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Acquired TTP: Initial treatment
Authors:
James N George, MD
Adam Cuker, MD, MS
Section Editor:
Lawrence LK Leung, MD
Deputy Editor:
Jennifer S Tirnauer, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Nov 06, 2017.

INTRODUCTION — Classification of thrombotic thrombocytopenic purpura (TTP) and related syndromes such as hemolytic uremic syndrome (HUS) is evolving. We now use TTP to refer to the thrombotic microangiopathy (TMA) caused by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. We divide TTP into acquired and hereditary syndromes, due to an autoantibody against ADAMTS13 and ADAMTS13 gene mutations, respectively. TTP is characterized by small-vessel platelet-rich thrombi, thrombocytopenia, and microangiopathic hemolytic anemia. In addition, some patients may have neurologic abnormalities, mild renal insufficiency, and low-grade fever.

Acquired autoimmune TTP is a medical emergency that is almost always fatal if appropriate treatment is not initiated promptly; with appropriate treatment, survival rates of up to 90 percent are possible.

This topic reviews our approach to the initial therapy for children and adults with acquired (autoimmune) TTP, defined by severe ADAMTS13 deficiency (activity level usually <10 percent) caused by an autoantibody.

The following aspects of care for individuals with acquired TTP are discussed in detail separately:

Clinical manifestations and diagnosis – (see "Acquired TTP: Clinical manifestations and diagnosis")

Management during recovery from the acute episode – (see "Acquired TTP: Management following recovery from an acute episode and during remission")

Therapy refractory or relapsed disease – (see "Acquired TTP: Treatment of refractory or relapsed disease")

The evaluation and management of other primary TMAs (including HUS) is also presented separately:

Overview of approach to the classification and initial evaluation – (see "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)")

Hereditary TTP (due to inherited biallelic ADAMTS13 mutation) – (see "Hereditary thrombotic thrombocytopenic purpura (TTP)")

Drug-induced TMA (DITMA), also sometimes referred to as drug-induced TTP – (see "Drug-induced thrombotic microangiopathy")

Complement-mediated TMA, also sometimes called complement-mediated HUS and commonly referred to as "atypical HUS" – (see "Complement-mediated hemolytic uremic syndrome", section on 'Treatment')

Diarrheal hemolytic uremic syndrome (HUS) – (see "Overview of hemolytic uremic syndrome in children", section on 'Treatment')

Pregnancy-associated syndromes (eg, hemolysis, elevated liver function tests, and low platelets [HELLP] syndrome, preeclampsia) – (see "HELLP syndrome" and "Thrombocytopenia in pregnancy", section on 'Preeclampsia with severe features/HELLP')

TERMINOLOGY — Terminology for TTP and related conditions has evolved as the etiology of these syndromes becomes clearer. We use the following terminology to refer to TTP and related syndromes:

Thrombotic microangiopathy (TMA) – TMA describes a pathologic lesion in which abnormalities in the vessel wall of arterioles and capillaries lead to microvascular thrombosis. The major hematologic findings are thrombocytopenia and microangiopathic hemolysis. TMA is a pathologic diagnosis, but its presence is commonly inferred from the observation of thrombocytopenia and microangiopathic hemolysis in the appropriate clinical setting. Several primary TMA syndromes have been described, of which TTP is one; these differ in their mechanisms, clinical presentations, and management. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Overview of primary TMA syndromes'.)

Acquired TTP – Acquired TTP refers to the TMA caused by autoantibodies to the von Willebrand factor protease ADAMTS13. These autoantibodies result in ADAMTS13 deficiency. However, the diagnosis is made clinically because ADAMTS13 activity testing does not have adequate sensitivity or specificity to be used in isolation, and the turnaround time for this testing is too slow to incorporate the information into immediate management decisions. (See "Acquired TTP: Clinical manifestations and diagnosis".)

Outcomes of acquired TTP – The following definitions apply to the clinical course of acquired TTP with treatment [1]

Response – Normalization of the platelet count with plasma exchange therapy (PEX); in some patients the platelet count may return to a stable level below 150,000/microL if there are conditions contributing to thrombocytopenia.

Exacerbation – Recurrent thrombocytopenia within 30 days of stopping PEX.

Remission – Maintenance of a normal platelet count for 30 days after stopping PEX.

Relapse – Recurrence of TTP following remission.

Hereditary TTP – Hereditary TTP refers to the TMA caused by biallelic ADAMTS13 mutations. These mutations result in severe ADAMTS13 deficiency that may present in childhood or adulthood (eg, during pregnancy). (See "Hereditary thrombotic thrombocytopenic purpura (TTP)".)

Drug-induced TMA – Drug-induced TMA (DITMA) refers to a TMA caused by exposure to a medication or other substance such as quinine. This condition is referred to by some as drug-induced TTP, but we prefer to avoid this term since drug-induced TMA is not associated with severe reductions in ADAMTS13 activity and is not treated with modalities directed at correcting such a deficiency (eg, DITMA is not treated with plasma exchange). We consider cases of severe ADAMTS13 deficiency to be TTP rather than DITMA. (See "Drug-induced thrombotic microangiopathy".)

ST-HUS – Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS) refers to a TMA caused by Shiga toxin, which is produced by diarrheal organisms (eg, some serotypes of Escherichia coli, such as O157:H7 and O104:H4; Shigella dysenteriae) that is acquired from exposure to farms or improperly prepared foods. (See "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children".)

Complement-mediated TMA – Complement-mediated TMA (also called complement-mediated HUS and sometimes referred to as atypical HUS) is the TMA caused by dysregulation of the complement system. Typically, factors that keep the alternative pathway of complement in check are impaired, resulting in excessive complement activation. Acquired and hereditary forms are seen. We avoid the term "atypical HUS" for these syndromes because this is a vague term that was used to describe non-diarrheal HUS in children before the multiple etiologies of non-diarrheal TMA were identified. (See "Complement-mediated hemolytic uremic syndrome".)

Where possible, we no longer use the term TTP-HUS to refer to the primary TMA syndromes, because the terminology presented above facilitates more accurate diagnosis and more appropriate therapy based on the specific underlying cause of the TMA.

OVERVIEW OF OUR APPROACH

Overview for TTP — Untreated, TTP typically follows a progressive course in which neurologic deterioration, cardiac ischemia, irreversible renal failure, and death are common [2]. The mortality rate prior to the 1980s, when effective therapy became available, was approximately 90 percent [2,3]. Prompt, effective treatment is essential for survival.

The mainstay of treatment for TTP is plasma exchange therapy (PEX; also called therapeutic plasma exchange [TPE]), which has converted TTP from a condition with a 90 percent mortality rate to one in which more than 80 percent of patients recover [3-9]. Subsequently, the addition of glucocorticoids to PEX and the use of rituximab have further improved outcomes while decreasing the required duration of PEX [10].

Although PEX can be life-saving, there are several challenges in its use. The first is in deciding whether to initiate PEX because the diagnosis of TTP is made using a combination of clinical and laboratory features. Results of ADAMTS13 activity and inhibitor testing often are not immediately available, and even when they are available, they cannot be used in isolation because they are not sufficiently sensitive or specific for diagnosis. (See "Acquired TTP: Clinical manifestations and diagnosis", section on 'Reduced ADAMTS13 activity'.)

PEX also carries substantial risks, and its use requires the mobilization of individuals with expertise in managing the procedure and operating the apheresis equipment, and in some cases transfer of the patient to another facility. Additionally, use of PEX should not take the place of other treatments directed at other causes of the patient's clinical findings such as complement blockade for complement-mediated hemolytic uremic syndrome (HUS) or antibiotics for sepsis (see "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)"). Other challenges include when to add additional therapies and when to discontinue PEX when a response occurs, or when there is no response and another etiology for MAHA and thrombocytopenia seems likely.

Our general approach is as follows (algorithm 1):

For any patient with a presumptive diagnosis of acquired TTP, we recommend urgent initiation of PEX therapy, together with glucocorticoids and rituximab; this should not be delayed while awaiting results of diagnostic testing. Transfer to a facility capable of performing PEX may be necessary. Early involvement of the consulting clinician with expertise in managing TTP is advised. (See 'Initiation of PEX for a presumptive diagnosis of TTP' below.)

Plasma infusion may be used as a temporizing measure while arranging for PEX, but it is not an alternative to PEX and should not delay initiation of PEX. (See 'Plasma infusion as a temporizing measure' below.)

We give glucocorticoids and rituximab to all patients. This represents a change from our previous approach, which has evolved over time. In the past, we reserved rituximab for selected individuals with severe, refractory, or relapsed disease. We use rituximab as part of initial therapy in all patients whose diagnosis is supported by ADAMTS13 activity <10 percent and/or who have clinical features that support the diagnosis of TTP, or unless there is a contraindication. This practice is based on emerging evidence that rituximab reduces the risk of exacerbation and relapse and may hasten response to therapy. (See 'Glucocorticoids' below and 'Rituximab' below.)

For patients with increasing platelet count during PEX, one of the authors (JNG) continues PEX, glucocorticoids, and rituximab until the platelet count is normal (≥150,000/microL) for at least two days. The other author (AC) continues PEX until the platelet count reaches a stable plateau in the normal or supranormal range for three days, based on the premise that a platelet count of 150,000/microL may not be "normal" for all patients. PEX is discontinued with additional observation, after which the central venous catheter is removed and glucocorticoids are tapered. Glucocorticoids and rituximab dosing and discontinuation are discussed below. (See 'Platelet count increasing' below.)

For patients whose platelet count does not increase, or those who develop a new neurologic abnormality, the diagnosis is reevaluated. Those for whom confidence in the diagnosis remains high are considered to have refractory disease. (See "Acquired TTP: Treatment of refractory or relapsed disease".)

All patients should have ongoing assessment for other diagnoses that may account for clinical worsening, exacerbation of clinical findings, development of new symptoms, or lack of response to PEX. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Platelet transfusion may be required in patients with severe thrombocytopenia who have clinically important bleeding or who require an invasive procedure. (See 'Bleeding/platelet transfusion' below.)

We also monitor all patients closely for complications during PEX, including allergic reactions to plasma and bacteremia or venous thrombosis related to the central venous catheter. (See 'PEX complications' below.)

We do not use eculizumab in the treatment of TTP.

Overview for HUS — The management of hemolytic uremic syndrome (HUS) depends on the underlying etiology, as discussed in separate topic reviews:

Shiga toxin-associated (ST-HUS) – Management in adults is similar to children and may include transfusions, volume and metabolic support, antihypertensive agents, and/or dialysis for acute kidney injury. (See "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children".)

Complement dysregulation – Management of complement-mediated thrombotic microangiopathy (TMA), sometimes referred to as complement-mediated HUS, may include PEX, anticomplement therapy, and/or renal transplantation in severe cases. (See "Complement-mediated hemolytic uremic syndrome".)

HUS following renal transplantation – A variety of causes may be responsible, and therapy depends on the underlying cause. (See "Recurrent and de novo HUS after renal transplantation".)

INITIATION OF PEX FOR A PRESUMPTIVE DIAGNOSIS OF TTP

Rationale and basis for presumptive diagnosis — TTP is a medical emergency that is almost always fatal if appropriate treatment is not initiated promptly. Thus, therapy is initiated in a patient with thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an apparent alternative etiology, who has acquired TTP until proven otherwise. For such patients, we recommend prompt initiation of plasma exchange (PEX) therapy rather than plasma infusion and/or immunosuppressive therapy alone. Therapy should not be delayed while awaiting the results of ADAMTS13 activity levels or inhibitor testing. Although some have suggested that the decision to initiate PEX should be based solely on ADAMTS13 activity, we believe that treatment decisions should be based primarily on clinical criteria (eg, MAHA, thrombocytopenia, neurologic symptoms, lack of an apparent alternative etiology), with ADAMTS13 activity used as supportive evidence [11,12].

The consulting specialist can assist in determining the possibility of another underlying cause of the patient’s symptoms and laboratory abnormalities, facilitate proper testing and initiation of PEX, and assist in identifying a medical center capable of performing PEX if necessary. Additional discussion of features that support a presumptive diagnosis of TTP (or make a presumptive diagnosis of TTP less likely) is presented separately. (See "Acquired TTP: Clinical manifestations and diagnosis".)

Evidence for efficacy of PEX — The use of urgent PEX for presumptive diagnosis of TTP is based on the documented high mortality of TTP without plasma exchange and high quality evidence supporting the use of PEX that was accumulated before routine measurement of ADAMTS13 activity was available. As an example, in a series of 255 patients, three-quarters died within three months; many of those who survived were subsequently diagnosed with another condition such as meningococcal infection [2]. The efficacy of PEX was established in two landmark clinical trials [3,13].

The initial and seminal trial, published in 1991, randomly assigned 102 patients with TTP (defined as MAHA and thrombocytopenia without another identifiable cause) to receive either PEX or plasma infusion for seven days [3]. All patients also received aspirin and dipyridamole, adjunctive treatments that are no longer used. Glucocorticoids were not standard treatment when this clinical trial was performed. Survival was greater in those assigned to PEX than those assigned to plasma infusion at nine days (96 versus 84 percent) and at six months (78 versus 63 percent). Response rates, defined by an increase in platelet count, were also higher with PEX than plasma infusion, both at nine days (47 versus 25 percent) and six months (78 versus 49 percent). The real benefit may be greater because patients whose disease did not respond were able to cross over to receive PEX. At six months, the 31 patients who were treated initially with plasma infusion and were able to cross over to receive PEX had a survival rate of 71 percent.

A second study, also published in 1991, treated 108 patients with TTP (defined by four out of five clinical findings [MAHA, thrombocytopenia, fever, renal dysfunction, central nervous system abnormalities]) [13]. Half of the patients presented with rapid clinical deterioration and received urgent PEX plus glucocorticoids. Half of the patients were clinically stable, without neurologic abnormalities, and received glucocorticoids alone (prednisolone, 200 mg daily); of these, 24 (44 percent) had no response and were then treated with PEX plus glucocorticoids. Of the 78 patients who ultimately received PEX, most responded; following recovery, they were treated with plasma infusion that was tapered over eight days. Exacerbations (referred to as "relapses") occurred in 69 patients (64 percent); most of these occurred within 30 days of diagnosis and would be classified as refractory disease by subsequently developed criteria [1]. There were 10 deaths, nine of which occurred within four days of diagnosis (overall survival, 91 percent).

Multiple subsequent studies have confirmed the efficacy of PEX in TTP, as defined by various criteria [1,9,14,15]. Our interpretation of the accumulated evidence is that PEX is highly effective in individuals with acquired autoimmune TTP [3-5,16]. Some individuals without documented ADAMTS13 deficiency also respond to PEX; some of these patients may have conditions other than TTP, which respond to a simultaneous intervention rather than PEX (eg, resolution of drug-induced thrombotic microangiopathy [DITMA] upon drug discontinuation) [1]. In addition, some patients with complement-mediated TMA may respond to PEX. If the diagnosis of TTP is uncertain but sufficiently likely to warrant the risks of PEX and the potential survival benefit, we initiate PEX and discontinue it subsequently if an alternative diagnosis is discovered, such as a systemic infection or malignancy, DITMA, or documented Shiga toxin-mediated TMA (algorithm 1) [5].

Plasma exchange procedure

Overview of procedure and plasma products — PEX involves removal of the patient’s plasma by apheresis and replacement with donor plasma. In TTP, this is assumed to work by replacing ADAMTS13 and removing the autoantibodies that are inhibiting ADAMTS13 activity as well as any residual ultralarge VWF multimers. Correcting ADAMTS13 deficiency in turn restores proper cleavage of ultralarge von Willebrand factor (VWF) multimers, prevents microvascular thrombosis, and reverses symptoms of organ damage [3,13,16,17]. Plasmapheresis with a non-plasma replacement fluid is not adequate therapy, because it does not replace ADAMTS13. Additional details of the pathophysiology of TTP and the mechanisms by which PEX reverses the underlying lesion in this disorder are presented separately. (See "Pathophysiology of acquired TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis' and "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

PEX therapy almost always requires a central venous catheter with a large bore and two lumens (eg, dialysis catheter) to facilitate the high volume of plasma exchanged at a rapid rate. Rarely, a patient will be able to undergo PEX via peripheral venous access, which avoids potential complications of the central venous catheter. We generally try to avoid use of a femoral catheter due to increased infectious risks; however, these risks are considered acceptable for a short period of time (eg, less than five to seven days) if a catheter is urgently required when a specialist is not available to place a central venous catheter. Additional strategies to minimize catheter complications such as the use of ultrasound guidance are presented separately. (See "Complications of central venous catheters and their prevention".)

Available donor plasma products include Fresh Frozen Plasma (FFP); Thawed Plasma (FFP that has been thawed and stored for up to five days at 1° to 6°C); Cryoprecipitate Reduced Plasma (plasma from which Cryoprecipitate has been removed, also called Cryo-Poor Plasma); and pathogen-inactivated products such as Solvent/Detergent (S/D)-treated or amotosalen-UVA-treated plasma. (See "Clinical use of plasma components", section on 'Plasma products' and "Pathogen inactivation of blood products", section on 'Plasma/FFP'.)

We believe that all of these products are equally efficacious for treating TTP, and the choice of product is determined by the physicians overseeing the procedure. Some clinicians prefer to use specific products; as an example, in the United Kingdom and Canada, S/D Plasma is used almost exclusively due to the potential for reduced viral transmission [18].

Evidence to support the equivalent efficacy of the plasma products comes from extensive personal experience and small trials and case series:

Cryo-Poor Plasma versus FFP – Two small trials (52 and 27 patients) that randomly assigned patients with TTP to receive PEX using Cryo-Poor Plasma versus FFP found no difference in outcomes [19,20]. These trials were conducted after retrospective studies suggested that Cryo-Poor Plasma might be superior to FFP, with the rationale that the lower content of VWF multimers in Cryo-Poor Plasma might reduce the formation of platelet-rich thrombi [17,21-23]. Cryo-Poor Plasma also has a lower content of factor VIII and fibrinogen; thus, if it is used, coagulation assays and fibrinogen levels should be monitored closely, and it should be alternated with another plasma product. (See 'Ongoing evaluation/monitoring' below.)

Pathogen-inactivated plasma versus FFP

A retrospective series of 108 patients with TTP in a French registry who underwent PEX using either S/D plasma or FFP found no difference in disease response between the two products [24].

A trial that randomly assigned 35 patients with TTP to receive PEX with amotosalen-UVA treated plasma or control FFP found comparable outcomes and safety [25].

Several small nonrandomized studies (≤16 patients) and reports comparing PEX for TTP using S/D Plasma versus FFP have found similar efficacy [26-30]. Concerns have been raised about a reduced concentration of the anticoagulant protein S in S/D Plasma, and it has been suggested that appropriate measures to prevent venous thromboembolism (VTE) be used in patients who receive S/D Plasma (eg, mechanical methods in those with severe thrombocytopenia; pharmacologic methods in those with platelets >50,000/microL) [31,32]. These practices are similar to our approach to VTE prevention in all acutely ill medical patients. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

In addition, two small in vitro studies found that the concentration of ADAMTS13 was similar in samples of freshly obtained plasma, FFP, Thawed Plasma, Cryo-Poor Plasma, and S/D Plasma from two different suppliers, further supporting the equivalence of these products in treating TTP [33,34].

Volume and schedule — The recommended volume to be exchanged at each procedure is one estimated plasma volume (approximately 40 mL/kg body weight). PEX is performed daily until recovery occurs (algorithm 1). One of us (JNG) defines recovery as a normal platelet count (≥150,000/microL) for two consecutive days. The other (AC) continues daily PEX until the platelet count reaches a stable plateau in the normal or supranormal range for three consecutive days based on the premise that a platelet count of 150,000/microL may not be normal for some patients. We stop PEX once recovery occurs; we do not taper. Usually, at this time, the hemolysis has also resolved or substantially improved, although schistocytes may remain present (see 'Expected time-course of recovery' below). Also, the serum lactate dehydrogenase (LDH) concentration has become normal or nearly normal, though this can be influenced by removal of LDH with PEX [5,35]. However, we use the platelet count as our definition of response even if other parameters have not returned to normal.

PEX removes plasma proteins and thus will remove rituximab. We adjust the timing such that the rituximab dose is given soon after PEX, rather than before, to minimize this effect. However, if rituximab is inadvertently given immediately before the PEX procedure is due, we do not delay PEX because it is the primary therapy for halting disease activity. Rituximab is effective when given with PEX, possibly because the conventional dose of 375 mg/m2 is more than is needed for an autoimmune disorder. (See 'Rituximab' below.)

Plasma infusion as a temporizing measure — Plasma infusion is not an adequate substitute for PEX in the treatment of acquired TTP, and PEX should not be delayed to allow for plasma infusion or because plasma infusion has been administered. Plasma infusion does not remove the inhibitor (autoantibody) to ADAMTS13, and the volume of plasma (and thus the amount of ADAMTS13) that can be delivered is significantly less than in PEX. This was illustrated in the landmark trial that compared plasma infusion with PEX, in which those undergoing infusion received an average of approximately 7 liters of plasma, compared with approximately 22 liters in those undergoing PEX [3].

However, PEX may not be immediately available to all patients, and plasma infusion may provide temporary benefit in some patients. This was illustrated by a retrospective analysis of 57 patients who received plasma infusion (25 to 30 mL/kg per day) versus PEX, in which infusion was inferior to PEX but was effective in some patients [36]. Adverse events were also greater in the infusion group; six were unable to tolerate the volume of plasma infused and were switched to PEX. Another retrospective review of 20 patients found that plasma infusion had similar efficacy to PEX if equivalent volumes of plasma were administered; however, this may not be feasible in the majority of patients [37].

Thus, for patients with an expected delay in initiating PEX (eg, more than six hours), we use infusion of donor plasma as long as it does not interfere with or delay the appropriate institution of PEX. A reasonable practice is infusion of two units of plasma (approximately 10 to 15 mL/kg); more may be used if tolerated.

IMMUNOSUPPRESSIVE AGENTS — We routinely add a glucocorticoid and rituximab to PEX as initial treatment. (See 'Glucocorticoids' below and 'Rituximab' below.)

As discussed below, the addition of rituximab for routine treatment is based on accumulating evidence that rituximab may reduce the risks of exacerbation and relapse and may hasten the response to therapy. (See 'Rituximab' below.)

Glucocorticoids — We suggest routinely adding glucocorticoids to PEX for initial treatment of patients with a presumptive diagnosis of acquired TTP (algorithm 1). Our practice is consistent with that of most hematologists, despite the lack of randomized trials [5,13,18,38]. The rationale is that the potential benefits in reducing inhibitor production and number of required plasma exchanges outweigh the risks, which are relatively minor for the limited duration of therapy given. Glucocorticoids are thought to reduce production of the ADAMTS13 inhibitor (autoantibody) by mechanisms similar to those in other autoimmune diseases. Other effects such as reduced cytokine production or decreased autoantibody-mediated clearance of ADAMTS13 may also contribute to the efficacy of glucocorticoids.

The dose and route of glucocorticoid administered may vary according to the severity of presentation. A typical dose for a patient who is alert and awake without neurologic abnormalities is oral prednisone (1 mg/kg per day orally); for a more severely affected patient, intravenous methylprednisolone (125 mg two to four times daily) may be appropriate [5]. The intravenous route is also appropriate for individuals with gastrointestinal symptoms who may not be able to take or absorb oral medications.

The glucocorticoid dose is reduced to prednisone 1 mg/kg daily when the platelet count begins to increase, and this regimen is continued after PEX is stopped. When it is determined that the platelet count recovery is sustained following discontinuation of PEX and the central venous catheter is removed (typically, five to seven days), glucocorticoids are tapered and discontinued over two to three weeks.

If the platelet count does not increase within three to four days, higher doses of glucocorticoids may be used (eg, methylprednisolone, 1000 mg daily for three days) [5]. (See "Acquired TTP: Treatment of refractory or relapsed disease", section on 'Refractory disease'.)

Potential toxicities of glucocorticoids are discussed in detail separately. (See "Major side effects of systemic glucocorticoids".)

Evidence for the efficacy of adding glucocorticoids to PEX for the initial treatment of acquired TTP comes from our extensive clinical experience and is illustrated by observational studies such as the following:

Prednisone given alone to patients with suspected acquired TTP who were in stable condition (200 mg daily, without PEX) resulted in some responses (30 of 54 patients; 56 percent), although this observation was made before routine testing for ADAMTS13 activity was available, and some of these patients may not have had acquired TTP [13].

In a trial that randomly assigned 60 patients with TTP to receive high-dose versus low-dose intravenous methylprednisolone (10 mg/kg versus 1 mg/kg daily for three days, followed by 2.5 mg/kg daily for all patients) in addition to PEX, the higher dose was associated with a greater rate of remission (77 versus 47 percent) and a trend towards better survival (one versus four deaths) [39]. Both doses were well tolerated. While this trial did not include a no-glucocorticoid arm, it did suggest a dose-response improvement with glucocorticoids.

Other reports suggesting a role for glucocorticoids in treating relapsed or refractory acquired TTP may be considered as evidence of a potential role for these agents in initial TTP therapy. (See "Acquired TTP: Treatment of refractory or relapsed disease", section on 'Plasma exchange' and "Acquired TTP: Treatment of refractory or relapsed disease", section on 'High-dose glucocorticoids'.)

Rituximab — Rituximab is a chimeric monoclonal antibody directed against CD20, a cell surface protein in mature B cells (not plasma cells) that is used as an immunosuppressive agent in various autoimmune disorders. Mechanisms by which rituximab suppresses autoantibody production are presented separately. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab'.)

Our practice with respect to rituximab has evolved, and we now suggest rituximab as initial therapy in all patients with suspected TTP unless there is a contraindication. This approach is based on emerging evidence from observational studies that rituximab may reduce the risks of exacerbation and relapse and may hasten response to therapy. In the past, we reserved rituximab for selected patients with severe, refractory, or relapsed disease. When confidence in the diagnosis of acquired TTP is high, we do not wait for the results of ADAMTS13 testing before starting rituximab. Rituximab may be delayed until results of ADAMTS13 testing are available in selected individuals (eg, lower confidence in the diagnosis of acquired TTP, greater risk of adverse events from rituximab); it is not clear whether a delay adversely affects the efficacy of rituximab in TTP. Some experts may reasonably omit rituximab due to concerns about toxicity, pending additional data on outcomes.

Randomized trials evaluating the benefit of adding rituximab to PEX therapy in the initial management of acquired TTP are lacking [40,41]. A randomized trial evaluating the benefit of adding rituximab to PEX and glucocorticoids was terminated due to poor accrual (The STAR trial, NCT00799773) [41-44]. The following observational studies illustrate the available evidence for the benefits of rituximab administration during the initial episode of TTP and information about dosing:

A 2017 retrospective cohort study from the United Kingdom TTP Registry evaluated different rituximab dosing regimens in 45 patients with TTP during 76 initial or recurrent episodes who were followed for a median of 15 months [45]. There were three relapses (4 percent), none associated with severe thrombocytopenia, and two of the three occurred in the same patient. Patients were retreated if they had an asymptomatic decrease in ADAMTS13 activity to ≤15 percent, and the proportion who had rituximab readministered were similar in those who received standard dosing (375 mg/m2 once per week for four weeks) or reduced dosing (200 mg once per week for four weeks [not adjusted for body surface area]). Retreatment was used less frequently in those treated with an intermediate dose (500 mg once per week for four weeks [not adjusted for body surface area]), but the duration of follow-up was much shorter, precluding a direct comparison. There were no dosage-based differences in the time to recovery of ADAMTS13 activity. Adverse events (mostly infusion reactions) occurred in 23 cases (30 percent).

Two observational studies (81 patients total) that reported on outcomes in individuals with acquired TTP according to whether they also received rituximab as part of initial therapy both observed a reduced relapse rate in the individuals who received rituximab (relapse rates with rituximab,13 and 11 percent; relapse rates without rituximab, 43 and 55 percent) [46,47]. Rituximab was not associated with major adverse events or excess infections at up to one year of observation, but numbers were very small.

A 2013 retrospective analysis evaluated a cohort of 54 patients for whom rituximab was started within three days of admission (some of whom were enrolled in the study described immediately above) versus a cohort of 32 patients for whom rituximab was started later than three days [48]. Earlier administration of rituximab appeared to be associated with faster attainment of remission and fewer PEX treatments, but numerous potential confounding factors make it difficult to interpret the data [40].

The optimal dose of rituximab in acquired TTP has not been established. We and some others use a dose of 375 mg/m2 intravenously once a week for four consecutive weeks, based on extensive experience with this dose in other conditions [46,49,50]. However, lower doses or other schedules may be equally effective. As an example, others have given the first three doses of rituximab within a week and the fourth dose one week after the third dose [51]. In the retrospective series involving 45 patients with TTP who had declines in ADAMTS13 activity during remission and were treated with different doses of rituximab (approximately two-thirds had more than one TTP episode and were treated more than once), relapse rates were low over a median follow up of 15 months (three relapses, 76 treatments [4 percent]) and showed a trend towards lower risk of relapse with higher rituximab dose that did not reach statistical significance [45]. A trial evaluating the efficacy of giving rituximab at lower doses (100 mg intravenously once per week for four consecutive weeks) together with PEX for the initial treatment of acquired TTP is ongoing, and results may be applicable to refractory disease as well (NCT01554514). The rationale is that autoimmune disorders may require lower doses than lymphoproliferative disorders.

Rituximab administration should be timed to occur immediately after the day's PEX rather than immediately before a cycle of PEX if possible, because PEX will deplete rituximab from the circulation. However, rituximab may be effective even if given on the same day prior to PEX; this may be because the dose of 375 mg/m2 is in excess of the dose required to deplete autoantibody-producing B cells [52].

Rituximab therapy in combination with PEX generally has been well tolerated, with major complications not reported in the larger case series [46,50,51]. 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 contains Boxed Warnings about infusion reactions, hepatitis B reactivation, and PML. These toxicities are discussed in more detail separately. (See "Overview of therapeutic monoclonal antibodies", section on 'Adverse events' and "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Rituximab' and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Our approach to the use of rituximab in the setting of remission and in refractory or relapsed TTP is discussed separately. (See "Acquired TTP: Management following recovery from an acute episode and during remission" and "Acquired TTP: Treatment of refractory or relapsed disease", section on 'Rituximab'.)

SUBSEQUENT THERAPY BASED ON PLATELET COUNT RESPONSE — After plasma exchange (PEX) is initiated, decisions about subsequent therapy are generally made based on the platelet count response. Although some have suggested decisions based solely on ADAMTS13 activity, we believe that treatment decisions should be based primarily on clinical criteria (eg, neurologic symptoms, platelet count) with ADAMTS13 activity used as supportive evidence [11,12]. We consider the entire clinical picture but regard the platelet count trend to be the most reliable measure of disease response.

Platelet count increasing — We use an increase in the platelet count as the primary measure of disease response, although this finding typically is accompanied by other signs of improvement.

Continuation and completion of therapy — As noted above, we continue PEX daily until platelet count recovery. (See 'Volume and schedule' above.)

For initial treatment, our practice is to discontinue PEX abruptly rather than tapering the exchanges because in most patients the response will be durable. This reduces the number of days the central venous catheter is in place, which thereby reduces the risks of catheter-related infections and reduces the total amount of donor plasma exposure.

We continue glucocorticoid treatment (typically prednisone, 1 mg/kg daily) at full dose for an additional five to seven days and then taper the dose over two to three weeks. We continue the full course of rituximab (eg, 375 mg/m2 once per week for four weeks). As noted above, the timing of PEX and rituximab should be adjusted to allow the maximum interval between rituximab administration and the next daily PEX procedure. (See 'Volume and schedule' above.)

We continue to monitor the platelet count at two- to three-day intervals (see 'Ongoing evaluation/monitoring' below). In many cases, this can be done on an outpatient basis, although this practice must be individualized based on the patient’s access to outpatient testing with rapid communication of results, caregiver support, and the ability of the patient to rapidly communicate any change in symptoms to their clinician, as an exacerbation could be life-threatening.

We generally keep the central venous catheter in place for several days after stopping PEX and discharging the patient (if it is an internal jugular or subclavian catheter) to be sure that the platelet count remains normal. This avoids the risks associated with placement of a new catheter if an exacerbation occurs.

The central venous catheter is typically left in place (for three to five days [JNG] or five to seven days [AC]) and the patient’s platelet count is measured every two to three days.

A femoral vein catheter, in contrast, is more prone to infection; these are removed as soon as possible. Even if PEX is ongoing, a femoral vein catheter should be left in place no longer than five to seven days in total due to the infectious risk.

If the platelet count remains normal during this period, we remove the central venous catheter and begin to taper the glucocorticoids rapidly (eg, over two to three weeks). Remissions are durable for the majority of patients, and a rapid taper minimizes glucocorticoid toxicities.

Individuals who have an exacerbation of symptoms or thrombocytopenia, incomplete recovery, or development of new neurologic abnormalities during this period are considered to have refractory disease. Management is presented separately. (See "Acquired TTP: Treatment of refractory or relapsed disease", section on 'Refractory disease'.)

Ongoing evaluation/monitoring — Patients with a presumptive diagnosis of TTP should have ongoing evaluation throughout their hospitalization and treatment, with the goal of identifying other conditions that might be responsible for their symptoms (eg, blood cultures to evaluate for systemic infection). This evaluation is discussed in detail separately. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Once a patient is diagnosed with acquired TTP based on a combination of clinical features and laboratory testing, we monitor the following, usually on a daily basis:

Complete blood count (CBC) with platelet count and review of the peripheral blood smear

Lactate dehydrogenase (LDH) level

Serum creatinine

We monitor coagulation tests (prothrombin time with international normalized ratio [PT/INR], activated partial thromboplastin time [aPTT], fibrinogen) in individuals receiving Cryo-Poor Plasma. (See 'Overview of procedure and plasma products' above.)

The expected improvements in hematologic parameters and creatinine are described below, and ongoing monitoring once PEX has been completed is discussed separately. (See 'Expected time-course of recovery' below and "Acquired TTP: Management following recovery from an acute episode and during remission".)

Patients with an apparent initial response who do not have a complete recovery should also be evaluated for other conditions that may have developed during therapy, such as central venous catheter-associated infection or drug-induced anemia or thrombocytopenia. (See "Acquired TTP: Treatment of refractory or relapsed disease", section on 'Reevaluation of the diagnosis'.)

Individuals who have a return of symptoms, microangiopathic hemolytic anemia (MAHA), or thrombocytopenia not attributable to another cause after stable recovery for a month or more are considered to have relapsed disease. Management is presented separately. (See "Acquired TTP: Treatment of refractory or relapsed disease", section on 'Relapse'.)

Expected time-course of recovery — Several days of PEX typically are required to observe an increasing platelet count, and a week of therapy (or often longer) is required to achieve a response (indicated by normalization of the platelet count). (See 'Terminology' above.)

Some observations of the course of recovery indicate that neurologic symptoms and the serum LDH tend to improve first (often within one day) and the platelet count starts to rise after two to three days. On average, 7 to 10 daily exchanges may be required, but some patients require shorter or longer durations [3,5,13].

Approximately 15 to 20 percent of patients have an exacerbation when PEX is discontinued. An exacerbation is commonly manifested by a decreasing platelet count and rarely by development of new neurologic symptoms. This provides the rationale for keeping the central venous catheter in place for an additional five to seven days after stopping PEX.

Approximately 20 to 25 percent of patients have a relapse of disease following remission, most within the first several years. This provides the rationale for close monitoring, especially during the first year after recovery.

Both of these percentages may be declining with the increasing initial use of glucocorticoids and rituximab.

Platelet count not increasing — There may be several possible explanations for lack of a platelet count increase within the first several days of therapy. In many cases, a change in management is required, either to intensify therapy or to treat another condition that is found to be the initial cause of MAHA and thrombocytopenia (eg, another primary thrombotic microangiopathy [TMA], infection, malignancy) or that has developed during initial therapy (eg, central venous catheter infection). Discussion with the consulting expert is advised to facilitate additional therapy or a change in therapy. Typical presentations of other primary TMAs are discussed separately. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Overview of primary TMA syndromes'.)

Refractory disease — Patients for whom confidence is high in the initial diagnosis of TTP but for whom the disease does not respond to PEX are considered to have refractory disease.

Features that increase our confidence in the initial diagnosis include the following:

Significant MAHA and thrombocytopenia

Mild to no renal insufficiency

Neurologic abnormalities characteristic of TTP (eg, transient focal abnormalities, transient confusion)

Lack of an alternative diagnosis to explain the findings

Severe ADAMTS13 deficiency (eg, activity <10 percent) with an ADAMTS13 inhibitor

Management of acquired TTP that is refractory to initial therapy is presented separately. (See "Acquired TTP: Treatment of refractory or relapsed disease", section on 'Refractory disease'.)

Alternative diagnosis — Patients for whom an alternative diagnosis is established should be treated for the other condition, which may be another primary TMA or a systemic disorder such as malignancy, infection, or pregnancy-associated syndrome.

If the other condition appears to be the primary cause of the initial MAHA and thrombocytopenia, then PEX does not need to be continued.

If the other condition appears to have arisen during therapy for TTP (eg, central venous catheter sepsis), then treatment for TTP should continue while the other condition is treated. The initial central venous catheter may need to be removed and a new central venous catheter placed.

A finding of ADAMTS13 activity >10 percent cannot be used in isolation to conclude that another condition is the cause of the patient’s clinical findings, because prior transfusions may falsely elevate ADAMTS13 activity and not all ADAMTS13 assays are equivalent [12,53], as discussed in more detail separately (see "Acquired TTP: Clinical manifestations and diagnosis", section on 'Reduced ADAMTS13 activity'). However, a patient with normal or only mildly reduced ADAMTS13 activity should have a thorough evaluation for other potential causes of MAHA and thrombocytopenia. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

The importance of continuing to evaluate the possibility of alternative diagnoses has been illustrated by our experience of occasionally finding a systemic malignancy or infection that only became apparent after extensive investigations [54-56].

PEX COMPLICATIONS — Patients undergoing plasma exchange (PEX) for acquired TTP are at risk for serious complications related to the central venous catheter and exposure to donor plasma (eg, allergic reactions, transfusion-related acute lung injury [TRALI]). (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)

Compared with patients undergoing PEX for other indications, those with TTP may be at greater risk of complications due to the large volume and long duration of PEX required for therapy. As an example, a full course of PEX may take one to two weeks; one study estimated that 115 units of plasma are needed to treat a 60 kg patient [25].

Major complications of PEX occur in approximately one-quarter of patients with TTP, and catheter-related complications, especially sepsis from the central venous catheter, tend to be more potentially life-threatening than effects of donor plasma exposure. This has been illustrated in a series of reports from the Oklahoma TTP-HUS Registry, which has reported data at three-year intervals from all consecutive patients presenting to 12 local hospitals who are referred for PEX therapy for suspected TTP beginning in 1996 [10,57].

In an overview of 342 patients, seven (2 percent) died from complications of PEX, four from sepsis, and three from catheter insertion (hemorrhage, pneumothorax) [58]. Additional major complications included the following:

Systemic infection – 12 percent

Catheter obstruction – 5 percent

Catheter-related venous thrombosis requiring systemic anticoagulation – 2 percent

Hemorrhage (eg, pulmonary, pericardial, retroperitoneal) – 1 percent

Plasma-related complications including hypotension, anaphylaxis, serum sickness, or hypoxia that required stopping PEX – 7 percent

A continuous decline in complications has been observed over a 15-year period of observation [10]. Compared with patients presenting at earlier time points, patients enrolled in the Oklahoma TTP-HUS Registry from 2008 to 2011 had the following improved outcomes:

Lower treatment-related mortality (no deaths from 2008 to 2011, versus seven deaths from 1998 to 2008)

Fewer catheter-related complications (27 versus 15 percent)

Fewer major complications

No change in complications related to donor plasma exposure

This decline in catheter-related complications likely reflects a reduction in the mean number of days of PEX due to the use of more aggressive immunosuppression (eg, glucocorticoids, rituximab) and stopping PEX abruptly rather than tapering the exchanges following recovery. Additional factors that may have contributed to the reduction in complications include the use of ultrasound guidance for central venous catheter insertion and enhanced prevention of nosocomial infections. (See "Central catheters for acute and chronic hemodialysis access", section on 'Ultrasound guidance' and "Prevention of intravascular catheter-related infections".)

Of note, we do not routinely premedicate patients before PEX; however, patients with allergic reactions to PEX (eg, hives) may be pretreated with diphenhydramine 50 mg intravenously and hydrocortisone 100 mg intravenously [59]. Hydrocortisone may reasonably be omitted for individuals receiving high-dose glucocorticoids as part of TTP therapy. For individuals with anaphylaxis to donor plasma, factor VIII concentrate containing sufficient amounts of ADAMTS13 (Koate-DVI) may be efficacious [60-62]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications", section on 'Anaphylactic reactions' and "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'Factor VIII concentrates and Von Willebrand factor'.)

BLEEDING/PLATELET TRANSFUSION — Clinically important bleeding is rare in patients with TTP in spite of severe thrombocytopenia. We do not use platelet transfusions to correct thrombocytopenia unless clinically important bleeding occurs, or unless an invasive procedure is required that may cause significant blood loss. In a large observational study comparing outcomes of platelet transfusion in patients with TTP versus other causes of platelet consumption, patients with TTP who had an arterial thrombosis were more likely than not to have received platelet transfusion [63]. However, these data cannot be interpreted as evidence that platelet transfusions were causally associated with arterial thrombosis. It is likely that platelet transfusions were given to patients with more severe illness and the occurrence of arterial thrombosis may have been unrelated to the platelet transfusion.

Importantly, we do not withhold platelet transfusions needed to manage bleeding for fear of "fueling the fire" [64]. This practice is supported by a systematic literature review of patients with TTP that included a prospective review of the clinical course of 54 consecutive patients, which concluded that there was no evidence of harm from platelet transfusions in TTP [64].

Additional information regarding the use of platelet transfusions for treatment of bleeding is presented separately. (See "Clinical and laboratory aspects of platelet transfusion therapy", section on 'Indications for platelet transfusion' and "Clinical and laboratory aspects of platelet transfusion therapy", section on 'TTP or HIT'.)

Insertion of a central venous catheter appears to be safe at any platelet count level, even levels <10,000/microL. However, the ultimate decision regarding platelet transfusion prior to central venous catheter placement is made by the person performing the procedure.

THERAPIES UNDER DEVELOPMENT — Therapies under development include recombinant ADAMTS13 and antibodies to von Willebrand factor (VWF).

Recombinant ADAMTS13 — Recombinant ADAMTS13 is being studied initially in clinical trials in patients with hereditary TTP, which will be the initial indication for this product if the trials are successful. The applicability of this therapy for patients with acquired TTP is uncertain. (See "Hereditary thrombotic thrombocytopenic purpura (TTP)", section on 'Therapies under development'.)

Anti-VWF (caplacizumab) — Binding of ultralarge von Willebrand factor (VWF) multimers to platelets is thought to be responsible for the formation of small vessel microthrombi in acquired TTP, and blocking the VWF-platelet interaction is expected to interrupt this process. (See "Biology and normal function of von Willebrand factor", section on 'Binding to platelets' and "Pathophysiology of acquired TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis'.)

Caplacizumab is a humanized monoclonal antibody-based fragment (a nanobody) that binds to VWF and blocks VWF interaction with platelet GPlb-IX-V. In a trial that randomly assigned 75 patients with acquired TTP to receive caplacizumab or placebo (all patients received standard plasma exchange [PEX]), caplacizumab was associated with a two-day reduction in the time to complete response (3 versus 4.9 days) [65]. Other endpoints also favored caplacizumab, including the frequency of complete remission (81 versus 46 percent) and the number of days of PEX (8 versus 12). Of interest, caplacizumab was associated with fewer TTP exacerbations during therapy but more exacerbations after therapy was stopped, suggesting a lack of effect on anti-ADAMTS13 antibody levels. There were no major adverse events. However, caplacizumab was associated with a greater risk of bleeding, consistent with its mechanism of blocking VWF-platelet binding. Bleeding was mostly minor and did not require administration of factor VIII or VWF. There were two deaths, both in the placebo group (one from refractory TTP and one from cerebral hemorrhage). Extended follow-up identified a lower rate of major thromboembolic events in the caplacizumab group compared with placebo (3 versus 19 percent); the majority of thromboembolic events occurred within the first month [66]. Caplacizumab is not yet available outside of a clinical trial [67].

SPECIAL SCENARIOS

Acquired TTP during pregnancy — Plasma exchange (PEX) is the treatment of choice for acquired TTP occurring during pregnancy, despite the resulting removal of pregnancy-maintaining hormones [13,68]. This practice is based on the observation of maternal and fetal mortality rates of approximately 90 percent without PEX. (See "Thrombocytopenia in pregnancy".)

In a series of 108 patients, nine women who were pregnant were in their third trimester at the time of initial presentation of acquired TTP; all successfully completed their pregnancies, with delivery of 10 healthy infants [13].

The UK TTP Registry reported their experience with 12 women with acquired TTP in whom the initial episode occurred during pregnancy [68]. Treatment included PEX and glucocorticoids.

Two women presented before 20 weeks gestation; one pregnancy resulted in intrauterine fetal demise; in the other, treatment of TTP was successful but the pregnancy was terminated for unrelated fetal abnormalities.

Four women presented between 21 to 29 weeks gestation; all were successfully treated but there was only one live birth; three pregnancies resulted in intrauterine fetal demise.

Six women presented after 30 weeks gestation; all were successfully treated and all had live births.

Delivery does not cause resolution of TTP; in fact, pregnancy-associated acquired TTP may occur more commonly postpartum. Thus, premature delivery should be considered only for obstetric indications, such as the presence of severe preeclampsia. (See "HELLP syndrome", section on 'Differential diagnosis'.)

There have been no reports of transmission of TTP from a pregnant woman to an infant [13,69,70]. However, intrauterine fetal death may occur due to placental infarction caused by thrombosis of the decidual arterioles [71].

Management of pregnancy following recovery from an episode of TTP is presented separately. (See "Acquired TTP: Management following recovery from an acute episode and during remission" and "Hereditary thrombotic thrombocytopenic purpura (TTP)", section on 'Pregnancy'.)

HIV infection — Acquired TTP is rare in patients with human immunodeficiency virus (HIV) infection [72]. For those patients with HIV who have acquired TTP (or with a high confidence in a presumptive diagnosis of acquired TTP), treatment with PEX therapy is similar to other patients, in addition to appropriate HIV treatment.

More commonly, HIV is associated with other causes of kidney disease, thrombocytopenia, or anemia [72]. Management of these complications is presented separately. (See "Overview of kidney disease in HIV-positive patients" and "Hematologic manifestations of HIV infection: Anemia" and "Hematologic manifestations of HIV infection: Thrombocytopenia and coagulation abnormalities" and "Mycobacterium avium complex (MAC) infections in HIV-infected patients".)

Patient who cannot accept plasma/Jehovah's Witness — Very rarely, a patient may not be able to accept plasma as a replacement fluid during PEX (eg, Jehovah’s Witness). As an alternative, such patients may be treated with high-dose glucocorticoids (eg, methylprednisolone, 1000 mg intravenously per day for three days followed by doses described above) (see 'Glucocorticoids' above) plus rituximab (see "Acquired TTP: Treatment of refractory or relapsed disease", section on 'Rituximab'). If the patient will accept plasma derivatives, factor VIII concentrates containing sufficient amounts of ADAMTS13 (eg, Koate-DVI) may be used [60-62]. Plasmapheresis with albumin as the replacement fluid and other forms of immunosuppression have also been used [73].

SUMMARY AND RECOMMENDATIONS

Thrombotic thrombocytopenic purpura (TTP) is a medical emergency that is almost always fatal if appropriate treatment is not initiated promptly. For patients with a presumptive diagnosis of TTP (eg, thrombocytopenia and microangiopathic hemolytic anemia [MAHA] without an obvious underlying cause), we recommend prompt initiation of plasma exchange (PEX) therapy rather than plasma infusion and/or immunosuppressive therapy alone (Grade 1B). Therapy should not be delayed while awaiting the results of ADAMTS13 activity levels (algorithm 1). Early involvement of the consulting specialist is advised to assist in decision making, testing, and facilitating urgent initiation of PEX. (See 'Overview of our approach' above and 'Initiation of PEX for a presumptive diagnosis of TTP' above.)

PEX is performed daily. The choice of replacement plasma (eg, Fresh Frozen Plasma [FFP], Solvent/Detergent [S/D] Plasma) is determined by the physicians overseeing the procedure. PEX therapy almost always requires a central venous catheter with a large bore and two lumens. (See 'Plasma exchange procedure' above.)

Plasma infusion is not an adequate substitute for PEX in the initial treatment of TTP, and plasma infusion should not delay initiation of PEX. However, we use plasma infusion as a temporizing measure if an unavoidable delay in PEX is expected. (See 'Plasma infusion as a temporizing measure' above.)

For patients with a presumptive diagnosis of acquired TTP, we suggest administration of a glucocorticoid (Grade 2C). A typical regimen is prednisone, 1 mg/kg per day orally or intravenous methylprednisolone 125 mg two to four times daily intravenously. (See 'Glucocorticoids' above.)

For patients with a presumptive diagnosis of acquired TTP, we suggest administration of rituximab (Grade 2C). This is based on accumulating evidence that rituximab may reduce the risks of exacerbation and relapse and may hasten response to therapy. We use a dose of 375 mg/m2 weekly for four weeks; lower doses may be equally effective. Some experts may reasonably omit rituximab due to concerns about toxicity, pending additional data on outcomes. (See 'Rituximab' above.)

Individuals whose platelet count responds receive continued PEX and glucocorticoids until platelet count recovery as defined above (see 'Volume and schedule' above), at which time PEX is discontinued. Additional monitoring is used to confirm disease response, after which the central venous catheter is removed and glucocorticoids are tapered rapidly. (See 'Platelet count increasing' above.)

There may be several possible explanations for lack of a platelet count increase within the first several days of therapy. In many cases, a change in management is required, either to intensify therapy or to treat another condition that is found to be the initial cause of MAHA and thrombocytopenia (eg, another primary thrombotic microangiopathy [TMA], infection, malignancy) or that has developed during initial therapy (eg, central venous catheter infection). (See 'Platelet count not increasing' above.)

Complications of PEX include those related to the central venous catheter and those related to donor plasma exposure (eg, allergic reactions, transfusion-related acute lung injury). Major complications of PEX occur in approximately one-quarter of individuals undergoing PEX for acquired TTP. (See 'PEX complications' above and "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)

We do not use routine prophylactic platelet transfusions in TTP. However, appropriate transfusions should not be withheld if needed for the treatment of bleeding or an invasive procedure. (See 'Bleeding/platelet transfusion' above.)

Acquired TTP during pregnancy (or postpartum) is treated with PEX. Delivery does not cause resolution of TTP, and premature delivery should be considered only for obstetric indications such as the presence of severe preeclampsia. (See 'Acquired TTP during pregnancy' above.)

Management following recovery from the acute episode of acquired TTP, and treatment of refractory and relapsed disease are presented separately. (See "Acquired TTP: Management following recovery from an acute episode and during remission" and "Acquired TTP: Treatment of refractory or relapsed disease".)

Management of related TMAs including hemolytic uremic syndrome (HUS), drug-induced TMA (DITMA), and complement-mediated TMA is discussed separately; definitions of these syndromes and the topic reviews that discuss their management are listed above. (See 'Terminology' above.)

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

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