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Immune TTP: Treatment of clinical relapse

Immune TTP: Treatment of clinical relapse
Literature review current through: Jan 2024.
This topic last updated: May 19, 2023.

INTRODUCTION — Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13 (activity <10 percent). It is characterized by small-vessel platelet-rich thrombi, thrombocytopenia, and microangiopathic hemolytic anemia (MAHA). Some patients may have neurologic abnormalities, mildly reduced kidney function, or low-grade fever. Immune TTP is caused by an autoantibody to ADAMTS13.

The use of therapeutic plasma exchange (TPE) and other therapies since the early 1990s has converted immune TTP from an almost uniformly fatal condition to a treatable disease. However, some patients with TTP will have refractory disease (transient, incomplete, or no response to treatment) and some will have one or more clinical relapses (additional episodes of TTP after initial recovery).

This topic reviews our approach to the patient with relapsed immune TTP or refractory disease. Refractory disease is becoming much less common due to the routine use of rituximab during initial therapy and in some patients caplacizumab.

Separate topics discuss:

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

Initial management – (See "Immune TTP: Initial treatment".)

Management during remission, including ADAMTS13 monitoring and preemptive rituximab – (See "Immune TTP: Management following recovery from an acute episode and during remission".)

Hereditary TTP – (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)".)

Drug-induced thrombotic microangiopathy – (See "Drug-induced thrombotic microangiopathy (DITMA)".)

TERMINOLOGY — The following definitions are used to describe outcomes following therapy [1]:

Clinical remission – A sustained clinical response (normal platelet count, no new or progressive symptoms of TTP) for ≥30 days after therapeutic plasma exchange (TPE) or caplacizumab is stopped.

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.

Clinical relapse – Recurrence of an acute episode, manifested by thrombocytopenia and microangiopathic hemolytic anemia, in a patient who had a disease remission following an episode of TTP [2,3]. Asymptomatic decreases in ADAMTS13 activity do not constitute relapse, although they probably portend an increased risk for relapse.

ADAMTS13 relapse – ADAMTS13 activity <20 percent following an ADAMTS13 remission. Our approach to using preemptive rituximab to reduce the risk of clinical relapse in individuals with an ADAMTS13 relapse is presented separately. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Rituximab during remission to prevent relapse'.)

Refractory TTP – Refractory TTP (lack of a clinical response to initial treatment, persistent thrombocytopenia, development of new or progressive organ ischemia due to TTP) is becoming very rare with the routine use of rituximab during initial therapy and in some cases caplacizumab.

Additional terminology is presented separately. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Terminology and response criteria'.)

REFRACTORY DISEASE

Overview of approach (refractory disease) — Refractory TTP is becoming very rare; with the use of caplacizumab it may be eliminated. Our approach to the management is as follows:

The diagnosis of refractory disease should be evaluated thoroughly, so as not to miss another cause of worsening symptoms or laboratory findings (algorithm 1). A common occurrence is sepsis related to the central venous catheter. (See 'Reevaluation of the diagnosis' below.)

If therapeutic plasma exchange (TPE) has been stopped, we restart it (algorithm 2). We do not increase the intensity or volume of plasma used [4]. (See "Immune TTP: Initial treatment", section on 'Therapeutic plasma exchange'.)

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.)

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]

Splenectomy is also a consideration.

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 acquired TTP is correct, it may be possible for a patient to develop a new condition, such as an infection during or after effective therapy 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 [19]. Systemic infection mimicking TTP was illustrated in a review of 415 consecutive patients in the Oklahoma TTP-HUS Registry, in which clinical features were subsequently attributed to a systemic infection in 31 (7 percent) [20]. Additional reports have described occult infection or newly acquired infections in patients who appeared to have refractory or relapsed TTP [21-25]. In such cases, symptoms have responded to treatment of the infection.

Malignancy – Occult malignancy may produce an ongoing stimulus for microangiopathic hemolysis and thrombocytopenia, with or without chronic DIC. A thorough history and physical examination, as well as measurement of plasma fibrinogen and D-dimer and a bone marrow examination in selected patients, may be appropriate [26,27]. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Diagnostic evaluation'.)

Medications – The drug/medication history is important in patients with suspected refractory disease or relapse because symptoms may be related to a 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) are among the most common causes of DITP. (See "Drug-induced immune thrombocytopenia".)

Quinine (table 1) is responsible for the majority of cases of DITMA, and many patients do not mention quinine use unless specifically asked about it. Questioning may reveal a previous temporal relationship with a specific drug that may not have been appreciated at the time. One dramatic example in our experience was a woman with recurrent acute episodes of thrombocytopenia, neutropenia, and fever during treatment for suspected TTP. Sepsis due to the central venous catheter was suspected repeatedly; only later did we learn that she had quinine-induced TMA and her husband was giving her quinine tablets in the hospital to relieve her leg cramps. (See "Drug-induced thrombotic microangiopathy (DITMA)".)

We do not routinely remeasure ADAMTS13 activity to guide our assessment of ongoing symptoms or acute changes in disease status that may signify refractory disease, because the results of ADAMTS13 activity testing are not available immediately, and clinical assessment based on symptoms and platelet count are the most relevant information for decision making.

However, 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 [28-30]. 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 "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Detecting and preventing relapse'.)

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 we raise the dose of glucocorticoids.

Caplacizumab – Caplacizumab is a monoclonal antibody fragment that blocks the interaction between von Willebrand factor (VWF) and platelets; this is the interaction that mediate thrombosis in TTP. Rapid blocking of ongoing thrombosis is the most important intervention in refractory TTP, and caplacizumab is an essential intervention in these cases. Caplacizumab was approved in Europe in late 2018 and in the United States in early 2019. Some individuals may not have access to caplacizumab due to cost or lack of authorization in some countries.

Dose – The dose of caplacizumab is 1 vial (10 mg in Europe; 11 mg in the United States; the actual amount is the same in the European and United States vials; only the labels differ). One dose is administered intravenously on day 1, followed by another dose subcutaneously and repeated once daily during TPE.

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 2). In a minority of patients, ADAMTS13 recovery may not occur or may only recover after months or years despite optimization of 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 continued done for initial treatment (eg, prednisone 1 mg/kg daily) followed by a rapid taper after PEX has been stopped and the platelet count has been normal for five to seven days after stopping PEX. (See "Immune TTP: Initial treatment", section on 'Glucocorticoids' and "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Monitoring and therapy after response to treatment'.)

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 of most patients with immune TTP. If rituximab was not started initially and disease is refractory, we add rituximab. 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. However, we do not delay rituximab to perform hepatitis B testing in a patient with refractory disease who is unstable or severely symptomatic.

Dose – The optimal dose of rituximab in refractory immune TTP has not been established, similar to in initial therapy. A dose of 375 mg/m2 intravenously once a week for four consecutive weeks appears reasonable, based on extensive experience with this dose in other conditions [28,31,32]. However, lower doses or other schedules may be equally effective, as discussed separately. (See "Immune TTP: Initial treatment", section on 'Rituximab'.)

TimingRituximab administration should be timed to occur immediately after the day's TPE rather than immediately beforehand, if possible, 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 [33]. (See "Overview of therapeutic monoclonal antibodies", section on 'Timing related to plasmapheresis or plasma exchange'.)

Adverse effectsRituximab therapy in combination with TPE has generally been well tolerated, with major complications not reported in the larger case series [31,32,34]. However, there are potential risks associated with rituximab, including infusion reactions, mucocutaneous reactions, prolonged immunosuppression, hepatitis B reactivation, and progressive multifocal leukoencephalopathy (PML), which is very rare. Our practice is not to place patients on antimicrobial prophylaxis, with the exception of patients with a history of hepatitis B virus infection, in whom antiviral therapy may be indicated. The decision regarding antiviral prophylaxis for hepatitis B is made in consultation with a hepatologist or infectious disease specialist. 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 rheumatoid arthritis".)

Rationale – Evidence demonstrating the efficacy of rituximab in refractory immune TTP comes from case reports and observational studies [5,32,34-45]. Larger studies include the following:

-One study compared outcomes of 21 patients with refractory TTP treated with rituximab (375 mg/m2 on days 1, 4, 7, and 14) with outcomes in 53 historical controls with refractory TTP who were treated with TPE with or without vincristine [34]. Platelet count recovery was seen within 35 days in all patients treated with rituximab, compared with 41 of 53 controls (78 percent). The mean time to platelet count normalization was 12±6.7 days with rituximab. There was a nonsignificant trend towards decreased relapse at one year, and no difference in relapse after one year.

-Another study that included 25 patients with refractory and/or relapsed TTP reported remission in all patients at a median of 11 days after initiating rituximab (375 mg/m2 once per week for at least four doses) [32]. Treatment beyond four doses, to a maximum of eight, was given to four patients who continued to have reduced ADAMTS13 activity or persistent anti-ADAMTS13 antibodies. There were no relapses at a median follow-up of 10 months.

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'.)

CLINICAL RELAPSE — The following discussion of relapse refers to clinical relapse, with thrombocytopenia and microangiopathic hemolytic anemia. Sometimes patients also have symptoms or findings of organ dysfunction. (See 'Terminology' above.)

Monitoring asymptomatic individuals for ADAMTS13 relapse (see 'Terminology' above) and preemptive rituximab to reduce the risk of clinical relapse is discussed separately. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Detecting and preventing relapse'.)

Risk of clinical relapse — Most patients will not have a relapse of TTP, especially in the era of routine initial rituximab and use of caplacizumab in some individuals.

In our experience (JNG) prior to the routine use of rituximab, relapse occurred in 23 of 67 patients (34 percent) who survived an acute episode of TTP [36]. However, the rate of relapse has been decreasing over time. In the decade from 2005 to 2014, only 6 of 34 patients (18 percent) have experienced a relapse, compared with 17 of 33 patients (52 percent) in the prior decade (1995 to 2004). Among patients treated with rituximab during their initial episode, only two (6 percent) of 16 patients have relapsed with a median follow-up of three years, which is significantly less than the frequency of relapse among patients who had not been treated with rituximab (9 of 21 [43 percent]) [46].

The main risk factor for relapse is persistent severe ADAMTS13 deficiency or ADAMTS13 relapse (activity <20 percent) during remission. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Natural history of ADAMTS13 activity during remission'.)

Patients who experience a relapse may have multiple subsequent relapses; however, half of our relapsed patients have had only a single relapse. This may be due in part to our use of rituximab for treatment of relapse episodes.

When relapses occur, they are most likely to do so in the first year following recovery (approximately half of relapses). Among all 23 patients who have relapsed, the timing of relapses was as follows:

First year – 11 patients (48 percent)

Years 1 to 3 – 7 patients (30 percent)

Years 5 to 14 – 5 patients (22 percent)

Relapses 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 "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Monitoring and therapy after response to treatment'.)

Symptoms of clinical relapse — Relapse episodes of TTP are typically less severe than initial episodes, presumably because patients are aware of the symptoms and promptly contact their hematologist who managed their initial episode. A comparison of initial episodes with the first relapse in 23 patients demonstrated fewer presentations with coma, seizure, and/or stroke but similar frequencies of transient focal neurologic abnormalities in relapse episodes [47]. Transient focal abnormalities were immediately recognized by the patients as indicating relapse, and they immediately contacted their hematologist. With relapse episodes, platelet counts and hematocrits were significantly higher and lactate dehydrogenase (LDH) levels were significantly lower than with the initial episodes.

It is especially important not to attribute minor symptoms to unrelated illnesses. Symptoms that are best treated with a "watch and wait" approach in patients without a history of TTP cannot be treated the same way in a patient with a history of TTP. A patient with a history of TTP who exhibits these or any other 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 'Clinical relapse' above and "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Monitoring and therapy after response to treatment'.)

Diagnostic evaluation for clinical relapse — The most important laboratory finding in TTP relapse is thrombocytopenia (platelet count <150,000/microL). Thrombocytopenia strongly suggests disease relapse, although other explanations (infection, drug-induced) are possible. 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. This may be facilitated by the patient carrying a wallet card to present to emergency department personnel or other clinicians who are unfamiliar with the patient's history or with TTP (form 1).

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 initiation of therapeutic plasma exchange (TPE) is necessary.

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 urgent 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.

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 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, and management decisions should not be delayed while awaiting the results.

Diagnosis of TTP relapse is the same as the initial episode (eg, thrombocytopenia [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 a diagnosis of TTP relapse is made, urgent TPE, glucocorticoids, and rituximab are appropriate. Details of acute therapy are similar to the initial episode and are discussed separately. (See "Immune TTP: Initial treatment".)

For selected individuals, we would include caplacizumab. Examples are similar to those that would prompt us to use caplacizumab in the initial presentation and include those whose relapse presented with severe disease (neurologic findings and/or elevated troponin levels) and those whose relapse was refractory to TPE, glucocorticoids, and rituximab. (See "Immune TTP: Initial treatment", section on 'Anti-VWF (caplacizumab)'.)

For selected individuals, we may omit rituximab. An example would be an individual who had a prior good response to TPE and glucocorticoids alone (ie, without rituximab) and who places a higher value on avoiding prolonged immunosuppression; for such an individual, rituximab may reasonably be omitted. Other potential reasons to omit rituximab include the following:

The patient just completed a course of rituximab

The patient previously did not have a response to rituximab (eg, ADAMTS13 activity did not increase)

The patient is in the second or third trimester of pregnancy

The patient has another condition or is receiving other medications that cause profound immunosuppression

The patient has a history of hepatitis B infection

The management of a relapse assumes the correct initial diagnosis of immune TTP and 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. (See 'Reevaluation of the diagnosis' above.)

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. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Rituximab during remission to prevent relapse'.)

Splenectomy – Several reports have described the use of splenectomy [48-51]. 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 acquired TTP who underwent splenectomy [52]. Cultured cells from both spleens produced anti-ADAMTS13 IgG antibodies that shared common complementarity-determining regions (CDRs). These findings were interpreted as suggesting that splenic B cells have a limited repertoire against ADAMTS13 and that these cells are critical in producing the ADAMTS13 inhibitor in acquired TTP. Following splenectomy, both patients have been free of relapse with normal ADAMTS13 activity for 8 and 11 years.

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 — The mortality of relapsed TTP is less than with the initial episode [53,54]. Potential reasons for this include the following:

Patients whose disease relapses have by definition had a disease remission in response to initial therapy, so it is likely that their disease will respond to therapy again.

Patients who have had a previous episode of TTP are familiar with the presenting symptoms and therefore do not delay in contacting their clinician.

There is less (or no) uncertainty about making the diagnosis and initiating therapy.

However, individuals with TTP are 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 "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Evaluation for complications of TTP'.)

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

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 – Terminology for thrombotic thrombocytopenic purpura (TTP) syndromes and outcomes of therapy are summarized above ADAMTS13 relapse (activity <20 percent without thrombocytopenia or symptoms of TTP) is treated differently from clinical relapse. (See 'Terminology' above and "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Detecting and preventing relapse'.)

Refractory disease – Refractory disease is the lack of a clinical response to initial treatment with therapeutic plasma exchange (TPE), glucocorticoids, rituximab, and in some cases caplacizumab; this is becoming increasingly rare in the era of routine rituximab and caplacizumab.

Evaluation – The diagnosis of refractory disease should be evaluated thoroughly, so as not to miss another cause of worsening symptoms or laboratory findings. A common occurrence is sepsis related to the central venous catheter. (See 'Reevaluation of the diagnosis' above.)

Management – Our approach is as follows (see 'Overview of approach (refractory disease)' above and 'Caplacizumab, glucocorticoids, and rituximab' above):

-If TPE has been discontinued, daily TPE should be reinitiated (algorithm 1). For patients with refractory TTP despite ongoing daily TPE, we suggest not increasing the frequency or intensity of TPE (Grade 2C).

-For patients who are not receiving caplacizumab (those who never received it or those who received it and then discontinued it), we suggest caplacizumab (Grade 2C). We continue therapy until ADAMTS13 activity is ≥20 percent on two measurements.

-We suggest an intensified glucocorticoid regimen, using methylprednisolone (eg, SoluMedrol) 1 gram intravenously, daily for three days (Grade 2C).

-For individuals who have not yet received rituximab for treatment of this episode of TTP, we recommend adding rituximab (Grade 1B).

Clinical relapse – Clinical relapse is recurrence of thrombocytopenia and microangiopathic hemolytic anemia without another cause following remission, which is later confirmed by documenting severe ADAMTS13 deficiency (activity <10 percent).

Evaluation – It is especially important not to attribute minor symptoms to unrelated illnesses. Symptoms that are best treated with a "watch and wait" approach in patients without a history of TTP cannot be treated the same way in a patient with a history of TTP. A patient with a history of TTP who exhibits these or any other 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 'Symptoms of clinical relapse' above and 'Diagnostic evaluation for clinical relapse' above.)

Management – A clinical relapse should be treated promptly with daily TPE and glucocorticoids, done for the initial episode (see "Immune TTP: Initial treatment"). For all patients with a first TTP relapse, we suggest adding rituximab, regardless of whether rituximab was administered with the initial episode (Grade 2B). Caplacizumab is reserved for selected individuals with high-risk features (neurologic findings and/or elevated troponin levels). Maintenance rituximab or splenectomy may also be an option, especially for those with multiple relapses. (See 'Clinical relapse' above.)

Prevention – Patients are monitored closely during tapering of therapy and after recovery. Rituximab is used in most cases of ADAMTS13 relapse to reduce the risk of clinical relapse (algorithm 2). (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Detecting and preventing relapse'.)

ACKNOWLEDGMENT — UpToDate acknowledges Andre A Kaplan, MD, who contributed to earlier versions of this topic review.

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Topic 99124 Version 19.0

References

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