Immune TTP: Management after recovery and treatment of refractory or relapsed disease

INTRODUCTION — 

Immune thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by autoantibodies against ADAMTS13, the von Willebrand factor-cleaving protease, leading to severe ADAMTS13 deficiency (activity <10 percent).

Therapeutic plasma exchange (TPE) and other therapies used since the early 1990s have converted immune TTP from an almost uniformly fatal condition to a treatable disease. Refractory disease is becoming less common due to the routine use of rituximab (and in some patients caplacizumab) during initial therapy.

However, some patients with TTP will have refractory disease and some will have one or more clinical relapses. Therefore, all patients who have recovered from an episode of TTP require lifelong clinical monitoring and rapid intervention at the first sign of a relapse, and some may benefit from prophylactic immunosuppression during remission.

This topic reviews management after recovery from an acute episode of immune TTP, including monitoring, prophylaxis to prevent relapse, treatment of relapse or refractory disease, and management of long-term morbidities.

Separate topics discuss other aspects of care for immune and hereditary TTP:

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

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

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

●Hereditary TTP (due to biallelic variants in the ADAMTS13 gene) – (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)".)

MONITORING AND THERAPY AFTER RESPONSE TO TREATMENT

Terminology for response criteria — The table (table 1) defines terms for outcomes following therapy [1].

Response is typically followed by clinical remission and ADAMTS13 remission:

●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 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 activity ≥20 percent but below the lower limit of normal for the assay.

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

Overview of monitoring — Once a patient recovers from the acute episode of TTP, monitoring helps guide tapering of therapy and identification of ADAMTS13 and clinical relapses, as illustrated in the figure (algorithm 1).

Importance of education and roles of different individuals — 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.

●Patient – The patient must be educated and 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 (table 2). The patient must insist on having a CBC with platelet count, even if symptoms seem minor, as these symptoms could indicate an exacerbation (within the first 30 days) or a relapse (after 30 days).

Many clinicians are unfamiliar with TTP and may not accept a patient's explanation of the importance of minor symptoms and the urgency required to evaluate them. To facilitate proper care, we provide our patients with a letter and wallet card that can be shown to emergency department personnel and shared with any new clinician (form 1). This explains the diagnosis and the required urgency of testing. An electronic version may be especially useful for some individuals.

If a patient moves to a different city, they should establish care with hematology and primary care as rapidly as feasible.

●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 hematologist generally follows the patient very closely after an episode of TTP. The timing for having the patient return to their primary care clinician is individualized depending on the patient’s clinical status, level of concern, and ability of the primary care clinician to respond immediately should symptoms of TTP recur. This may include a period of overlap 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 life-long risk for relapse.

Critically, do not attribute minor symptoms such as nonspecific symptoms of tiredness, fatigue, and/or gastrointestinal upset to a viral illness and do not 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 'Clinical relapse' below.)

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 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 'Clinical relapse' below.)

Because the risk for relapse persists for the lifetime of the patient, 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.

Clinical and ADAMTS13 monitoring — We monitor for clinical relapse and ADAMTS13 relapse:

●Clinical monitoring - For all patients, 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 3). Monitoring intervals are extended further after TTP therapies have been discontinued (table 3).

Clinical relapses are defined by recurrent thrombocytopenia (platelet count <150,000/microL) (table 1), often identified when patients develop symptoms, including any neurologic abnormalities from headache to confusion to focal abnormalities, or symptoms similar to their original TTP episode (table 2).

Symptoms heralding a clinical relapse may be extremely variable and may include nonspecific symptoms of anemia or gastrointestinal upset. Because TTP is rare, patients, families, and caregivers must educate themselves about the importance of paying close attention to their symptoms and of seeking medical care immediately for a suspected relapse. (See 'Clinical relapse' below.)

If a patient has symptoms, the clinician (or emergency department personnel) must 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 or a member of their practice must be accessible for any concerns about a relapse of TTP and must be prepared to ensure immediate hospitalization and treatment. (See 'Evaluation of clinical relapse' below.)

Any patient with a history of immune TTP whose platelet count decreases 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. Patients with clinical relapse require immediate initiation of TTP therapy, as discussed below and in more detail separately. (See 'Management of clinical relapse' below and "Immune TTP: Initial treatment".)

For individuals receiving caplacizumab, a normal platelet count may suggest that TTP disease activity has declined when in fact it has not. This is because caplacizumab does not affect the TTP disease process; it only blocks platelet adhesion to von Willebrand factor (VWF), allowing platelet count recovery and resolution of symptoms. If there is concern about relapse, other parameters including ADAMTS13 activity should be assessed. (See "Immune TTP: Initial treatment", section on 'Anti-VWF (caplacizumab)'.)

●ADAMTS13 monitoring – ADAMTS13 relapse is defined by ADAMTS13 activity <20 percent (table 1). ADAMTS13 relapse 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 'Preemptive rituximab for ADAMTS13 relapse' below.)

ADAMTS13 activity is monitored after TPE has been discontinued, weekly for the first month and then extended based on the results (table 3). A routine CBC is obtained at the same time.

•ADAMTS13 activity ≥60 percent – When the ADAMTS13 activity increases to ≥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.

•ADAMTS13 activity <40 percent – If the ADAMTS13 activity falls from normal to <40 percent, we resume monthly measurements. Some patients who have had an extremely complicated acute episode, or multiple acute episodes, are followed with more frequent ADAMTS13 measurements. If ADAMTS13 activity decreases to <20 percent, we discuss the use of preemptive rituximab to reduce the risk of clinical relapse. (See 'Interventions to prevent clinical relapse' below.)

•ADAMTS13 activity 40 to 60 percent – 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. Mild deficiencies or low-normal values may predict a risk for thrombotic events other than TTP, such as stroke and cardiovascular disease [2,3]. (See 'Hypertension, cardiovascular disease, stroke, and kidney impairment' below.)

REFRACTORY DISEASE

Overview of approach (refractory disease) — Refractory disease is defined as TTP with thrombocytopenia, high LDH, or progressive or new ischemic organ injury that does not respond to initial treatment. Exacerbations (platelet count decrease to <150,000/microL that occurs within the first 30 days after stopping TPE or caplacizumab) are also considered to be refractory disease. This is becoming rare due to the routine incorporation of rituximab.

Our approach is as follows:

●Re-evaluate the diagnosis – The diagnosis should be evaluated thoroughly so as not to miss another cause of worsening symptoms or laboratory findings (algorithm 2). A common occurrence is sepsis related to the central venous catheter. (See 'Reevaluation of the diagnosis' below.)

●Restart TPE – If therapeutic plasma exchange (TPE) has been stopped, we restart it (algorithm 1). We do not increase the intensity or volume of plasma used [4]. (See "Immune TTP: Initial treatment", section on 'Therapeutic plasma exchange (TPE)'.)

●Add caplacizumab and rituximab, increase glucocorticoid dose – We add caplacizumab in all individuals with refractory TTP. Rituximab is also added if the patient is not already receiving rituximab, and we raise the dose of glucocorticoids. (See 'Caplacizumab, glucocorticoids, and rituximab' below.)

●Other immunosuppression options – For individuals who cannot receive caplacizumab or those who have persistent severe ADAMTS13 deficiency and are maintained in clinical remission with ongoing caplacizumab and rituximab, additional immunosuppressive therapy is needed. Limited evidence from case reports provides information about other immunosuppressive therapies that may be helpful, with the choice among them individualized.

Options include:

•Cyclophosphamide [5-7]

•Bortezomib [8-12]

•Cyclosporin [13-16]

•Mycophenolate mofetil [17,18]

•Azathioprine [19]

•Sirolimus [20]

•Daratumumab [21]

•Splenectomy [22]

●rADAMTS13 – For those who have persistently low ADAMTS13 activity despite maximal immunosuppressive therapy and caplacizumab, recombinant ADAMTS13 (rADAMTS13) has been used successfully [23]. rADAMTS13 may also be used for patients who cannot receive TPE but has limited availability. (See 'Recombinant ADAMTS13' below and "Immune TTP: Initial treatment", section on 'Patient who cannot accept plasma/Jehovah's Witness'.)

We do not use eculizumab for immune TTP, although it does have a role in complement-mediated thrombotic microangiopathies. Consultation with a TTP expert is advised.

Reevaluation of the diagnosis — Reevaluation of the diagnosis is essential in a patient whose disease does not respond to initial therapy or who has an exacerbation during or after stopping TPE. For some patients, a new diagnosis may be uncovered, such as a systemic infection, malignancy, or drug-induced thrombotic microangiopathy (DITMA). Even when the initial diagnosis of immune TTP is correct, it may be possible for a patient to develop a new condition, such as an infection during or drug-induced thrombocytopenia (DITP).

●Infection – Infection may be present but unappreciated at the time of TTP diagnosis, or it may develop during therapy (eg, as a complication of an indwelling central venous catheter), with or without acute disseminated intravascular coagulation (DIC). Bacteremia related to the central venous catheter is common, and patients being treated with glucocorticoids may only have thrombocytopenia without fever [24].

●Medications – The drug/medication history is important in patients with suspected refractory disease or relapse because symptoms may be related to drug-induced thrombocytopenia (DITP) or drug-induced thrombotic microangiopathy (DITMA).

Patients with TTP are often treated with antibiotics because of the initial suspicion of infection, and some antibiotics (eg, vancomycin, piperacillin [as a component of piperacillin-tazobactam]) are among the most common causes of DITP. (See "Drug-induced immune thrombocytopenia".)

If facilities for prompt measurements are available, a repeat ADAMTS13 activity measurement may be helpful, particularly in patients with persistent or recurrent thrombocytopenia whose diagnosis is uncertain [25-27]. However, resumption of TPE for suspected relapse should be urgent and should not be delayed while awaiting ADAMTS13 results. The continued presence of severe ADAMTS13 deficiency is consistent with continued activity of TTP as the cause of persistent or recurrent thrombocytopenia. Conversely, non-severely deficient ADAMTS13 activity (activity ≥10 percent) in a patient who has not received recent TPE is suggestive of an alternative process.

Monitoring of ADAMTS13 activity in remission, when there is not urgent time pressure to act on the results, is discussed in detail separately. (See 'Interventions to prevent clinical relapse' below.)

Caplacizumab, glucocorticoids, and rituximab — We add caplacizumab in all individuals with refractory TTP, if available. Rituximab is also added if the patient is not already receiving rituximab, and there should be a low threshold for raising the glucocorticoid dose.

●Caplacizumab – Caplacizumab is a monoclonal antibody fragment that blocks the interaction between von Willebrand factor (VWF) and platelets; this interaction mediates thrombosis in TTP. Some individuals may not have access to caplacizumab due to cost or lack of authorization in some countries.

•Dose – The first dose is administered intravenously followed by daily subcutaneous doses.

•Duration of therapy – The package information states that caplacizumab should be continued during TPE and for 30 days after TPE has been stopped. Instead of using a fixed duration, we check ADAMTS13 activity weekly and stop caplacizumab when ADAMTS13 activity is ≥20 percent for two consecutive measurements (algorithm 1). In a small proportion of patients, ADAMTS13 recovery may require prolonged immunosuppression. It is uncertain how long caplacizumab should be continued in such patients.

•Rationale – Supporting evidence for caplacizumab in TTP is presented separately. (See "Immune TTP: Initial treatment", section on 'Anti-VWF (caplacizumab)'.)

●High-dose glucocorticoids – Glucocorticoids are routinely used in initial therapy, with high-dose glucocorticoids used for individuals with high-risk features. If an individual receiving lower-dose glucocorticoids has refractory disease, we raise the dose.

•Dose – We often use methylprednisolone (eg, SoluMedrol) 1 gram intravenously daily for three days. This is followed by resumption of initial treatment (eg, prednisone 1 mg/kg daily) followed by a rapid taper after TPE has been stopped. (See "Immune TTP: Initial treatment", section on 'Glucocorticoids' and 'Monitoring and therapy after response to treatment' above.)

•Rationale – Evidence to support a specific dose of glucocorticoids is lacking; however, this regimen is standard treatment for patients who are critically ill with other autoimmune disorders such as lupus nephritis. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Glucocorticoid dosing and taper'.)

●Rituximab – Rituximab has become routine initial treatment for immune TTP. Exceptions may include an individual who is unable to tolerate rituximab or for whom there are concerns about rituximab use (eg, known hepatitis B infection), for whom a different immunosuppressive agent may be used.

•Dose – A dose of 375 mg/m² intravenously once a week for four consecutive weeks is routine for rituximab, based on extensive experience with other conditions [25,28,29]. Lower doses or other schedules may be equally effective, as discussed separately. (See "Immune TTP: Initial treatment", section on 'Rituximab'.)

•Timing – Rituximab administration should be timed to occur immediately after the day's TPE because TPE will deplete rituximab from the circulation. However, rituximab may be effective even if given on the same day prior to TPE; this may be because the dose of 375 mg/m² is in excess of the dose required to deplete autoantibody-producing B cells [30]. (See "Overview of therapeutic monoclonal antibodies", section on 'Timing related to plasmapheresis or plasma exchange'.)

•Adverse effects – The potential risks of rituximab, including severe infusion reactions, mucocutaneous reactions, prolonged immunosuppression, hepatitis B reactivation, and progressive multifocal leukoencephalopathy (PML), are rare. Antiviral therapy may be indicated in patients with a history of hepatitis B virus infection. Prescribing information for rituximab contains boxed warnings about infusion reactions, hepatitis B reactivation, and PML. These toxicities are discussed in more detail separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Rituximab: Principles of use and adverse effects in rheumatologic disease".)

Evidence for rituximab in the first-line setting (as initial therapy) also supports its addition for refractory disease. (See "Immune TTP: Initial treatment", section on 'Rituximab'.)

Recombinant ADAMTS13 — rADAMTS13 can rapidly raise ADAMTS13 activity in some individuals. While it was approved for treating hereditary TTP (hTTP), it may also have a role in refractory immune TTP and/or in patients with immune TTP who cannot receive TPE. (See "Immune TTP: Initial treatment", section on 'Patient who cannot accept plasma/Jehovah's Witness'.)

A case report described a patient with immune TTP refractory to TPE who had persistent severe thrombocytopenia, life-threatening bleeding, and undetectable ADAMTS13 activity despite prednisone, rituximab, intravenous immune globulin, bortezomib, caplacizumab, and increasing TPE to 1.5 plasma volumes twice daily [23]. Once treatment with rADAMTS13 was started, she had "rapid and striking" improvement in clinical status, including cessation of bleeding, increase in platelet count, and improvement in numerous markers of TTP activity.

CLINICAL RELAPSE

Clinical versus ADAMTS13 relapse — Clinical relapse is distinguished from ADAMTS13 relapse (table 1); both occur following recovery from the initial episode:

●Clinical relapse – Platelet count decrease to <150,000/microL after remission not due to another cause of thrombocytopenia, confirmed by documented 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. ADAMTS13 relapse is associated with increased risk for clinical relapse, as well as increased risk of stroke. This informs the importance of monitoring and interventions to reduce the risk of clinical relapse. (See 'Interventions to prevent clinical relapse' below.)

In addition to increasing the risk of clinical relapse (see 'Risk of clinical relapse' below), ADAMTS13 relapse also increases the risk of stroke. A report of 170 consecutive individuals treated for TTP from 1995 through 2018 reported that of 29 individuals in clinical remission with ADAMTS13 activity ≤70 percent, 28 percent had a stroke [3]. In contrast, there were no strokes in individuals with ADAMTS13 activity >70 percent during remission. In another study by the same group, silent cerebral infarcts were present in 50 percent of patients with immune TTP in clinical remission, and these silent infarcts were associated with impaired cognition [31].

Risk of clinical relapse — Most patients will not have a relapse of TTP. However, 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.)

The main risk factor for clinical relapse is persistent severe ADAMTS13 deficiency or ADAMTS13 relapse (activity <20 percent) during remission. (See 'Natural history of ADAMTS13 activity during remission' below.)

Relapses occur most commonly within the first one to two years (corresponding to the kinetics of B cell repopulation) but have also been observed at much longer intervals (up to 16 years in our experience). Thus, monitoring is most critical during the first year but remains important indefinitely. (See 'Monitoring and therapy after response to treatment' above.)

We expect that clinical relapse frequency will decrease over time with greater routine use of rituximab for the treatment of initial episodes and preemptive rituximab for ADAMTS13 relapse during clinical remission. Before the use of rituximab, one-half of patients with immune TTP who had long-term follow-up relapsed [2]. With rituximab as routine initial treatment, relapse is less frequent [2,32]. (See 'Preemptive rituximab for ADAMTS13 relapse' below and "Immune TTP: Initial treatment", section on 'Rituximab'.)

Evaluation of clinical relapse — Monitoring for clinical relapse is discussed above, but, as noted, most clinical relapses come to medical attention due to patient symptoms (table 2) rather than routine monitoring. (See 'Overview of monitoring' above.)

●Symptoms – Relapse episodes of TTP are typically less severe than initial episodes because patients are aware of the symptoms and promptly contact their hematologist who managed their initial episode [33].

It is important not to attribute minor symptoms to unrelated illnesses. A patient with a history of TTP who exhibits any symptoms of illness requires an immediate (same-day) evaluation of the complete blood count (CBC) with platelet count and immediate intervention if thrombocytopenia is found. (See 'Overview of monitoring' above.)

●CBC with platelet count – For any symptoms that may suggest a relapse, it is critical that a CBC with platelet count be obtained and reviewed 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. This is not adequate for a patient with a history of TTP and suspected clinical relapse, for whom new thrombocytopenia is a medical emergency that may require immediate reinstitution of TPE. (See 'Management of clinical relapse' below.)

A platelet count <150,000/microL strongly suggests disease relapse, although other explanations (infection, drug-induced) are possible.

•Platelet count <100,000/microL – For any symptomatic patient with a platelet count <100,000/microL, urgent additional diagnostic evaluations are essential, including review of the peripheral blood smear for schistocytes and measurement of LDH and haptoglobin to assess hemolysis. If these initial observations are consistent with TTP, immediate therapeutic plasma exchange (TPE) initiation is necessary. (See 'Management of clinical relapse' below.)

•Platelet count 100 to 150,000/microL – If an asymptomatic patient is discovered to have a platelet count between 100,000 and 150,000/microL on a routine CBC, management is individualized. Some patients for whom this represents a major decrease in platelet count may require evaluation for a TTP relapse and initiation of TPE, whereas for others it may be appropriate to monitor the platelet count daily to determine the etiology.

●Additional testing – Any patient with suspected relapse due to worrisome symptoms and/or thrombocytopenia requires urgent (same-day) evaluation. If thrombocytopenia has already been documented, the evaluation should occur in the hospital with the understanding that urgent caplacizumab and TPE may be required. We do the following:

•CBC with platelet count, if not already done

•Review of the peripheral blood smear for schistocytes

•Testing for hemolysis, including total bilirubin, LDH, and haptoglobin

•Serum creatinine, to evaluate any worsening of kidney function

•ADAMTS13 activity level

The ADAMTS13 activity level may not be available for several days, so management decisions should not be delayed while waiting for the results.

●Diagnosis of relapse – Diagnosis of TTP relapse is the same as the initial episode (eg, platelet count <150,000/microL and microangiopathic hemolytic anemia, with or without neurologic findings or reduced kidney function, without another apparent cause). (See "Diagnosis of immune TTP", section on 'Evaluation and diagnosis'.)

Management of clinical relapse — Once TTP relapse is diagnosed, urgent TPE, glucocorticoids, and rituximab are appropriate, as with any acute TTP episode. Details are discussed separately. (See "Immune TTP: Initial treatment".)

For selected individuals, we add caplacizumab. Examples are similar to those that would prompt us to use caplacizumab in the initial presentation and include:

●Relapse with severe disease (neurologic findings and/or elevated troponin levels)

●Relapse was refractory to TPE, glucocorticoids, and rituximab

Some experts recommend caplacizumab in all patients rather than restricting it to those with severe or refractory disease.

Successful treatment of patients who lack severe symptoms and severe thrombocytopenia with only caplacizumab and rituximab and without hospitalization and TPE has been reported [34]. However, we continue to manage all clinical relapses with TPE. (See "Immune TTP: Initial treatment", section on 'Anti-VWF (caplacizumab)'.)

The management of a relapse assumes the correct initial diagnosis of immune TTP and the determination that the thrombocytopenia and recurrent symptoms, if present, are not due to an alternative diagnosis. Checking ADAMTS13 activity in patients with suspected relapse is important to confirm the diagnosis of relapsed TTP, but, as with initial treatment, therapy should not be delayed while awaiting the results of this testing.

INTERVENTIONS TO PREVENT CLINICAL 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 ADAMTS13 activity measurements since 2004 [35]. 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 repeatedly from undetectable to normal and to undetectable again without treatment and without symptoms or thrombocytopenia.

●A French observational study of 233 patients followed for ≥1 year after an acute episode of immune TTP identified 48 (20 percent) who had ADAMTS13 activity <10 percent during clinical remission [36]. Among these, 30 were treated with "preemptive" rituximab; 18 were not treated with rituximab due to different management practices at different institutions. 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), although there were limitations to the data, such as different lengths of observation.

These data from two different registries document that 20 to 30 percent of patients in clinical remission will have ADAMTS13 activity <10 percent (ADAMTS13 relapse), which is associated with a greater risk for clinical relapse (see 'Risk of clinical relapse' above). 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.

Preemptive rituximab for ADAMTS13 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. (See 'Risk of clinical relapse' above.)

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 [37].

●Suggested approach – 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:

•ADAMTS13 <20 percent – 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 (hTTP)", section on 'Epidemiology'.)

•ADAMTS13 <10 percent – 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 despite 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) [38].

•Multiple relapses – 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 'Multiple relapses' below.)

●Efficacy – 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 [39]. Some patients had received rituximab during the acute episode of TTP. Preemptive rituximab was given during remission when ADAMTS13 activity remained severely deficient (activity <10 percent). 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.

●Dosing —The optimal dose and schedule of preemptive rituximab have 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 (UK) 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) [40]. 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.

●Alternatives – If a patient is unable to tolerate rituximab, an alternative anti-CD20 agent such as ofatumumab or obinutuzumab can be considered. This practice is supported by data from the UK TTP Registry [41].

Multiple relapses — For individuals with multiple relapses, the following options may be appropriate in addition to treating the acute event:

●Rituximab – Maintenance rituximab is sometimes used, such as a single dose of 375 mg/m² once every three months for two to three years [38]. (See 'Preemptive rituximab for ADAMTS13 relapse' above.)

Although this has not been extensively studied in TTP, 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 [42]. (See "Rituximab: Principles of use and adverse effects in rheumatologic disease".)

●Splenectomy – Splenectomy was previously used for patients with frequent relapses, but with rituximab and other immunosuppressive drugs, it is rarely necessary. Several reports have described the use of splenectomy [43-46]. All of these describe success in preventing or decreasing the frequency of subsequent relapses. The rationale for this is the identification of ADAMTS13-specific memory B cells in the spleens of two patients with immune TTP who underwent splenectomy [47].

Splenectomy carries risks of infections, especially with encapsulated organisms, as well as thrombosis and perioperative risks. Surgical expertise is critical, and laparoscopic procedures appear to be associated with lower risks of adverse events. Patients should be educated regarding these risks and their mitigation, and appropriate immunizations should be provided before the procedure, as discussed in more detail separately. (See "Prevention of infection in patients with impaired splenic function" and "Elective (diagnostic or therapeutic) splenectomy", section on 'Postoperative risks'.)

Prognosis after relapse — Immune TTP, like systemic lupus erythematosus, is a lifelong disorder. It should never be described as cured. Continuing follow-up is required to prevent relapse. Patients with mild or moderate ADAMTS13 deficiency have increased risk for stroke, indicating that relapse of TTP is not the only risk [3].

Individuals with TTP are also at risk for long-term complications including heart disease, kidney disease, hypertension, cognitive decline, and depression. Thus, they require lifelong monitoring for these complications and appropriate treatment as indicated. (See 'Evaluation for complications of TTP' below.)

Management of pregnancy in a patient who previously had TTP is presented separately. (See "Immune TTP: Initial treatment", section on 'Pregnancy'.)

ROUTINE MEDICAL CARE DURING REMISSION

Vaccinations — Recurrent TTP has been observed following vaccination, leading to a suggestion to measure ADAMTS13 activity prior to any vaccination [48]. 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. (See 'Preemptive rituximab for ADAMTS13 relapse' above.)

Rituximab or other immunosuppressive agents blunt the immune response to vaccinations for at least six months [49]. 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, if possible.

An exception is the influenza vaccination and coronavirus disease 2019 (COVID-19) 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" and "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 immune TTP [50,51].

Hypertension, cardiovascular disease, stroke, and kidney impairment — Patients who have recovered from TTP have an increased risk for hypertension [52]. Other cardiovascular risks are also increased. In a long-term study of 222 patients with immune TTP, overall mortality was approximately twofold greater than expected for age- and sex-matched controls and was highest in individuals with persistent ADAMTS13 deficiency during remission [53].

We have also observed patients who have developed stroke, cardiomyopathy and congestive heart failure, presumably as a result of previous diffuse microvascular thrombosis [51].

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) [3]. 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 'Preemptive rituximab for ADAMTS13 relapse' above.)

●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)".)

●Prophylaxis with aspirin has been proposed [54].

Severe acute kidney injury and advanced chronic kidney disease are rare in patients with immune TTP [55]. However, many of our patients who have recovered from an episode of TTP have had microalbuminuria, which is associated with a greater risk of cardiovascular death [56].

Management of these complications is similar to the general population, as discussed separately:

●Hypertension – (See "Overview of hypertension in adults".)

●Cardiovascular disease – (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

●Stroke – (See "Overview of secondary prevention of ischemic stroke".)

●Microalbuminuria – (See "Evaluation of proteinuria in adults".)  

Depression and cognitive impairment

●Depression – Major depression has occurred in 29 percent of patients who have recovered from an episode of immune TTP [52,57]. The mechanism is not understood, but depression is known to occur more frequently in individuals with medical disorders. (See "Minor depression in adults: Epidemiology, clinical presentation, and diagnosis", section on 'General medical comorbidity'.)

Depression is often not appreciated by patients and their families, 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). (See "Screening for depression in adults".)

Even when depression is diagnosed, patients may be reluctant to seek counseling or medication. (See "Minor depression in adults: Management" and "Major depressive disorder in adults: Approach to initial management".)

●Cognitive impairment – Minor cognitive impairment is common following recovery from an episode of TTP [57,58]. This has been a consistent topic of conversation at TTP support group meetings at the authors' centers [59,60].

Many patients state that they do not feel the same as before their TTP episode. 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 without TTP. Some patients have more noticeable neurocognitive problems.

We test patients for cognitive function using a standard brief questionnaire like the Montreal Cognitive Assessment (MoCA). More formal neuropsychiatric testing may be appropriate in individuals who have an abnormal MoCA. (See "Evaluation of cognitive impairment and dementia".)

Management is individualized depending on the specific areas of impairment. Occupational therapy consultation may help patients with problems that interfere with 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 immune TTP, with an incidence as great as 11 percent in our experience [52,61,62]. SLE has been diagnosed before 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. (See "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis", section on 'Evaluation'.)

The frequency of other autoimmune disorders is also increased [61,62]. Among the 10 (11 percent) of 90 patients in the Oklahoma Registry who have developed SLE, three had an additional autoimmune disorder, and five developed multiple autoimmune disorders [62]. Four patients have developed Graves' disease. Two patients each have developed Addison's disease, immune thrombocytopenia (ITP), and an acquired factor VIII inhibitor.

PREGNANCY AFTER AN EPISODE OF TTP — 

Most pregnancies following recovery from immune TTP are uncomplicated [63,64]. However, we advise patients about the risks of relapse and preeclampsia and the need for more intensive monitoring [63].

Pregnancy in an individual who has recovered from immune 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. (See 'Evaluation of clinical relapse' above.)

●Preconception/planning – We obtain a complete blood count (CBC) and ADAMTS13 activity measurement before conception.

If the ADAMTS13 activity level is low (eg, <20 percent), we suggest preemptive rituximab to raise the ADAMTS13 level before attempting pregnancy. If the ADAMTS13 activity remains <20 percent, we advise the patient of the increased risk of relapse during pregnancy. However, 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 rare (<1 percent of uncomplicated pregnancies) [65]. Thus, any platelet count <100,000/microL in a pregnant individual with a history of TTP requires immediate evaluation. (See 'Clinical relapse' above 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 helps with interpretation of 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 [63].

•Blood pressure – Individuals with a history of immune 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 [63]. 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 an MFM specialist. (See "Preeclampsia: Prevention".)

●Management of clinical relapse during pregnancy – Clinical relapse during pregnancy is treated similarly to relapses in nonpregnant 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 [66]. (See "Immune TTP: Initial treatment", section on 'Pregnancy' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Rituximab'.)

We do not use caplacizumab in pregnancy unless the disease is refractory to TPE, glucocorticoids, and rituximab, or the patient is critically ill, since the effects of caplacizumab on the fetus are not well-studied. However, safe use of caplacizumab during pregnancy has been reported [67-69].

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'.)

●Pregnancy outcomes – More than two-thirds of individuals have successful full-term deliveries. 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 immune TTP reported successful full-term delivery in 18 (78 percent) [63]. 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) [63]. Both relapses occurred postpartum (9 and 29 days) following a pregnancy complicated by preeclampsia but with the delivery of a healthy child.

•A report from the United Kingdom TTP Registry described outcomes following recovery from immune TTP in 26 pregnancies in 18 women managed at 14 centers [64]. 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)".)

PATIENT PERSPECTIVE TOPIC — 

Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Thrombotic thrombocytopenic purpura (TTP)".)

SUMMARY AND RECOMMENDATIONS

●Definitions – For immune thrombotic thrombocytopenic purpura (TTP), we distinguish between clinical and ADAMTS13 remission and relapse. The table defines this and other TTP terminology (table 1). (See 'Terminology for response criteria' above and 'Clinical versus ADAMTS13 relapse' above.)

●Monitoring – Once a patient recovers from the acute episode of TTP, monitoring helps guide tapering of therapy and identification of relapse (ADAMTS13 relapse and clinical relapse) (algorithm 1). (See 'Overview of monitoring' above.)

•Roles – Patients must be aware of important symptoms to report (table 2). Clinicians must impress upon the patient the importance of a same-day complete blood count (CBC) with platelet count, not to attribute minor symptoms to a viral illness, and not defer urgent evaluation with a "watch and wait" approach. Hematologists continue to see patients indefinitely, monitor for morbidities of TTP, facilitate hospitalization if needed, and determine the need for preemptive rituximab. (See 'Importance of education and roles of different individuals' above.)

•Schedule – The table summarizes a monitoring schedule for symptoms, CBC, platelet count, and ADAMTS13 activity (table 3). (See 'Clinical and ADAMTS13 monitoring' above.)

•Actions – Platelet count <150,000/microL is an indication for further evaluation; platelet count <100,000/microL is an indication for immediate hospitalization, urgent additional diagnostic evaluation, and immediate treatment if the results of the evaluation are consistent with clinical relapse (algorithm 2).

●Refractory disease – Refractory disease is becoming increasingly rare but can occur. Reevaluation of the diagnosis is critical so as not to miss another cause of worsening symptoms such as catheter sepsis or drug-induced thrombocytopenia. (See 'Reevaluation of the diagnosis' above.)

•TPE – For patients with refractory TTP despite ongoing daily TPE, we suggest maintaining the same frequency of TPE rather than increasing it (Grade 2C). (See 'Overview of approach (refractory disease)' above.)

•Other therapies – For patients with refractory disease, we suggest adding caplacizumab and rituximab (if not already receiving) and raising the glucocorticoid dose to methylprednisolone 1 gram intravenously daily for three days, followed by standard dosing (Grade 2C). Recombinant ADAMTS13 is an option if these therapies are ineffective. (See 'Caplacizumab, glucocorticoids, and rituximab' above and 'Recombinant ADAMTS13' above.)

●Relapse – Any illness, surgery, or major trauma may trigger a relapse, or there may be no apparent trigger. (See 'Risk of clinical relapse' above.)

•Evaluation – Any new symptoms suggestive of clinical relapse require same-day testing (table 2). ADAMTS13 activity is obtained but treatment is not delayed while awaiting the results. (See 'Evaluation of clinical relapse' above.)

•Treatment – Our approach includes:

-TPE – For individuals with a TTP relapse, we recommend immediate TPE (Grade 1B), as done with the initial episode (algorithm 2). (See "Immune TTP: Initial treatment", section on 'Therapeutic plasma exchange (TPE)'.)

-Glucocorticoids – We suggest prednisone 1 mg/kg daily (Grade 2C). (See "Immune TTP: Initial treatment", section on 'Glucocorticoids'.)

-Rituximab – For individuals who are not receiving rituximab (or have not received it within the prior month), we suggest rituximab (Grade 2C). Data from observational studies suggest this improves survival and reduces the risk of further relapses. (See "Immune TTP: Initial treatment", section on 'Rituximab'.)

-Caplacizumab – For individuals with high-risk features (neurologic findings, elevated troponin), we suggest caplacizumab (Grade 2C). For individuals without high-risk features, omitting caplacizumab is reasonable. However, some experts use caplacizumab in all patients. (See "Immune TTP: Initial treatment", section on 'Anti-VWF (caplacizumab)'.)

•Prevention – For individuals with ADAMTS13 relapse (activity <20 percent), we suggest preemptive rituximab to reduce the risk of clinical relapse (Grade 2C). (See 'Preemptive rituximab for ADAMTS13 relapse' above.)

●Sequelae – Risks are increased for hypertension, cardiovascular disease, abnormal kidney function, depression, minor cognitive impairment, and autoimmune disorders. Lifelong follow-up and assessment for these complications is required. (See 'Evaluation for complications of TTP' above.)

●Pregnancy – Most pregnancies following recovery are successful, but risks of preeclampsia and severe preeclampsia are increased. Close follow-up is required, preferably by a high-risk obstetrician and hematologist. CBC and ADAMTS13 are checked before and during pregnancy.

For individuals with ADAMTS13 <20 percent before conception, we suggest deferring conception and treating with preemptive rituximab (Grade 2C). Relapses during pregnancy are treated with TPE, glucocorticoids, and rituximab in the first trimester. Rituximab crosses the placenta in the second and third trimesters, but it may be used if the disease does not respond to TPE and glucocorticoids. Birth/delivery does not affect TTP and should be reserved for obstetric reasons. (See 'Pregnancy after an episode of TTP' above.)

●Diagnosis and initial treatment – These are discussed separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Diagnosis of immune TTP" and "Immune TTP: Initial treatment".)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Lawrence LK Leung, MD, who contributed to earlier versions of this topic review.