Immune TTP: Initial treatment

INTRODUCTION — Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) caused by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13, which leads to small-vessel platelet-rich thrombi, thrombocytopenia, and microangiopathic hemolytic anemia. Some patients may have neurologic abnormalities, mild renal insufficiency, and/or low-grade fever. We divide TTP into immune (autoimmune, acquired) and hereditary syndromes, which are due to an autoantibody against ADAMTS13 and biallelic ADAMTS13 gene variants, respectively.

This topic reviews our approach to the initial therapy of immune TTP, defined by severe ADAMTS13 deficiency (activity level usually <10 percent). This condition is a medical emergency that is almost always fatal if appropriate treatment is not initiated promptly; with appropriate treatment, survival rates of more than 95 percent are possible.

The following aspects of care for individuals with immune TTP are discussed separately:

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

●Management during recovery – (See "Immune TTP: Management following recovery from an acute episode and during remission".)

●Refractory/relapsed disease – (See "Immune TTP: Treatment of clinical relapse".)

The evaluation and management of other primary TMAs is also presented separately:

●Evaluation – (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

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

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

●TMAs with acute kidney injury (AKI) (adults) – (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)

●TMAs with AKI (children) – (See "Complement-mediated hemolytic uremic syndrome in children" and "Overview of hemolytic uremic syndrome in children".)

●Pregnancy syndromes – (See "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)" and "Thrombocytopenia in pregnancy", section on 'Preeclampsia with severe features/HELLP (PE/HELLP)'.)

TERMINOLOGY — Terminology for TTP and related conditions has evolved as the etiology of these syndromes becomes clearer. Our preferred terminology is summarized briefly here and in the table (table 1) and discussed in more detail in the linked topic reviews:

●Thrombotic microangiopathy (TMA) – TMA describes a pathologic lesion in which abnormalities in the vessel wall of arterioles and capillaries lead to microvascular thrombosis, microangiopathic hemolysis, and thrombocytopenia. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Overview of primary TMA syndromes'.)

●Immune TTP versus hereditary TTP – Immune TTP (iTTP; also called acquired or autoimmune TTP) is the TMA caused by autoantibodies to ADAMTS13, the protease that cleaves ultralarge von Willebrand factor (VWF) multimers. Hereditary TTP refers to the TMA caused by biallelic ADAMTS13 mutations. (See "Diagnosis of immune TTP".)

●Outcomes of immune TTP – The following outcomes may be seen after treatment (TPE, glucocorticoids, rituximab, and sometimes anti-VWF therapy such as caplacizumab) [1]:

•Response and remission (table 1)

-Clinical response – Sustained normalization of the platelet count and LDH <1.5 times the upper limit of normal with therapeutic plasma exchange (TPE) and/or anti-VWF therapy (caplacizumab), with no new or progressive manifestations of ischemic organ injury.

-Clinical remission – Either a sustained clinical response for ≥30 days after stopping TPE and caplacizumab or attainment of a partial or complete ADAMTS13 remission (whichever occurs first).

-ADAMTS13 remission – ADAMTS13 activity recovery to ≥20 percent is a partial ADAMTS13 remission; ADAMTS13 activity recovery to the lower limit of normal for the assay or greater is a complete ADAMTS13 remission.

•Refractory disease and relapse

-Refractory disease – Lack of a clinical response; becoming increasingly rare with use of rituximab and anti-VWF therapy.

-Disease exacerbation – Recurrence of thrombocytopenia without another cause following a response but ≤30 days after stopping TPE or anti-VWF therapy.

-Clinical relapse – Recurrence of thrombocytopenia following a remission without another cause (subsequently must be confirmed by documenting ADAMTS13 activity <10 percent).

-ADAMTS13 relapse – ADAMTS13 activity <20 percent following an ADAMTS13 remission.

Monitoring for these outcomes and interventions for exacerbation and relapse are discussed separately. (See "Immune TTP: Management following recovery from an acute episode and during remission" and "Immune TTP: Treatment of clinical relapse".)

We no longer use the broad term TTP-HUS to refer to the primary TMA syndromes because the terminology presented above specifies the underlying cause of the TMA and facilitates appropriate therapy.

OVERVIEW OF TREATMENT APPROACH — Several therapies are available for treatment of TTP, including therapeutic plasma exchange (TPE), glucocorticoids, rituximab, and caplacizumab. They differ in their mechanisms of action, short- and long-term efficacy, risks, burdens, and costs. When deciding on the use of these treatments, we risk-stratify patients based on clinical and laboratory findings at presentation. (See 'PLASMIC score to quantify a presumptive diagnosis of TTP' below and 'Incorporating results of ADAMTS13 testing' below.)

Virtually every decision point in the therapy of TTP is based on a combination of clinical and laboratory features, and the best choice involves a risk-benefit analysis for the individual patient, as illustrated in the figure (algorithm 1). Early involvement of the consulting clinician with expertise in managing TTP is advised.

We do not use eculizumab for treatment of TTP.

PLASMIC score to quantify a presumptive diagnosis of TTP — The PLASMIC score is used to quantify the likelihood of TTP, which may support initiation of presumptive treatment before ADAMTS13 activity is available.

The PLASMIC score assigns points for a number of positive and negative clinical features (thrombocytopenia; hemolytic anemia; lack of cancer, macrocytosis, coagulopathy, or renal failure) (calculator 1).

We make a presumptive diagnosis of TTP when the PLASMIC score is in the intermediate to high range (5 to 7 points) or if there are other reasons to have a high suspicion of immune TTP. A presumptive diagnosis is sufficient to initiate treatment while awaiting confirmatory ADAMTS13 testing, as discussed below (see 'Plasma exchange for all patients with a presumptive diagnosis of TTP' below). The use of the PLASMIC score in the presumptive diagnosis of TTP is discussed in more detail separately. (See "Diagnosis of immune TTP", section on 'Presumptive diagnosis'.)

Incorporating results of ADAMTS13 testing — TTP is initially a clinical diagnosis that is confirmed by a subsequent finding of severely deficient ADAMTS13 activity. (See 'PLASMIC score to quantify a presumptive diagnosis of TTP' above and "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Deficient ADAMTS13 activity'.)

Few institutions have immediate access to the results of ADAMTS13 activity testing; in many institutions, this is a send-out test with a turnaround time of up to a week, although this may change as the potential benefits of rapid turnaround time for this testing become more apparent (see "Diagnosis of immune TTP", section on 'ADAMTS13 testing'). If ADAMTS13 activity results are not rapidly available, therapy is initiated and continued based on the clinical diagnosis, with results of ADAMTS13 activity incorporated when they do become available.

For those who have immediate access to ADAMTS13 activity, this may be incorporated into initial decision-making. In such cases, activity <10 percent, indicative of severe deficiency, can provide confidence in the diagnosis of TTP (algorithm 1).

ADAMTS13 measurements have some sources of error (see "Diagnosis of immune TTP", section on 'Assay considerations'), but we generally use the following interpretations:

●ADAMTS13 <10 percent – If the ADAMTS13 activity is <10 percent, this constitutes severe deficiency and confirms the clinical diagnosis of TTP.

●ADAMTS13 10 to 20 percent – If the ADAMTS13 activity is between 10 and 20 percent, this may support the diagnosis of TTP in some individuals (eg, those for whom TPE was already ongoing when the ADAMTS13 test was sent), and we continue TPE along with other therapies. However, we also search more aggressively for other causes of the patient's presenting symptoms and laboratory findings in these individuals. (See 'Ongoing search for other causes of MAHA and thrombocytopenia' below.)

●ADAMTS13 >20 percent – If the ADAMTS13 activity is >20 percent, the diagnosis of TTP becomes very unlikely, and it is often appropriate to discontinue TTP therapy, unless the clinical features are especially compelling for the diagnosis of TTP [2]. (See 'Alternative diagnosis' below.)

There are rare exceptions, in which patients with severely deficient ADAMTS13 activity can have an alternative etiology for thrombocytopenia and MAHA. We have seen 5 patients in whom ADAMTS13 activity was <10 percent but clinical features suggested an alternative diagnosis that was subsequently confirmed [3]. Alternatively, some patients with TTP may have initial ADAMTS13 activity measurements of 10 to 20 percent [4]. A unique patient had ADAMTS13 activity of 53 percent at presentation; his ADAMTS13 activity was <10 percent when subsequent relapses occurred [2]. This may represent dissociation of the inhibitory autoantibody from ADAMTS13 during the incubation for the assay.

Plasma exchange for all patients with a presumptive diagnosis of TTP — Therapeutic plasma exchange (TPE) remains the mainstay of treatment for TTP [5]. All patients with a presumptive clinical diagnosis of TTP and/or a confirmed diagnosis based on severely deficient ADAMTS13 activity are treated with TPE until their platelet count recovers or until an alternate diagnosis is established. (See 'Therapeutic plasma exchange' below.)

TPE is used for all patients because, if untreated, TTP typically follows a progressive course in which neurologic deterioration, cardiac ischemia, irreversible renal failure, and death are common [6]. Supporting evidence for TPE is discussed below. (See 'Evidence for efficacy of TPE' below.)

Although TPE can be life-saving, the decision to initiate TPE can be challenging because it is a clinical decision that synthesizes clinical and laboratory features; results of ADAMTS13 activity and inhibitor testing often are not immediately available. Even when ADAMTS13 results become available, they cannot be used in isolation because they are not sufficiently sensitive or specific for diagnosis of an acute TTP episode.

TPE also carries substantial risks, and its use requires the mobilization of individuals with expertise in managing the procedure and operating the apheresis equipment. In some cases, transfer of the patient to another facility may be required. Plasma infusion may be used as a temporizing measure while arranging for TPE, especially if the patient requires transfer to another facility and can be treated with plasma prior to transport, but it is not an alternative to TPE and should not delay initiation of TPE. (See 'TPE complications' below and 'Plasma infusion as a temporizing measure' below.)

Medical therapies (glucocorticoids, rituximab, caplacizumab) — We generally make decisions about medical therapy based on clinical features quantified in the PLASMIC score, since ADAMTS13 activity may not be immediately available.

In centers with access to very rapid turnaround of ADAMTS13 results (hours), it may be reasonable to wait to start these therapies until severe ADAMTS13 deficiency (typically <10 percent) is documented. (See 'Incorporating results of ADAMTS13 testing' above.)

●Glucocorticoids – We use glucocorticoids in addition to TPE in all patients in whom TTP is suspected (based on PLASMIC score in the intermediate or high-risk range, 5 to 7 points) or confirmed (severe ADAMTS13 deficiency, activity <10 percent). Glucocorticoids were a strong recommendation in the 2020 International Society on Thrombosis and Haemostasis (ISTH) Guidelines [5]. We generally use oral prednisone for routine presentations and high-dose methylprednisolone for presentations with high-risk features as defined below. (See 'Glucocorticoids' below.)

●Rituximab – We do not use rituximab until severe ADAMTS13 deficiency is confirmed. Once severe ADAMTS13 deficiency is confirmed, we add rituximab for all patients. (See 'Rituximab' below.)

●Caplacizumab – We use caplacizumab as initial treatment only for patients who warrant more aggressive initial therapy. Examples include:

•Severe features of TTP:

-Neurologic abnormalities (seizures, focal weakness, aphasia, dysarthria, confusion, coma)

-Symptoms suggesting encephalopathy (eg, "It seemed like I could not wake her up this morning")

-High serum troponin levels

•Thrombocytopenia due to TTP that does not improve after 2 to 3 days of TPE, glucocorticoids, and rituximab

This is based on our experience and uncertainty about the use of caplacizumab in unselected patients [7]. (See 'Anti-VWF (caplacizumab)' below.)

Additional information about the efficacy, dosing, and adverse effects of glucocorticoids, rituximab, and caplacizumab is presented below. (See 'Glucocorticoids' below and 'Rituximab' below and 'Anti-VWF (caplacizumab)' below.)

Other aspects of supportive care — Most patients will improve with treatment. However, vigilance is needed for other potential complications of TTP, complications of the TPE catheter, or adverse effects of transfusion or medications. As examples:

●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.)

●Treatment may be required for complications during TPE, including allergic reactions to plasma, and bacteremia or thrombosis related to the central venous catheter. (See 'TPE complications' below.)

●Individuals with neurologic findings should be evaluated by the neurology consultant. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".)

●Individuals with increased troponin should be evaluated by the cardiology consultant. (See "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome".)

●Thrombocytopenia is not protective against thrombosis. Venous thromboembolism prophylaxis should be administered, though mechanical prophylaxis may be preferred over pharmacologic prophylaxis in patients with severe thrombocytopenia (platelet count <30,000/microL) or active bleeding. Treatment of thrombosis (venous or arterial) should not be withheld if indicated. (See "Anticoagulation in individuals with thrombocytopenia".)

Ongoing search for other causes of MAHA and thrombocytopenia — Individuals with a suspected diagnosis of TTP may have a primary thrombotic microangiopathy (TMA) other than TTP (eg, drug-induced TMA [DITMA]) or another cause of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia such as cancer or disseminated intravascular coagulation (DIC). 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 TPE. Other possible diagnoses are summarized separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Ongoing evaluation is especially important for patients whose platelet count does not increase with treatment, including caplacizumab, those with an ADAMTS13 activity >20 percent, those who have transient improvement followed by worsening, or those who develop a new neurologic abnormality. In some cases, a patient with TTP may develop a complication such as catheter-associated sepsis. (See 'TPE complications' below.)

Those for whom confidence in the diagnosis of TTP remains high but for whom therapy (including caplacizumab) does not result in recovery are considered to have refractory disease, which is expected to be extremely rare in the caplacizumab era. (See "Immune TTP: Treatment of clinical relapse".)

THERAPEUTIC PLASMA EXCHANGE — We use TPE for all patients with a presumptive clinical diagnosis of TTP or a confirmed diagnosis of TTP based on severely deficient ADAMTS13 activity (<10 percent) (algorithm 1).

Volume and schedule — The recommended volume to be exchanged at each procedure is one estimated plasma volume (approximately 40 mL/kg body weight). This is continued once daily until recovery or until the diagnosis of TTP has been excluded and an alternative diagnosis has been established. Plasma is used as the replacement fluid. (See 'Overview of procedure and plasma products' below.)

TPE removes certain biologic therapies including monoclonal antibodies. Therapeutic monoclonal antibodies should therefore be administered after the TPE session:

●Rituximab – Rituximab is given soon after TPE, rather than before, to minimize removal of rituximab by TPE. However, if rituximab is inadvertently given immediately before the TPE procedure is due, we do not delay TPE; TPE is the primary therapy for halting disease activity. Rituximab may be effective even if given on the same day prior to TPE; this may be because the standard dose of 375 mg/m² is in excess of the dose required to deplete autoantibody-producing B cells [8]. (See 'Rituximab' below.)

●Caplacizumab – Caplacizumab is given as an initial intravenous dose followed by subcutaneous administration. The product information for caplacizumab specifies that the first dose be given at least 15 minutes prior to initiation of TPE, and that the first subcutaneous dose be given after completion of plasma exchange on day 1 (two doses are given on the same day; one intravenously before TPE and the other subcutaneously after TPE). (See 'Anti-VWF (caplacizumab)' below.)

Discontinuation of TPE is discussed below. (See 'Continuation and completion of therapy' below.)

Venous access — TPE 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 TPE 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 (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 "Central venous catheters: Overview of complications and prevention in adults".)

Overview of procedure and plasma products — Plasma is used as the replacement fluid because it repletes ADAMTS13. Plasmapheresis with a non-plasma replacement fluid is not adequate therapy.

Available 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 effective for treating TTP, and the choice of product is determined by the clinicians overseeing the procedure and product availability. Some clinicians prefer to use specific products; as an example, in the United Kingdom and Canada, S/D Plasma may be used due to the potential for reduced viral transmission [9].

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 TPE using Cryo-Poor Plasma versus FFP found no difference in outcomes [10,11]. 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 [12-15]. 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.

●Pathogen-inactivated plasma versus FFP

•A retrospective series of 108 patients with TTP in a French registry who underwent TPE using either S/D plasma or FFP found no difference in disease response between the two products [16].

•A trial that randomly assigned 35 patients with TTP to receive TPE with amotosalen-UVA-treated plasma or control FFP found comparable outcomes and safety [17].

•Several small nonrandomized studies (≤16 patients) and reports comparing TPE for TTP using S/D Plasma versus FFP have found similar efficacy [18-22]. 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 >30,000/microL) [23,24]. 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".)

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 [25,26].

Evidence for efficacy of TPE — TPE 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 removing residual ultralarge von Willebrand factor (VWF) multimers. Correcting ADAMTS13 deficiency in turn restores proper cleavage of ultralarge VWF multimers, prevents microvascular thrombosis, and reverses symptoms of organ damage [12,27-29].

The efficacy of TPE was established in a landmark randomized clinical trial published in 1991 [27]. A separate review of the experience of a single institution supported the efficacy of TPE and of glucocorticoids (which were not used in the randomized trial) [28].

●The initial and seminal trial randomly assigned 102 patients with TTP (defined as MAHA and thrombocytopenia without another identifiable cause) to receive either TPE or plasma infusion for seven days [27]. 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 TPE than in 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 TPE than plasma infusion, both at nine days (47 versus 25 percent) and six months (78 versus 49 percent). The real benefit of TPE compared with plasma infusion may be even greater because patients whose disease did not respond to plasma infusion were able to cross over to receive TPE. At six months, the 31 patients who were treated initially with plasma infusion and who were able to cross over to receive TPE 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, kidney dysfunction, central nervous system abnormalities]) [28]. Half of the patients presented with rapid clinical deterioration and received urgent TPE 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 TPE plus glucocorticoids. Of the 78 patients who ultimately received TPE, 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 [30]. 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 TPE in TTP, as defined by various criteria [30-33]. Our interpretation of the accumulated evidence is that TPE is highly effective in individuals with immune TTP [27,29,34,35].

Some individuals with features typical of TTP who do not have documented ADAMTS13 deficiency also have a response to TPE; some of these patients may have conditions other than TTP that respond to a simultaneous intervention rather than TPE (eg, resolution of drug-induced thrombotic microangiopathy [DITMA] upon drug discontinuation) [36]. In addition, some patients with complement-mediated TMA may have a response to TPE [36].

Additional details of the pathophysiology of TTP and the mechanisms by which TPE reverses the underlying lesion in this disorder are presented separately. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis' and "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

TPE complications — Complications may be 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 TPE for other indications, those with TTP may be at greater risk of complications due to the large volume and multiple courses of TPE required for therapy. As an example, a full course of TPE may take one to two weeks; one study estimated that 115 units of plasma are needed to treat a 60 kg patient [17].

We do not routinely premedicate patients before TPE; however, patients with allergic reactions to plasma (hives) may be pretreated with diphenhydramine 50 mg intravenously and hydrocortisone 100 mg intravenously [37]. 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 effective [38-40]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications", section on 'Anaphylactic reactions' and "Hemophilia A and B: Routine management including prophylaxis", section on 'Factor VIII products for hemophilia A'.)

Major complications of TPE 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 Registry.

In a series of 68 patients who had an initial episode of TTP between 1996 and 2014, three individuals (4.4 percent) died from complications of TPE (one from pulmonary hemorrhage caused by central venous catheter insertion and two from sepsis) [3]. Among the 65 survivors, 36 (55 percent) patients had nonfatal major complications of TPE, which included the following:

●Systemic infection (documented bacteremia) – 12 patients (18 percent)

●Catheter-related venous thrombosis requiring systemic anticoagulation – 3 patients (5 percent)

●Adverse effects of plasma: anaphylaxis, cardiac arrest – 1 patient

A decline in complications has been observed over a 15-year period of observation [41]. This likely reflects a reduction in the mean number of days of TPE due to the use of more aggressive immunosuppression (glucocorticoids, rituximab) and stopping TPE 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 venous catheters for acute and chronic hemodialysis access and their management" and "Routine care and maintenance of intravenous devices".)

Plasma infusion as a temporizing measure — Plasma infusion is not an adequate substitute for TPE in the treatment of immune TTP, and TPE 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 TPE. This was illustrated in the landmark trial that compared plasma infusion with TPE in which those undergoing infusion received an average of approximately 7 liters of plasma, compared with approximately 22 liters in those undergoing TPE [27]. (See 'Evidence for efficacy of TPE' above.)

However, TPE 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 TPE, in which infusion was inferior to TPE but was effective in some patients [42]. Adverse events were also greater in the infusion group; six were unable to tolerate the volume of plasma infused and were switched to TPE. Another retrospective review of 20 patients found that plasma infusion had similar efficacy to TPE if equivalent volumes of plasma were administered; however, this may not be feasible in the majority of patients [43].

Like plasma infusion, caplacizumab may serve as a temporizing measure if TPE is not immediately available. (See 'Anti-VWF (caplacizumab)' below.)

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

IMMUNOSUPPRESSIVE AGENTS — The addition of glucocorticoids and rituximab has further improved outcomes while decreasing the required duration of therapeutic plasma exchange (TPE) [41]. We give glucocorticoids to all patients with an intermediate to high PLASMIC score (5 to 7 points) (algorithm 1). We add rituximab for all patients once severe ADAMTS13 deficiency (activity <10 percent) is confirmed. 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 'Glucocorticoids' below and 'Rituximab' below.)

Glucocorticoids — Glucocorticoids are thought to hasten recovery because they 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.

●Indications – We routinely add glucocorticoids to TPE for initial treatment of patients with a presumptive diagnosis of immune TTP. Our practice is consistent with a 2020 Guideline from the International Society on Thrombosis and Haemostasis (ISTH), despite the lack of randomized trials [5,9,28,35,44]. The rationale is that the potential benefits in reducing inhibitor production and number of required TPE treatments outweigh the risks, which are relatively minor for the limited duration of therapy given [5].

●Dosing – There is limited evidence to guide glucocorticoid dosing. We generally adjust the dose and route of administration according to the severity of presentation [35]. (See 'Medical therapies (glucocorticoids, rituximab, caplacizumab)' above.):

•Standard risk – A typical dose for a patient who is alert and awake without neurologic abnormalities or elevated troponin is prednisone 1 mg/kg per day orally. If the patient is receiving prednisone 1 mg/kg per day orally and the platelet count does not increase within three to four days, we switch to methylprednisolone 1000 mg per day intravenously until a response is seen. Caplacizumab may also be added if available. (See 'Anti-VWF (caplacizumab)' below.)

•High risk – For a more severely affected patient (neurologic or cardiac abnormalities, platelet count not improving), intravenous methylprednisolone 1000 mg as a single daily dose for three days or 125 mg two to four times daily may be appropriate. This is continued as long as the patient remains at high risk. For most individuals, we taper this dose to avoid potentially severe side effects. The taper is individualized based on the patient's clinical status. If the patient is clinically improving, we switch to prednisone 1 mg/kg per day orally [35]. These doses are based on extrapolating from doses in other severe autoimmune disorders such as systemic lupus erythematosus, and even in those conditions, there is very limited evidence to guide optimal dosing [45]. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus".)

The intravenous route is also appropriate for individuals with gastrointestinal symptoms who may not be able to take or absorb oral medications.

●Duration – Prednisone 1 mg/kg daily is continued after TPE is stopped. Tapering and discontinuation is discussed below. (See 'Continuation and completion of therapy' below.)

●Adverse effects – Potential toxicities of glucocorticoids are discussed separately. (See "Major adverse effects of systemic glucocorticoids".)

●Supporting evidence – Evidence for the efficacy of adding glucocorticoids to TPE for the initial treatment of immune TTP comes from our extensive clinical experience and is illustrated by observational studies such as the following:

•Prednisone given alone to patients with suspected immune TTP who were in stable condition (200 mg daily, without TPE) 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 TTP [28].

•A randomized clinical trial involving 26 patients that compared prednisone at 1 mg/kg daily versus cyclosporine at 2 to 3 mg/kg daily found that prednisone was superior to cyclosporine for increasing ADAMTS13 activity and suppressing anti-ADAMTS13 antibodies [46].

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

●Indication – We suggest rituximab as initial therapy in all patients with a confirmed diagnosis of TTP (ADAMTS13 activity <10 percent) unless there is a contraindication (algorithm 1). In patients in whom confidence in the diagnosis is high, it may be reasonable to start rituximab before the ADAMTS13 activity result returns, especially if a prolonged turnaround time is anticipated. Some experts may reasonably omit rituximab due to concerns about toxicity, pending additional data on outcomes; the 2020 Guideline from the ISTH gives a conditional recommendation for rituximab for a first episode of TTP [5].

●Dose – The optimal dose of rituximab in immune 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 [47-49]. 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 [50]. A prospective study that used a lower rituximab dose (100 mg approximately once per week for four weeks) reported similar response rates and reductions in relapse, suggesting that this approach may provide similar efficacy with reduced costs and burdens [51]. The rationale is that autoimmune disorders may require lower doses than lymphoproliferative disorders. Additional study is needed to determine whether toxicity and long-term outcomes are better with the lower dose.

●Timing – As noted above, rituximab administration should be timed to occur immediately after the day's TPE rather than immediately before a cycle of TPE, if possible, because TPE will remove rituximab from the circulation. (See 'Volume and schedule' above.)

●Adverse effects – Rituximab therapy in combination with TPE generally has been well tolerated, with major complications not reported in the larger case series [48-50]. 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: Principles of use and adverse effects in rheumatoid arthritis", section on 'Adverse effects' and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

●Supporting evidence – Support for using rituximab up front comes from observational studies that demonstrate reduced rates of exacerbation and relapse and possibly faster response to therapy. Studies were summarized in a meta-analysis from 2019 that reported improved outcomes with rituximab [52]:

•Lower relapse rate when used during the acute TTP episode (odds ratio [OR] 0.40, 95% CI 0.19-0.85)

•Lower relapse rate when used preemptively during recovery (OR 0.09, 95% CI 0.04-0.24)

•Lower mortality rate during follow-up (OR 0.41, 95% CI 0.18-0.91)

Randomized trials evaluating the benefit of adding rituximab to TPE in the initial management of immune TTP are lacking [53,54]. A randomized trial evaluating the benefit of adding rituximab to TPE and glucocorticoids as initial treatment was terminated due to poor accrual (The STAR trial, NCT00799773) [54].

Use of preemptive rituximab during remission is discussed separately. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Rituximab during remission to prevent relapse'.)

ANTI-VWF (CAPLACIZUMAB) — Caplacizumab is a humanized monoclonal antibody fragment (a bivalent, variable-domain-only fragment) that binds to von Willebrand factor (VWF) and blocks VWF interaction with platelet glycoprotein lb-IX-V (GPlb-IX-V). Binding of ultralarge VWF multimers to platelets is thought to be responsible for the formation of small vessel microthrombi in immune TTP, and by blocking the VWF-platelet interaction, caplacizumab reduces formation of these microthrombi. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis'.)

Based on its mechanism of action (blocking the interaction of VWF on the vessel wall with platelets), caplacizumab is expected to rapidly halt the formation of microthrombi that cause disease complications, but it is not expected to reduce production of the autoantibody against ADAMTS13 that is responsible for blocking ADAMTS13 activity and promoting microthrombi.

Caplacizumab is available in a restricted fashion in Europe and was approved by the US Food and Drug Administration in February 2019. The indication for approval was for initial treatment of TTP together with therapeutic plasma exchange (TPE) and immunosuppressive agents.

●Indications – The optimal incorporation of caplacizumab into clinical practice remains to be determined. Many hematologists are using caplacizumab as routine initial treatment, together with TPE, glucocorticoids, and rituximab. Our use of caplacizumab is increasing but we do not use it for all patients. We are more likely to use caplacizumab in patients with severe features because the absolute benefit and cost-effectiveness is likely to be greatest in this group (algorithm 1). The 2020 International Society on Thrombosis and Haemostasis Guideline makes a conditional recommendation in favor of using caplacizumab for immune TTP [5].

•For patients with a presentation that includes severe features such as critical illness, neurologic findings, or high troponin levels, we suggest caplacizumab as a component of initial therapy. The rationale is that these individuals are most likely to die during the acute episode and early death may be reduced by a more rapid halting of the underlying disease process. Supporting evidence is discussed below.

•For individuals without severe features on presentation, we suggest not using caplacizumab initially (ie, reserving it for refractory disease) (see "Immune TTP: Treatment of clinical relapse", section on 'Caplacizumab, glucocorticoids, and rituximab'). The rationale is that most individuals who lack severe features will improve with TPE and immunosuppression alone and are less likely to die or have long-term complications from the acute episode. Moreover, caplacizumab is very expensive and can increase the risk of bleeding, and its cost-effectiveness has been questioned [7].

We also recognize that there are rare situations in which caplacizumab can replace TPE as initial treatment. Examples include:

-Patients who decline or refuse blood products [55]

-Patients who have a severe allergic reaction to plasma or a need to avoid TPE for other reasons [56,57]

-Patients who have a rapid platelet count response to caplacizumab and therefore TPE is deferred [58]

While there have been successful cases of caplacizumab administration without TPE, we would avoid this approach until it has been more thoroughly studied [57].

●Dose – The unit dose of caplacizumab for the initial intravenous and subsequent subcutaneous administrations is one vial. The amount of the product listed in the United States package insert is 11 mg. However, this is the same dose that was referred to as 10 mg in clinical trials and approved for use in Europe labeled as 10 mg. This apparent difference reflects a different interpretation of the measurements of the amount of drug recovered from the vial.

The dose and schedule of caplacizumab from clinical trials was 10 mg intravenously on day 1 followed by 10 mg subcutaneously on day 1 after TPE (ie, two doses on the first day) and continued once daily subcutaneously for 30 days after TPE has been stopped. We base discontinuation on an increase in ADAMTS13 activity to above 20 to 30 percent rather than on a fixed duration of treatment. (See 'Continuation and completion of therapy' below.)

●Adverse effects – Caplacizumab can increase the risk of bleeding. Among two randomized trials and three real-world studies, minor bleeding occurred in approximately one-third of patients and major bleeding in 13 out of 343 total patients (4 percent) [59]. Caplacizumab was discontinued due to bleeding in 17 patients total (5 percent). If caplacizumab-associated clinically significant bleeding occurs, this may be treated with VWF concentrate, although clinical experience is extremely limited, as noted below.

●Supporting evidence – Evidence to support the efficacy of caplacizumab in TTP comes from two randomized trials (HERCULES and TITAN) as well as published reports of real-world experience.

•Randomized trials – The HERCULES trial randomly assigned 145 patients (mostly adults) with a clinical diagnosis of immune TTP to receive caplacizumab or placebo daily until 30 days beyond the last TPE procedure [60].All patients received daily TPE and glucocorticoids, and slightly less than half received rituximab. Caplacizumab treatment resulted in:

-Fewer deaths (1 with caplacizumab versus 3 with placebo [1 versus 4 percent]).

-Faster normalization of the platelet count, which correlated with fewer days of TPE (mean, 5.8 versus 9.4).

-Fewer exacerbations (12 versus 38 percent). Exacerbations occurred up to 25 days after stopping TPE.

-Shorter hospitalization (mean, 9.9 versus 14.4 days) and fewer days in the intensive care unit (mean, 3.4 versus 9.7).

Caplacizumab was well tolerated but was associated with more bleeding (65 versus 48 percent). One caplacizumab-treated patient with severe epistaxis was treated with VWF concentrate.

The TITAN trial (75 patients randomly assigned to caplacizumab or placebo) reported essentially the same results as HERCULES, with faster responses, reduced use of TPE, and fewer exacerbations [61].

•Real world – Additional studies have compared outcomes in caplacizumab-treated patients (235 patients total from among three studies, including children) with historical controls [62-64]. These all showed similar findings to those from the randomized trials, with more rapid improvement in the platelet count of caplacizumab-treated patients (typically within three to four days) than seen with controls. Bleeding occurred with caplacizumab but it was mostly mild; rare, severe cases were treated with VWF concentrate as mentioned above. In some individuals, the platelet count increased to above the normal range (thrombocytosis).

SUBSEQUENT THERAPY BASED ON RESPONSE — After therapeutic plasma exchange (TPE) is initiated, patients should have ongoing evaluation throughout their hospitalization and treatment. This evaluation is discussed in detail separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Our approach to tapering therapy is illustrated in the figure (algorithm 2) and summarized below.

Monitoring schedule (platelet count and ADAMTS13 activity) — We usually monitor the platelet count as the primary measure of disease response; an increase in the platelet count is typically accompanied by other signs of improvement. We consider good evidence of a platelet count response to be a platelet count ≥150,000/microL for at least two days or a stable plateau in the normal or supranormal range for three days. (See 'Continuation and completion of therapy' below.)

●Daily – Complete blood count (CBC) with platelet count and lactate dehydrogenase (LDH). Microangiopathic changes (schistocytes) may persist on the blood smear after thrombocytopenia has resolved.

●Weekly – We usually monitor the ADAMTS13 activity on a weekly basis after discontinuation of TPE, with the understanding that results may not be immediately available. This continues after discharge from the hospital. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Monitoring and therapy after response to treatment'.)

Decisions about subsequent therapy are generally made based on the platelet count response and clinical criteria (eg, resolution of neurologic symptoms), with ADAMTS13 activity used as supportive evidence (algorithm 2). We consider the entire clinical picture but regard the platelet count trend to be the most reliable measure of clinical response. ADAMTS13 activity is a useful adjunct to other findings in helping to guide therapy, but we do not use results of ADAMTS13 activity in isolation to guide initial decision-making [65,66]. Preemptive rituximab for ADAMTS13 relapse is discussed separately. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Rituximab during remission to prevent relapse'.)

Platelet count increasing

Continuation and completion of therapy — An approach to withdrawing therapy after recovery is summarized briefly here and presented in more detail separately. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'First month'.)

Therapy is continued and completed based on the following schedule:

●TPE – TPE can be stopped abruptly once clinical recovery has occurred. One of the authors (JNG) continues TPE until the platelet count is normal (≥150,000/microL) for at least two days. The other author (AC) continues TPE 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. We discontinue TPE abruptly rather than tapering because tapering has not been shown to increase the likelihood of a durable response. Eliminating the taper reduces the number of days the central venous catheter is in place, thereby reducing the risks of catheter-related infections and the total amount of donor plasma exposure.

●Central venous catheter – Timing of catheter removal depends on the risks and burdens of having to replace the catheter if the platelet count drops and TPE needs to be restarted. We generally keep the central venous catheter in place for several days (eg, for three to five days [JNG] or five to seven days [AC]) after stopping TPE 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. In some centers in which catheter replacement is easy to perform, the catheter may be removed earlier. A femoral vein catheter, in contrast, is more prone to infection; these are removed as soon as possible. Even if TPE 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.

●Glucocorticoids – We continue glucocorticoid treatment (typically prednisone, 1 mg/kg daily) at full dose after stopping TPE. We initiate a glucocorticoid taper once the ADAMTS13 activity is above 20 to 30 percent. The taper is completed over the ensuing two to three weeks. Responses are durable for the majority of patients, and this rapid taper minimizes glucocorticoid toxicities.

●Rituximab – We continue the full course of rituximab (eg, 375 mg/m² once per week for four weeks). As noted above, the timing of TPE and rituximab should be adjusted to allow the maximum interval between rituximab administration and the next daily TPE procedure. (See 'Volume and schedule' above.)

●Caplacizumab – For patients treated with caplacizumab, we continue therapy after TPE is stopped. Continuing therapy until ADAMTS13 activity recovers is important to avoid exacerbations of disease upon discontinuation of caplacizumab. We discontinue caplacizumab once the ADAMTS13 activity is above 20 to 30 percent, even if this is before the 30-day continuation period recommended in the US Food and Drug Administration package insert. If the ADAMTS13 activity has not recovered to over 20 to 30 percent by 30 days after the end of TPE, we continue the caplacizumab until the ADAMTS13 activity recovers (ie, longer than specified in the package insert). For individuals who have persistent severe ADAMTS13 deficiency despite a course of rituximab, discontinuation of caplacizumab is individualized; one approach is to discontinue caplacizumab 30 days after completion of the course of rituximab.

We continue to monitor the platelet count at two- to three-day intervals. 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 a clinical exacerbation could be life-threatening.

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

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

Recovery may be more rapid if caplacizumab is incorporated into initial therapy. (See 'Anti-VWF (caplacizumab)' 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 [27,28,35].

●Approximately 15 to 20 percent of patients have an exacerbation when TPE is discontinued. A clinical exacerbation is commonly manifested by a decreasing platelet count and rarely by development of new neurologic symptoms. Use of caplacizumab until ADAMTS13 recovery reduces the occurrence of exacerbations.

●Approximately 40 percent of patients have a clinical relapse following remission when rituximab is not used; most of these relapses occur within the first several years. With rituximab, the frequency of relapse was decreased to 13 percent [52]. As noted above, this supports the routine use of rituximab at the time of initial therapy. (See 'Immunosuppressive agents' above.)

Platelet count not increasing — There may be several possible explanations for lack of a platelet count increase (or incomplete platelet count recovery) 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. Discussion with the consulting expert is advised to facilitate additional therapy or a change in therapy.

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

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

●Significant microangiopathic hemolytic anemia (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 immune TTP that is refractory to initial therapy is presented separately. (See "Immune TTP: Treatment of clinical relapse", section on 'Refractory disease'.)

Alternative diagnosis — A condition other than immune TTP may be responsible for the entire clinical picture (eg, drug-induced TMA [DITMA]), or may have arisen after treatment for TTP was initiated (eg, development of central catheter-associated sepsis). Patients with an apparent initial response who do not have a complete recovery should be evaluated for these possibilities. 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 [67-69].

●If the other condition appears to be the primary cause of the initial MAHA and thrombocytopenia, then TPE 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 [66,70], as discussed in more detail separately. (See "Diagnosis of immune TTP", 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 "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

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 [71]. 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 not have been causally related to the platelet transfusion.

Importantly, we do not withhold platelet transfusions needed to manage bleeding for fear of "fueling the fire" [72]. 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 [72].

Additional information regarding the use of platelet transfusions for treatment of bleeding is presented separately. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Indications for platelet transfusion' and "Platelet transfusion: Indications, ordering, and associated risks", 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

Recombinant ADAMTS13 — Recombinant ADAMTS13 is being studied in clinical trials in patients with hereditary and immune TTP. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)".)

SPECIAL SCENARIOS

Immune TTP during pregnancy — Therapeutic plasma exchange (TPE) is the treatment of choice for immune TTP occurring during pregnancy, despite the resulting removal of pregnancy-maintaining hormones [28,73]. This practice is based on the observation of maternal and fetal mortality rates of approximately 90 percent without TPE. (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 immune TTP; all successfully completed their pregnancies, with delivery of 10 healthy infants [28].

●The United Kingdom TTP Registry reported their experience with 12 women with immune TTP in whom the initial episode occurred during pregnancy [73]. Treatment included TPE 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.

Rituximab can be given safely during the first trimester of pregnancy because immunoglobulins do not cross the placenta during the first trimester [74]. (See "Placental development and physiology", section on 'Immunoglobulin G transfer'.)

There is no information about the safety of caplacizumab during pregnancy.

Delivery does not cause resolution of TTP; in fact, pregnancy-associated immune 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 (hemolysis, elevated liver enzymes, and low platelets)", section on 'Differential diagnosis'.)

There have been no reports of transmission of TTP from a pregnant woman to an infant [28,75,76]. However, intrauterine fetal death may occur due to placental infarction caused by thrombosis of the decidual arterioles [77].

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

HIV infection — Immune TTP is rare in patients with HIV infection [78]. For those patients with HIV who have immune TTP (or with a high confidence in a presumptive diagnosis of immune TTP), treatment with TPE 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 [78]. Management of these complications is presented separately. (See "Overview of kidney disease in patients with HIV" and "HIV-associated cytopenias" and "Mycobacterium avium complex (MAC) infections in persons with HIV".)

Patient who cannot accept plasma/Jehovah's Witness — Very rarely, a patient may not be able to accept plasma as a replacement fluid during TPE, as is the case with some Jehovah's Witnesses. (See "Approach to the patient who declines blood transfusion", section on 'Jehovah's Witnesses'.)

Options for such patients include the following:

●Discussion with their religious advisors, as practice with respect to use of plasma and other non-cellular blood products varies widely even within a common belief system.

●Caplacizumab. (See 'Anti-VWF (caplacizumab)' above.)

Caplacizumab without TPE has not been studied systematically. However, we successfully used caplacizumab to treat a Jehovah's Witness with immune TTP (ADAMTS13 activity <5 percent) who declined TPE and whose disease did not respond to immunosuppressive therapy [55]. She had a dramatic improvement in platelet count within one day of starting caplacizumab and remained well with normal ADAMTS13 activity following a 30-day course.

●High-dose glucocorticoids (eg, methylprednisolone, 1000 mg intravenously per day for three days followed by doses described above) plus rituximab [79]. (See 'Immunosuppressive agents' above.)

●If the patient will accept plasma derivatives, factor VIII concentrates containing sufficient amounts of ADAMTS13 (eg, Koate-DVI) may be used [38-40]. Plasmapheresis with albumin as the replacement fluid and other forms of immunosuppression have also been used [80].

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

SUMMARY AND RECOMMENDATIONS

●Initial treatment – Thrombotic thrombocytopenic purpura (TTP) is a medical emergency that is almost always fatal if appropriate treatment is not initiated promptly. Therapeutic plasma exchange (TPE) is the mainstay of treatment for all individuals with a presumptive diagnosis of TTP based on a PLASMIC score (calculator 1) in the intermediate- to high-risk range (5 to 7 points) and confirmed by a finding of severe ADAMTS13 deficiency. We use glucocorticoids routinely for all patients, rituximab for all patients with confirmed TTP, and caplacizumab for selected patients (algorithm 1). (See 'Overview of treatment approach' above.)

•TPE – For all patients with a presumptive or confirmed diagnosis of immune TTP, we recommend prompt initiation of TPE rather than plasma infusion and/or immunosuppressive therapy alone (Grade 1B). (See 'Evidence for efficacy of TPE' above.)

-TPE is performed daily with plasma as the replacement fluid. Complications include catheter-associated sepsis and transfusion reactions. (See 'Overview of procedure and plasma products' above and 'Volume and schedule' above and 'TPE complications' above.)

-Plasma infusion does not substitute for TPE and should not delay TPE initiation but can be used as a temporizing measure. (See 'Plasma infusion as a temporizing measure' above.)

•Glucocorticoids – In addition to TPE, for all patients with a presumptive or confirmed diagnosis of immune TTP, we suggest a glucocorticoid (Grade 2C). A typical regimen is prednisone, 1 mg/kg per day orally; for individuals with high-risk features, methylprednisolone 1000 mg per day intravenously for the first three days followed by prednisone 1 mg/kg/day may be used. (See 'Glucocorticoids' above.)

•Rituximab – Once TTP is confirmed (ADAMTS13 activity <10 percent), we suggest rituximab (Grade 2C). Rituximab reduces risks of exacerbation and relapse and may hasten clinical response. We administer 375 mg/m² weekly for four weeks; lower doses may be equally effective. Some experts may reasonably omit rituximab due to concerns about toxicity. (See 'Rituximab' above.)

•Caplacizumab – For patients with severe features (critical illness, neurologic findings, high troponin), we suggest caplacizumab (Grade 2B). Some experts may reasonably use caplacizumab more broadly, and some may omit caplacizumab. (See 'Anti-VWF (caplacizumab)' above.)

●When to stop – We discontinue TPE when the platelet count is ≥150,000/microL for at least two days or in the normal or supranormal range for three days (algorithm 2). Daily platelet counts and weekly ADAMTS13 activity are monitored after TPE is discontinued. Tapering of glucocorticoids and discontinuation of caplacizumab are based on ADAMTS13 activity recovery. Once-weekly rituximab is continued for four weeks total. Terminology for remission is summarized in the table (table 1). Management following recovery is discussed separately. (See 'Subsequent therapy based on response' above and "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Rituximab during remission to prevent relapse'.)

●Lack of response – Possible explanations include refractory disease, alternative diagnoses, or development of a complication (catheter-associated sepsis). A change in management is often required. (See 'Platelet count not increasing' above.)

●Pregnancy – Immune TTP during pregnancy (or postpartum) is treated with TPE. Delivery does not treat TTP, and premature delivery should be considered only for obstetric indications. (See 'Special scenarios' above.)

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