacerbation. However, this is no longer routine practice, as CVCs increase the risk for infection, including sepsis, and we anticipate exacerbations will no longer be a concern in individuals treated with rituximab and in some cases caplacizumab.

Glucocorticoids – We continue the glucocorticoids during the first week. If the platelet count is stable or increasing, we start to taper glucocorticoids during the second week. (See 'First month' below.)

Rituximab – We continue the initial course of weekly rituximab (if started at the time of the acute event). We generally use the conventional regimen of 375 mg/m2 once per week for four weeks. There is no evidence or experience that this is the optimal rituximab regimen for patients with TTP; lower doses and/or fewer doses of rituximab may be equally effective. (See "Immune TTP: Initial treatment", section on 'Rituximab'.)

Based on our experience, approximately half of individuals who did not receive rituximab during initial therapy may have a recurrence (exacerbation or clinical relapse) [2]. Inclusion of rituximab as routine initial treatment together with TPE and glucocorticoids is likely to reduce these early recurrences.

First month — Monitoring intervals are extended and therapies are gradually discontinued as follows (table 2):

Clinical status and CBC – Clinical status is monitored on an ongoing basis. The interval of CBC and platelet count monitoring is increased to once weekly and then to every other week. Some individuals may have a platelet count that exceeds their baseline and then decreases or fluctuates before stabilizing in the patient's normal range. Once the platelet count has been maintained in the normal range for one month after discontinuing TPE or caplacizumab, we are confident that a durable remission has occurred. (See 'Monitoring for clinical relapse' below.)

If the serum creatinine and/or LDH were abnormal at the time of hospital discharge, they are monitored until they become normal or another explanation for the abnormality is found. If the serum creatinine and LDH were normal at the time of hospital discharge, they do not require continued monitoring. The hemoglobin concentration generally will recover more slowly, and schistocytes may also persist for a few weeks and do not affect management.

Glucocorticoids and rituximab – For individuals who have a normal (or increasing) platelet count following the first week, we taper and discontinue the glucocorticoids rapidly, over two to three weeks. In our experience, a shorter glucocorticoid taper reduces adverse effects and does not increase relapses. For those who were started on rituximab at the time of the acute event, we continue and complete the course of rituximab during the first month.

ADAMTS13 activity – We measure ADAMTS13 activity one week after TPE was stopped and weekly during the first month. If ADAMTS13 activity does not recover (remains <20 percent), we continue caplacizumab. If activity is >20 percent, we extend the monitoring interval to once per month, followed by once every two months, followed by once every three months (see 'First year and beyond' below). An exception is an individual who lacks an ADAMTS13 inhibitor; such individuals may be evaluated for hereditary TTP. (See "Hereditary thrombotic thrombocytopenic purpura (TTP)", section on 'When to suspect the diagnosis'.)

We believe that ADAMTS13 activity of 20 to 60 percent indicates protection from relapse but requires more frequent monitoring. When ADAMTS13 activity is normal (>60 percent [or above the lower limit of normal for the assay]), we begin to measure it less frequently.

Caplacizumab – For individuals started on caplacizumab at the time of the acute event, we continue the caplacizumab until the ADAMTS13 activity recovers to >20 percent, indicating ADAMTS13 remission and low risk for an exacerbation. We discontinue caplacizumab when the ADAMTS13 activity is >20 percent for two consecutive measurements, which we perform ≤1 week apart.

First year and beyond — Monitoring intervals are extended further and TTP therapies have been discontinued (table 2); rituximab retreatment may be appropriate if ADAMTS13 activity declines to <20 percent (ADAMTS13 relapse).

Clinical - Clinical relapses are identified quickly when the patient pays close attention to their symptoms and their clinician (or emergency department personnel) address any potential symptoms of relapse promptly with a same-day evaluation including CBC with platelet count. It is important for the patient's hematologist and primary care clinician to collaborate closely. The hematologist must be accessible for any concerns about a relapse of TTP and must be prepared to ensure immediate hospitalization and treatment. (See 'Monitoring for clinical relapse' below.)

Laboratory – For individuals who remain asymptomatic, we monitor the ADAMTS13 activity as follows, with a routine CBC obtained at the time of ADAMTS13 measurements:

If and when the ADAMTS13 activity becomes normal (≥60 percent or above the lower limit of normal for the assay), we repeat the measurement one month later. If that measurement is also normal, we repeat the measurement at two months and then at three-month intervals for the first two years after remission, since relapse is most common in the first two years. If all of these measurements have been normal, we then repeat ADAMTS13 measurements once per year.

If the ADAMTS13 activity falls from normal to <40 percent, we resume monthly measurements; we are concerned that continued decreases elevate the risk for clinical relapse. Some patients who have had an extremely complicated acute episode, or multiple acute episodes, are followed more closely with ADAMTS13 activity measurements. If ADAMTS13 decreases to <20 percent, we discuss the use of preemptive rituximab for impending biochemical relapse, to reduce the risk of clinical relapse. (See 'Detecting and preventing relapse' below.)

If the ADAMTS13 activity is 40 to 60 percent (not normal but probably safely above risk for relapse) we measure activity at three-month intervals to determine whether this mild deficiency is stable. Mild deficiencies or low-normal values may predict a risk for thrombotic events other than TTP, such as stroke and cardiovascular disease [3]. (See 'Hypertension, cardiovascular disease, and stroke' below.)

DETECTING AND PREVENTING RELAPSE

Natural history of ADAMTS13 activity during remission — Observational data illustrate the natural history of ADAMTS13 activity during remission:

One of us (JNG) has followed patients with annual measurement of ADAMTS13 activity since 2004 [4]. During this time (until 2017), patients were not treated with rituximab during remission to prevent relapse. The most remarkable observation from this follow-up is that ADAMTS13 activity can vary from undetectable to normal without treatment in the same patient across time.

A French observational study of 233 patients who were followed for a year or more following an acute episode of immune TTP identified 48 (20 percent) who had ADAMTS13 activity <10 percent during clinical remission [5]. Among these, 30 were treated with "preemptive" rituximab with the goal of preventing a subsequent relapse; 18 were not treated with rituximab due to different management practices at different institutions. Although there were limitations to the data such as different length of observation, it appeared that relapse-free survival was longer in the rituximab-treated patients (median relapse-free survival was 9.3 years in the untreated patients and was not reached in the treated patients; p = 0.049).

These data from two different registries of patients document that 20 to 30 percent of patients will have ADAMTS13 activity <10 percent (ADAMTS13 relapse) after recovery, which is associated with a greater risk for clinical relapse However, clinical relapse was far from imminent; median relapse-free survival following observation of ADAMTS13 activity <10 percent in the two cohorts was five and nine years, respectively.

We incorporate these data into our thinking about treatment during remission, although we recognize that practices may differ. (See 'Rituximab during remission to prevent relapse' below.)

Monitoring for clinical relapse — Some patients with acquired TTP do not experience a relapse, and the use of rituximab as routine initial treatment is likely to make relapses less frequent [6]. (See "Immune TTP: Treatment of clinical relapse", section on 'Risk of clinical relapse'.)

However, it is important to appreciate that any illness, surgery, or major trauma may trigger a relapse. Relapse can also occur with no apparent triggering event. Pregnancy is a special consideration because the risk for preeclampsia is increased along with the risk for TTP relapse. (See 'Pregnancy after an episode of TTP' below.)

Clinical relapses become less likely as time passes, but in our experience, a first relapse may occur years later. As an example, a patient in our practice had a clinical relapse 16 years after treatment (the longest interval in our experience).

Clinical relapses are generally identified because the patient develops symptoms similar to their initial episode such as bruising, dark urine, neurologic symptoms, or unexplained severe fatigue; it is very rare to discover a clinical relapse from a routine CBC in an asymptomatic patient. Thus, optimal care for the patient in remission requires an appropriate degree of attention to symptoms on the part of the patient, family members, caregivers, and all clinicians involved in the patient's care. Any new symptoms require prompt complete blood count (CBC) with platelet count and immediate interventions for thrombocytopenia. (See "Immune TTP: Treatment of clinical relapse", section on 'Clinical relapse'.)

Patient – The patient must be responsible to seek medical attention immediately for any signs or symptoms of any illness, such as fever, abdominal pain, gastrointestinal symptoms, bruising, dark urine, neurologic symptoms, severe headache, or unexplained fatigue. The patient must insist on having a CBC with platelet count, even if symptoms seem minor; this may be facilitated by the use of a card that can be shown to emergency department personnel (form 1). If a patient moves to a different city, they should establish care with a new hematologist. (See "Immune TTP: Treatment of clinical relapse", section on 'Clinical relapse'.)

Family/caregivers – Family members and caregivers are also informed about the potential symptoms of relapse and the importance of obtaining a CBC with platelet count and reviewing results on the same day they were obtained. These individuals can help determine if there has been a change from baseline and may help advocate for the patient and provide needed support.

Primary care clinicians – The patient's primary care clinician typically begins to see the patient after the first month, together with the hematologist. All clinicians involved in the patient's care must be aware that the patient has a history of TTP and is at risk for relapse.

It is especially important not to attribute minor symptoms such as nonspecific symptoms of tiredness, fatigue, and/or gastrointestinal upset to a viral illness and not to adopt a "watch and wait" approach for a patient with a history of TTP who has these symptoms. Unlike those in the general population, for an individual with a history of TTP, these symptoms must be managed as the possible initial evidence of a clinical relapse. (See "Immune TTP: Treatment of clinical relapse", section on 'Clinical relapse'.)

During the first year, the patient's primary clinician may also begin to manage the sequelae of TTP, such as minor cognitive impairment, major depression, and hypertension. (See 'Evaluation for complications of TTP' below.)

Hematologist – During the first year, it is appropriate for the hematologist to see the patient at intervals of several months. Initial visits may focus on assessing for longer-term complications of the disease (eg, depression) or the treatment (eg, glucocorticoid- or rituximab-induced immunosuppression) as well as reviewing possible symptoms of relapse. (See 'Evaluation for complications of TTP' below.)

The hematologist may be called upon to facilitate rapid hospitalization and therapy if a clinical relapse occurs. (See "Immune TTP: Treatment of clinical relapse", section on 'Clinical relapse'.)

Because the risk for relapse persists for many years, we recommend that the hematologist continue to see patients indefinitely. After the first year, we continue to follow our patients in clinical remission at least annually. Patients should know how to contact their hematologist or hematologist practice at all times.

Laboratory results – The results of the CBC must be available promptly (on the same day) to ensure that if thrombocytopenia is discovered, immediate evaluation for a clinical TTP relapse is undertaken. Many urgent care facilities and physician offices only receive laboratory results on the following day. For a patient with a history of TTP and suspected clinical relapse, this is not adequate, because new thrombocytopenia is a medical emergency that may require immediate reinstitution of TPE.

To facilitate these steps, we provide our patients with a letter and wallet card (form 1) that explain the diagnosis and required urgency of testing to share with any new clinician, as many clinicians are unfamiliar with TTP and may not accept a patient's explanation.

Rituximab during remission to prevent relapse — Emerging data suggest that preemptive rituximab in patients with ADAMTS13 relapse (decrease in ADAMTS13 activity to <20 percent) leads to reduced rates of clinical relapse.

This has led most experts and guidelines, including 2020 guidelines from the International Society on Thrombosis and Haemostasis (ISTH), to suggest preemptive (prophylactic) rituximab for individuals with an ADAMTS13 relapse [7].

Based on our clinical experience and that of our colleagues, we suggest the following approach, with patient values and preferences as an important consideration in decisions regarding the aggressiveness of monitoring and prophylactic therapy:

If the ADAMTS13 activity is <20 percent, we treat with a single dose of rituximab (375 mg/m2), and then we recheck the ADAMTS13 activity in one month. If the ADAMTS13 activity remains <40 percent, we complete the empirical conventional regimen by giving three additional doses of rituximab (375 mg/m2 per dose; one dose per week). If the ADAMTS13 activity still remains <40 percent, we follow the patient at monthly intervals without further treatment. The possibility of hereditary TTP, although unlikely, may be considered. (See "Hereditary thrombotic thrombocytopenic purpura (TTP)", section on 'Epidemiology'.)

If a patient has had multiple relapses of TTP and also has continuous ADAMTS13 activity <10 percent during remission, we may use maintenance rituximab, such as one infusion of 375 mg/m2 every three months for two to three years. In two of our patients (who have had four and seven relapses of TTP, respectively) who had persistent ADAMTS13 activity <10 percent during remission in spite of rituximab treatment for relapses, this has resulted in sustained normal ADAMTS13 activity and a durable remission for at least one to two years after rituximab was stopped (with observation ongoing) [8].

In patients with multiple relapses who do not have an ADAMTS13 response to maintenance rituximab, especially those with a history of frequent or severe episodes, we discuss treatment with splenectomy or other immunosuppressive agents. (See "Immune TTP: Treatment of clinical relapse", section on 'Clinical relapse' and "Immune TTP: Treatment of clinical relapse", section on 'Refractory disease'.)

The benefit of preemptive rituximab was demonstrated in a series from the French Thrombotic Microangiopathies Reference Center that evaluated outcomes in 92 individuals who had recovered from an episode of immune TTP and were followed for at least a year [9]. Some of the patients had received rituximab at the time of the acute episode of TTP. Preemptive rituximab was given during remission when ADAMTS13 activity remained severely deficient (activity <10 percent) or became severely deficient during clinical remission. Compared with a historical group of 23 people with TTP who had severe ADAMTS13 deficiency and did not receive rituximab, those who received preemptive rituximab for severe ADAMTS13 deficiency had fewer relapses (74 percent during a median follow-up of seven years in controls versus 15 percent during a follow-up period of approximately three years with rituximab treatment).

Despite the potential benefit of rituximab in reducing relapses, data on long-term efficacy and toxicity remain limited, and patient values and preferences substantially influence our practice. Those who place a high value on avoiding relapse may have more frequent ADAMTS13 activity measurements and more aggressive treatment to prevent relapse. Those who place a high value on avoiding treatment and its potential toxicities may choose to monitor symptoms and/or platelet counts rather than receive treatment for asymptomatic decreases in ADAMTS13.

The optimal dose and schedule of preemptive rituximab has not been determined; it is uncertain whether the conventional regimen used for hematologic malignancies [375 mg/m2/week for four weeks] is required or whether lower doses or shorter courses of therapy may be sufficient.

A study of 45 patients from the United Kingdom TTP Study Registry who were treated with rituximab during remission for a decline in ADAMTS13 activity (≤15 percent) compared outcomes with standard dosing (375 mg/m2 once per week for four weeks), reduced dosing (200 mg once per week for four weeks, not adjusted for body surface area [BSA]), and intermediate dosing (500 mg once per week for four weeks, not adjusted for BSA) [10]. The need for retreatment for ADAMTS13 relapse during the subsequent years of follow-up was not significantly different in the standard and reduced dosing groups (50 and 74 percent, respectively). There were no dose-based differences in the time to recovery of ADAMTS13 activity.

Some patients with rheumatologic disorders have received rituximab for several years and have tolerated the therapy without a major increase in adverse events compared with shorter durations of exposure [11]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

ROUTINE MEDICAL CARE DURING REMISSION

Vaccinations — Recurrent TTP has been observed following COVID-19 vaccination, leading to a suggestion to measure ADAMTS13 activity prior to any vaccination [12]. We measure ADAMTS13 activity prior to vaccination, treat with preemptive rituximab if ADAMTS13 activity is <20 percent (ADAMTS13 relapse), and wait at least six months after rituximab administration before providing vaccinations.

Rituximab or other immunosuppressive agents may blunt the immune response to vaccinations for at least six months [13]. Thus, we ensure that all appropriate vaccinations (figure 1 and figure 2) are updated approximately six months after the patient finishes the course of rituximab.

An exception is the influenza vaccination, which should be given at the appropriate time of year regardless of whether the patient is receiving rituximab. (See "Standard immunizations for nonpregnant adults".)

Individuals with a history of TTP should receive appropriate vaccinations for SARS-CoV-2 to prevent coronavirus disease 2019 (COVID-19). (See "COVID-19: Vaccines".)

Evaluation for complications of TTP — Long-term follow-up observations have documented increased risks for multiple health problems in individuals who have recovered from an episode of acquired TTP [14,15]. As a result, patients who have recovered from TTP require lifelong monitoring.

Hypertension, cardiovascular disease, and stroke — Patients who have recovered from TTP have an increased risk for hypertension [16]. Other cardiovascular risks are also increased. As an example, a long-term follow up study of 222 patients with immune TTP documented that cardiovascular disease-related mortality was as common as death from relapsed TTP (each accounting for 28 percent of deaths) [17]. Overall mortality was approximately two-fold greater than expected for age- and sex-matched controls and was highest in individuals with persistent ADAMTS13 deficiency during remission.

We have also observed patients who have developed stroke, cardiomyopathy and congestive heart failure, presumably as a result of previous diffuse microvascular thrombosis [15].We are more worried about the risk of cardiovascular disease in individuals with persistent ADAMTS13 deficiency.

Low ADAMTS13 activity during clinical remission appears to be a risk factor for stroke. In a study of 51 patients in clinical remission, 0 of 22 with complete ADAMTS13 remission (activity ≥70 percent) had a stroke, whereas stroke occurred in 8 of 29 patients (28 percent) with partial ADAMTS13 remission (activity between 20 and 70 percent) [18]. These findings raise the question of what can be done to reduce the risk of stroke in patients with partial ADAMTS13 remission.

Preemptive rituximab may be impractical in individuals with ADAMTS13 activity >20 percent. However, rituximab is often used for ADAMTS13 activity <20 percent. (See 'Rituximab during remission to prevent relapse' above.)

Prophylaxis with aspirin has been proposed and requires testing in a clinical trial [19].

In the absence of other proven interventions, we emphasize aggressive management of modifiable cardiovascular risk factors including control of blood pressure and lipid disorders and abstinence from smoking. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Management of hypertension, cardiovascular disease, and stroke is similar to the general population, as discussed separately. (See "Overview of hypertension in adults" and "Overview of secondary prevention of ischemic stroke" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Reduced kidney function — Severe acute kidney injury and advanced chronic kidney disease are rare in patients with acquired TTP [20]. However, many of our patients who have recovered from an episode of TTP have had microalbuminuria, which is associated with a greater risk for cardiovascular death [21]. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)

Depression — Major depression has occurred in 29 percent of patients who have recovered from an episode of acquired TTP [16,22]. The mechanism is not understood.

Depression is often not appreciated by patients and their family, as they may report their symptoms as fatigue and problems of memory and concentration. We screen patients annually for depression by a standard brief questionnaire such as the Patient Health Questionnaire (PHQ). Any version of the questionnaire with two to nine questions is appropriate. (See "Screening for depression in adults".)

Even when depression is diagnosed, patients may be reluctant to seek counseling or medication. The primary care clinician may need to become actively involved to assist the patient to receive appropriate care. (See "Unipolar minor depression in adults: Management" and "Unipolar major depression in adults: Choosing initial treatment".)

Minor cognitive impairment — Minor cognitive impairment has also been seen frequently in patients following recovery from an episode of TTP [22,23]. This has been a consistent topic of conversation at TTP support group meetings at the authors' centers [24,25]. Many patients state that they do not feel the same as they did before their episode of TTP. Almost all our patients have returned to their normal activities and professions; however, as a group, they perform less well than age- and education-matched controls. Some patients have more noticeable neurocognitive problems.

We test patients for cognitive function using a standard brief questionnaire such as the Montreal Cognitive Assessment (MoCA). (See "Evaluation of cognitive impairment and dementia".)

Management is individualized depending on the specific areas of impairment. Occupational therapy consultation may help patients who have problems that interfere with activities of daily living. (See "Mild cognitive impairment: Prognosis and treatment".)

SLE and other autoimmune disorders — The frequency of systemic lupus erythematosus (SLE) is significantly greater among patients with TTP, with an incidence as great as 11 percent in our experience [16,26]. SLE has been diagnosed prior to the initial episode of TTP, concurrently with the initial episode of TTP, and many years after recovery from TTP. At each evaluation, we evaluate for the cardinal clinical features of SLE, including malar rash, discoid rash, oral ulcers, sun sensitivity, and arthritis. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Evaluation'.)

The frequency of other autoimmune disorders is also increased [26]. In addition to the 10 (11 percent) of 90 patients in the Oklahoma Registry who have developed SLE, nine patients have had other autoimmune disorders; five of these 19 patients have developed multiple autoimmune disorders [27]. Four patients have developed Graves' disease; Addison's disease, ITP, and acquired factor VIII inhibitors have occurred in two patients each.

PREGNANCY AFTER AN EPISODE OF TTP — Most pregnancies following recovery from acquired TTP are uncomplicated [28,29]. However, we advise patients about the risks of relapse and preeclampsia and the need for more intensive monitoring [28].

Pregnancy in an individual who has recovered from acquired TTP must be followed closely; preferably they are co-managed by a hematologist and maternal-fetal medicine (MFM) expert or obstetrician with experience in managing high-risk pregnancies. As with nonpregnant individuals, the most important aspect of monitoring is close attention to symptoms of relapse from the patient, family members, and involved clinicians, with prompt (same-day) measurement of the platelet count if such symptoms occur.

Preconception – We obtain a complete blood count (CBC) and ADAMTS13 activity measurement prior to conception. If the ADAMTS13 activity level is low (eg, <20 percent), we suggest preemptive rituximab to raise the ADAMTS13 level prior to attempting pregnancy. If the ADAMTS13 activity remains <20 percent, we advise the patient of the increased risk of relapse during pregnancy, but we do not consider severe ADAMTS13 deficiency an absolute contraindication to pregnancy because the pregnancy may be uncomplicated.

Monitoring during pregnancy

CBC – A CBC including platelet count should be obtained at each prenatal visit and/or if there are symptoms suggestive of a clinical relapse. Pregnancy may be associated with a mild decrease in platelet count, but a decrease to <100,000/microL is very rare (<1 percent of uncomplicated pregnancies) [30]. Thus, any platelet count <100,000/microL in a pregnant woman with a history of TTP requires immediate evaluation. (See "Immune TTP: Treatment of clinical relapse", section on 'Clinical relapse' and "Thrombocytopenia in pregnancy".)

ADAMTS13 – We monitor ADAMTS13 activity during pregnancy; the frequency depends on how long ago the previous TTP episode occurred and subsequent ADAMTS13 activity levels during recovery. Knowledge of ADAMTS13 activity is helpful in interpreting symptoms such as fatigue and findings such as thrombocytopenia, which are common during pregnancy but may also herald a clinical relapse. We do not intervene preemptively for low ADAMTS13 activity (ADAMTS13 relapse) with therapeutic plasma exchange (TPE) or immunosuppressive therapy in the absence of symptoms and thrombocytopenia, as the maternal and fetal risks of preemptive therapy may outweigh potential benefits [28].

Blood pressure – Individuals with a history of acquired TTP are at greater risk for preeclampsia. In our analysis from the Oklahoma TTP-HUS Registry, 5 of the 13 pregnancies (38 percent) were complicated by preeclampsia, a frequency that is significantly greater than the general United States population estimates of 2.1 to 3.2 percent [28]. In three of the five women, features of preeclampsia were severe. Preventive measures such as low-dose aspirin may be appropriate, under the direction of a maternal-fetal medicine specialist. (See "Preeclampsia: Prevention".)

Management of clinical relapse– Clinical relapse during pregnancy is treated similarly to relapses in non-pregnant individuals, with urgent initiation of TPE and glucocorticoids. However, we do not use rituximab in the second and third trimesters unless TTP is refractory to TPE and glucocorticoids. We are less restrictive of our use of rituximab in the first trimester because rituximab does not cross the placenta until approximately 18 weeks of gestation [31]. (See "Immune TTP: Initial treatment", section on 'Immune TTP during pregnancy' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Rituximab'.)

We do not use caplacizumab in pregnancy unless disease is refractory to TPE, glucocorticoids, and rituximab or the patient is critically ill, since effects of caplacizumab on the fetus are unknown.

Unlike preeclampsia and other pregnancy-associated causes of thrombocytopenia, in TTP, delivery of the infant does not affect the course of the TTP, and delivery should only be performed for obstetric reasons. (See "Thrombocytopenia in pregnancy", section on 'Management decisions'.)

Outcomes data – Evidence for the likelihood of a successful pregnancy following an episode of TTP and the risk of relapse during pregnancy includes the following:

An analysis of all 23 pregnancies in 13 women from the Oklahoma TTP-HUS Registry from 1999 to 2016 who had recovered from acquired TTP reported successful full-term delivery in 18 (78 percent) [28]. Unsuccessful outcomes included one individual who had two early fetal deaths (12 and 13 weeks of gestation), and one with pregnancy loss at 20 weeks, possibly due to placental abruption; her subsequent pregnancy was uncomplicated and successful. One woman had fetal growth retardation with delivery at 26 weeks (her baby died 10 days later) and mid-trimester fetal death in her next pregnancy. Relapse of TTP occurred in 2 of 13 women (representing 9 percent of 23 total pregnancies) [28]. Both relapses occurred postpartum (9 and 29 days) following a pregnancy complicated by preeclampsia but with delivery of a healthy child.

A report from the United Kingdom TTP Registry described outcomes following recovery from acquired TTP in 26 pregnancies in 18 women managed at 14 centers [29]. Twenty-three pregnancies (88 percent) had successful full-term deliveries. The three pregnancy losses included one termination due to refractory TTP at six weeks of gestation, one second-trimester intrauterine fetal demise, and one fetal loss related to group B streptococcal infection. Relapse of TTP occurred during pregnancy in 2 of the 18 women (11 percent of the women, 8 percent of the pregnancies). One additional woman had a relapse postpartum that was treated successfully.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thrombotic microangiopathies (TTP, HUS, and related disorders)".)

SUMMARY AND RECOMMENDATIONS

Initial treatment – The initial treatment of immune thrombotic thrombocytopenic purpura (TTP) is discussed in detail separately (see "Immune TTP: Initial treatment"). Definitions of terms that describe the course of following initial treatment are listed above. (See 'Terminology and response criteria' above.)

Exacerbation – Most exacerbations of acquired TTP occur during the first week after stopping TPE or caplacizumab. Patients are monitored closely for symptoms and recurrent thrombocytopenia during the first week after stopping these treatments (table 2). (See 'First week' above.)

Tapering therapy – For individuals who have a normal (or increasing) platelet count following the first week after discontinuing therapeutic plasma exchange (TPE), we suggest tapering and discontinuing the glucocorticoids rapidly (over two to three weeks) rather than a slower taper (Grade 2C). The rituximab course is completed during the first month. This approach is summarized above and illustrated in the figure (algorithm 1). The likelihood of refractory disease is declining with availability of caplacizumab and increased use of rituximab during initial therapy. (See 'Monitoring and therapy after response to treatment' above and "Immune TTP: Treatment of clinical relapse", section on 'Refractory disease' and 'Vaccinations' above.)

Monitoring ADAMTS13 activity and preemptive rituximab for ADAMTS13 relapse – We generally monitor ADAMTS13 activity starting one week after discontinuation of TPE and/or caplacizumab (if administered), extending the interval over time (table 2). For those who develop an ADAMTS13 relapse (activity <20 percent), we suggest administration of rituximab preemptively to reduce the risk of relapse (Grade 2C). However, individuals who place a high value on avoiding the potential toxicities or burdens of rituximab may reasonably choose close clinical monitoring rather than prophylactic rituximab, pending further data on risks and benefits. (See 'Monitoring and therapy after response to treatment' above and 'Rituximab during remission to prevent relapse' above.)

Clinical relapse – TTP relapses are generally identified more quickly than the initial episode because the patient and their clinician are familiar with the symptoms of TTP. Relapses may present with nonspecific symptoms of anemia, gastrointestinal symptoms, and/or neurologic changes ranging from headache or confusion to focal abnormalities. Any new symptoms suggestive of possible clinical relapse require prompt (same-day) testing and review of the complete blood count (CBC) and platelet count, with immediate intervention if thrombocytopenia is present (immediate hospitalization, urgent additional diagnostic evaluation), and immediate initiation of TPE if findings are consistent with relapse (algorithm 2). (See 'Monitoring for clinical relapse' above and "Immune TTP: Treatment of clinical relapse", section on 'Clinical relapse'.)

Sequelae – Long-term observations have documented increased risks for minor cognitive impairment, major depression, hypertension, abnormal kidney function, and development of systemic lupus erythematosus (SLE) and other autoimmune disorders. Lifelong follow-up and assessment for these complications is required. (See 'Evaluation for complications of TTP' above.)

Pregnancy – Most pregnancies following recovery from acquired TTP are successful, although the risks of preeclampsia and severe preeclampsia are increased. Pregnancy following recovery requires close follow up, preferably by an obstetrician with experience in high-risk pregnancies. Relapses during pregnancy are treated similarly to individuals who are not pregnant, with urgent initiation of TPE and glucocorticoids. Rituximab is only used during the second and third trimesters if the disease does not respond appropriately to TPE and glucocorticoids. Delivery of the infant does not affect the course of the TTP and should only be performed for obstetric reasons. (See 'Pregnancy after an episode of TTP' above.)

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References