Thrombotic Thrombocytopenic Purpura (TTP)

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Practice Essentials

Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder characterized by clotting in small blood vessels (thromboses), resulting in a low platelet count.[1, 2] In its full-blown form, the disease consists of the following pentad:

To make an accurate diagnosis, the clinician must recognize the similarity between TTP and hemolytic-uremic syndrome (HUS).[3] In addition to HUS, the differential diagnosis includes immune thrombocytopenia (ITP) and disseminated intravascular coagulation (DIC), two entities with very different modes of therapy (see the image below).



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Differential diagnosis of immune thrombocytopenia (ITP), thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC).

Secondary TTP has been associated with the use of certain drugs, including chemotherapy drugs such as gemcitabine and mitomycin and antiplatelet agents such as clopidogrel and ticlopidine.[4] If secondary TTP is suspected, the offending drug should be discontinued.

Signs and symptoms

TTP can affect any organ system, but involvement of the peripheral blood, the central nervous system, and the kidneys causes the clinical manifestations. Patients with TTP typically report an acute or subacute onset of symptoms related to neurologic dysfunction, anemia, or thrombocytopenia, as follows:

See Presentation for more detail.

Diagnosis

Laboratory studies for suspected TTP include a CBC, platelet count, peripheral blood smear, coagulation studies, BUN and creatinine, and serum bilirubin and lactate dehydrogenase.

Most sporadic cases of TTP appear to be associated with severe deficiency of ADAMTS13 activity due to autoantibodies against this protease.[5, 6, 7]  Measuring ADAMTS13 activity level may aid in diagnosis.

Imaging studies and biopsies are not required for diagnosis.

See Workup for more detail.

Management

The therapy of choice for TTP is plasma exchange with fresh frozen plasma. Because only 20-30% of patients present with the classic pentad, initiating total plasma exchange is justified by the presence of microangiopathic hemolytic anemia (schistocytes, elevated LDH, and indirect hyperbilirubinemia) and thrombocytopenia in the absence of other obvious causes (DIC, malignant hypertension). 

Octaplas (Octapharma) is a sterile, frozen solution of pooled human plasma from several donors. It is a viable alternative to single-donor plasma, and it is treated with a solvent detergent process, which reduces the risk of infection.[8]

Caplacizumab (Cablivi), a nanobody that targets von Willebrand factor (vWF), is approved for treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in combination with plasma exchange and immunosuppressive therapy. It has been shown to reduce time to platelet count response and also to reduce aTTP-related death, recurrence, or major thromboembolic events.[9]

A recombinant ADAMTS13 (Adzynma) was approved by the FDA in 2023 for prophylactic or on-demand enzyme replacement therapy in adults and children with congenital thrombotic thrombocytopenic purpura (cTTP).

In patients with TTP refractory to plasma exchange, using cryopoor plasma (or cryosupernatant) has sometimes led to a response. This is fresh frozen plasma that has had the cryoprecipitate removed and is thus depleted of high-molecular-weight von Willebrand multimers, which have a pathogenic role in TTP.

Corticosteroids may also be used in refractory TTP. Rituximab, although not approved for use in TTP, is increasingly recommended for refractory cases.

See Treatment and Medication for more detail.

Pathogenesis

TTP can affect any organ system, but involvement of the peripheral blood, the central nervous system, and the kidneys causes the clinical manifestations. The classic histologic lesion is one of bland thrombi in the microvasculature of affected organs. These thrombi consist predominantly of platelets, with little fibrin and red cells compared with thrombi that occur secondary to intravascular coagulation.

Patients with TTP have unusually large multimers of von Willebrand factor (vWF) in their plasma, and they have functional deficiency of a plasma protease that is responsible for the breakdown of these ultralarge vWF multimers. This protease has been isolated and cloned and is designated ADAMTS13 (A Disintegrinlike And Metalloprotease with ThromboSpondin type 1 motif 13).[10]  The accumulation of ultralarge vWF multimers on the endothelial surface results in platelet aggregation and eventually thrombus formation.[2]

In more than 95% of cases, TTP is an acquired disorder that is due to autoantibodies that inhibit plasma ADAMTS13 activity; this form is termed immune-mediated TTP.[11, 12]  In the remainder of cases, TTP is an inherited disorder in which mutations in the ADAMTS13 gene result in severe deficiency of functional plasma ADAMTS13.[13, 5] Hereditary or congenital TTP,  also called Upshaw‐Schulman syndrome, accounts for less than 5% of all TTP cases but may account for 25% to 50% of cases in some patient populations, such as young children and pregnant women.[11]  

In addition to immune and congenital TTP, a third form of TTP has been tentatively identified, and termed unidentified TTP. In contrast to immune TTP, anti-ADAMTS13 IgG antibodies are lacking in unidentified TPP. Significantly, whereas in patients with immune TTP, ADAMTS13 circulates in plasma in an open configuration, which makes it available for autoantibodies to bind with it, in unidentified TPP ADAMTS13 circulates in closed conformation, as is typical of healthy persons. Compared with immune TTP, unidentified TTP is less likely to occur in women, it tends to occur in older individuals, and patients more often have associated cancers and less often have accompanying autoimmune diseases.[14, 15]

While ADAMTS13 deficiency seems a necessary etiologic factor, by itself it may not be sufficient to induce TTP. Endothelial activation, caused by  endogenous or exogenous factors and affecting mainly microvascular cells, has been proposed as a "second hit" that triggers TTP.[16]  Triggers for TTP include infections, such as COVID-19[17] ; pregnancy; autimmune disease; hematopoietic stem cell transplantation; and drugs, such as mitomycin, cyclosporine, cisplatin, bleomycin, quinine, ticlopidine and alemtuzumab.[18] Whether the drugs and/or their metabolites have a direct effect on the vascular endothelium or whether alteration of the endothelial cells results in a neoantigen that leads to autoantibody formation remains unknown.

Although the signs and symptoms of TTP overlap with those of classic hemolytic-uremic syndrome (HUS), ADAMTS13 activity is normal in most patients with classic HUS. This suggests a differing pathogenesis of these closely related entities.[19]

Epidemiology

Exact incidence figures for the United States are not available, although TTP is thought to be rare. In one series, the frequency was approximately 1 in 50,000 hospital admissions. Over a 25-year period in the Sacramento, California region (population at risk, 1.2 million), at least 176 documented cases of TTP were reported. In another 1-year study, 20 institutions reported 115 patients with TTP.

Analysis of a French national registry found that the rate of TTP in France was 13 cases per million population.[7]  The age-sex standardized incidence of TTP has been estimated at 2.2 cases per million population per year in the United Kingdom and 3.2 cases per million population per year in Saskatchewan, Canada.[20]  A systematic review estimated that worldwide, the incidence rate of acute episodes of immune TTP was 1.81-3.93 per million persons per year.[21]

Mortality/morbidity

Untreated, TTP has a mortality rate of as high as 90%. With plasma exchange, the mortality rate is reduced to 10-20%.

Acute morbidities include ischemic events such as stroke, transient ischemic attacks, myocardial infarction and cardiac arrhythmia, bleeding, and azotemia. TTP during pregnancy may precipitate fetal loss.[22]

In general, survivors have no long-term sequelae, with the exception of residual neurologic deficits in a minority of patients. However, relapses are not uncommon, occurring in 13-36% of patients.

Racial, sexual, and age-related disparities

An ethnic predisposition to TTP is not established. In the larger series reported, a female predominance of approximately 2:1 has been noted.

In several large studies, the median age at TTP diagnosis is approximately 40 years. However, in the authors' series of 126 consecutive patients, the median age was 52 years. This stands in contrast with HUS; 90% of cases of HUS occur in children. Bouw et al have presented a review article of TTP in children.[23]

Prognosis

The overall response rate to plasma exchange is 75-90%.The early mortality rate is 10-20%.

Long-term survival depends largely on the presence or absence of serious underlying comorbidities such as cancer, HIV infection, or solid organ transplantation. In the authors' series of 126 patients, the estimated 10-year survival rate of patients without comorbid conditions was 82%, compared with a survival rate of 50% in those with comorbid conditions.

A clinical severity score, incorporating the presence or absence of neurologic symptoms, creatinine, platelet count, and hemoglobin, was shown to be predictive of 30-day mortality in the authors' retrospective analysis. The absence of fever and a higher creatinine level was associated with a higher rate of relapse. However, upon further analysis of a larger cohort of patients (as yet unpublished), these factors are no longer predictive.

A study by Staley et al of 73 patients with immune-mediated TTP found that the following findings on admission were associated with higher mortality[24] :

Other findings predictive of higher mortality included the following[24] :

Shumak et al reported that more than one third of patients who survive an acute episode of TTP will have at least one relapse in the following 10 years.[25] French researchers found that patients who have had acute TTP are at increased risk for development of an autoimmune disorder—most often, systemic lupus erythematosus (SLE) or Sjögren syndrome—for as long as 12 years afterward. Risk was highest in patients who had anti–double-stranded (ds)DNA antibodies (hazard ratio [HR] 4.98) or anti-SSA antibodies (HR 9.98) at the time of TTP diagnosis. These researchers recommend prolonged follow-up to detect any autoimmune disorder early in its course.[26]

History

Patients with thrombotic thrombocytopenic purpura (TTP) typically report an acute or subacute onset of the following signs and symptoms related to central nervous system (CNS) dysfunction, anemia, or thrombocytopenia:

Clinical manifestations may also include the following:

Physical Examination

Patients with TTP have no characteristic physical findings. Findings upon examination depend on the severity of involvement of the target organ systems.

Hemolytic anemia and thrombocytopenia cause pallor, jaundice, and petechiae. Abnormal findings on neurologic examination consist of mental status changes and/or focal neurologic deficits. These defects can be evanescent and, thus, present as transient ischemic attacks. Organomegaly is not typical.

Laboratory Studies

Complete blood count (CBC) findings in patients with thrombotic thrombocytopenic purpura (TTP) are usually as follows:

Peripheral blood smears reveal moderate-to-severe schistocytosis. Early in the course of the illness, schistocytes may not be seen, but eventually they will be present. Some experts consider schistocytosis the sine qua non for diagnosis.

Prothrombin time (International Normalized Ratio) and activated partial thromboplastin time results typically are normal in both TTP and in hemolytic-uremic syndrome (HUS), although some series report patients with slight elevations on both tests.

D-dimer and fibrinogen assay findings are as follows:

Evaluation of kidney function with a blood urea nitrogen (BUN) and creatinine level is necessary to establish the presence and severity of acute kidney injury. This also aids in differentiating HUS from TTP, but patients classified as TTP in some studies have had an elevated creatinine level and those with HUS have had neurologic abnormalities, again emphasizing that these are clinical diagnoses.

Lactate dehydrogenase (LDH) and bilirubin (direct and total) levels are indirect measures of the degree of hemolysis. An LDH level in the 1000 IU/L range (normal, < 200 IU/L) is not unusual. Generally, a moderate degree of hyperbilirubinemia (2.5-4 mg/dL) is present, with the indirect form predominating.

The direct antiglobulin (Coombs) test determines the presence of antibodies on red cells. Antibodies, if present, are more consistent with autoimmune hemolytic anemia.

Because of the association of TTP/HUS with HIV infection, serologic evaluation for HIV infection should be obtained in all newly presenting patients.

Although not routinely available, measurement of von Willebrand factor–cleaving protease (ADAMTS13) activity holds the promise of helping diagnose TTP with greater certainty. Ideally, patients with TTP have either an inherited or an acquired lack of this protease activity, whereas those with HUS do not have an abnormality of the enzyme.

To date, however, studies with different variations of the activity assay have not clearly distinguished between patients thought to have TTP from patients thought to have HUS. In addition, patients with other causes of thrombocytopenia—as well as liver disease, pregnancy, and sepsis—may have moderately depressed levels of ADAMTS13 activity. Thus, the diagnostic utility of the assays has yet to be demonstrated.

Wu et al reported that ADAMTS13 response to early plasma exchange therapy in patients with acquired TTP has prognostic value. In their study of 19 patients, recovery of ADAMTS13 activity to more than 10% within 7 days was significantly associated with a timely clinical response. In contrast, patients whose ADAMTS13 level failed to exceed 10% by 7 days tended to experience TTP exacerbation, treatment refractoriness, or death.[28]

Imaging Studies

Imaging studies generally are not required in the evaluation of patients for TTP or HUS. In patients where stroke is suspected, CT scan or MRI may be performed to rule out infarct and/or hemorrhage.

Histologic Findings

Biopsy is not required for the diagnosis of HUS or TTP. When biopsies have been performed, they generally have revealed thrombi that are relatively platelet-rich and fibrin-poor in the microcirculation (white clot). These lesions are most prominent in the kidneys and the CNS.

Medical Care

Therapy should be initiated if the diagnosis of thrombotic thrombocytopenic purpura (TTP) is seriously considered.[29] Only a minority of patients (20-30%) present with the classic pentad of microangiopathic hemolytic anemia, thrombocytopenic purpura, neurologic abnormalities, fever, and kidney disease. Consequently, the presence of microangiopathic hemolytic anemia (schistocytes, elevated lactate dehydrogenase [LDH] level, and indirect hyperbilirubinemia) and thrombocytopenia in the absence of other obvious causes (eg, disseminated intravascular coagulation, malignant hypertension) is justification to begin total plasma exchange—preferably within 4–8 hours, according to British TTP guidelines.[30]

Shah et al have described the use of ADAMTS13 (thrombospondin type 1 motif, member 13) measurement to guide the use of plasma exchange in patients with TTP. In their study, plasma exchange was initiated only in patients with ADAMTS13 activity < 10%. Not initiating plasma exchange in patients without severe ADAMTS13 deficiency—or discontinuing plasma exchange after a short course, when baseline ADAMTS13 levels became available and were found to be >11%—proved to be a safe approach, with no increase in mortality.[31]

Because TTP is a medical emergency, long turnaround times for ADAMTS13 activity assay results preclude the use of this test in the decision whether to start plasma exchange. Connell et al reported a significant reduction in plasma utilization for patients with suspected TTP, with no increase in mortality, with the implementation of an assay with a rapid turnaround time.[32]

Plasma exchange with fresh frozen plasma is the therapy of choice for TTP. Octaplas is a pooled plasma (human) that has been treated with a solvent detergent process. This blood product provides a viable alternative to single-donor fresh-frozen plasma, with a reduced risk of certain viral transmissions. Replacement with normal saline and albumin is not adequate. When immediate plasma exchange is not available, simple plasma infusion can be performed until the patient can be transferred to a facility that performs plasma exchange.[33]

A recombinant ADAMTS13 (Adzynma) was approved by the FDA in 2023 for prophylactic or on-demand enzyme replacement therapy in adults and children with congenital thrombotic thrombocytopenic purpura (cTTP). Approval was based on data from a randomized, open-label crossover phase 3 trial and continuation study in which none of the 38 patients experienced acute TTP events during a mean of 13.2 months of recombinant ADAMTS13 prophylaxis, whereas one acute TTP event occurred in a patient receiving plasma-based therapies. No subacute TTP events occurred with recombinant ADAMTS13, compared with 5 subacute TTP events in 4 patients on plasma-based therapies.[34, 35]  

Treatment regimens for congenital TTP should be individualized according to the patient's phenotype, with some patients requiring regular infusions and others with a mild phenotype needing only occasional treatment. Pregnant women with congenital TTP should attend a specialist center and receive ADAMTS13 supplementation regularly throughout pregnancy and the post-partum period.[30]

Although recombinant ADAMTS13 is approved for use only in patients with cTTP, a case report by Bendapudi et al describes its effective use in a critically ill patient with immune TTP that was refractory to all available treatments. Administration of recombinant ADAMTS13 was followed by rapid suppression of disease activity and complete recovery.[36]

Usually, at least five plasma exchanges are performed in the first 10 days. The authors' routine is to exchange 1.5 plasma volumes with each exchange for 5 consecutive days, although some physicians exchange 1 predicted plasma volume. If the first course of exchanges produces no response, a second course of five exchanges can be performed. Others have used a course of at least seven exchanges during the first 9 days of therapy. In the author's cohort, the vast majority of responses were seen within the first 10 plasma exchanges. However, a few patients took up to 15 exchanges to respond.

Plasma exchange generally is well tolerated, although some patients do have intravenous access problems, hypotension, and reactions to plasma. Hypotension can result from the necessary extracorporeal volume in the apheresis device. For small patients, this may represent a considerable fraction of their total blood volume. Using a smaller bowl and/or priming the machine with colloid can circumvent this problem. In addition, the patient can be given a small colloid bolus prior to beginning the procedure.

Complete response criteria differ depending on the investigator, but they generally include the following:

Adequate initial response is fulfilled if neurologic signs and symptoms disappear, the platelet count climbs to greater than 50,000/μL, and the LDH level declines. In patients who respond to plasma exchange, the mean time to resolution of neurologic changes is approximately 3 days, to a normal LDH is 5 days, to a normal platelet count is 10 days, and to normal kidney function is 15 days.

The total number of exchanges necessary for sustained response is not established. Anecdotally, the rate of relapse is increased if plasma exchange is stopped abruptly, although no prospective, or even retrospective, study has shown this to be true. Regardless, many apheresis services taper the exchanges from three per week to one per week before stopping therapy. In the author's experience, a direct correlation existed between the number of exchanges required to reach a platelet count of 150,000/μL and the risk of relapse.

Marn Pernat et al reported their 11-year experience with membrane plasma exchange for the treatment of TTP.[37] Therapy was immediately initiated in 56 patients, then administered once or twice daily until platelet counts normalized, with an average number of 19 ± 17 plasma exchanges per patient. Nearly 1100 plasma exchange procedures were performed, in which 1-1.5 plasma volumes (3606 ± 991 mL) were replaced with fresh frozen plasma, with an average duration of 23 ± 17 days.[37] Although impaired kidney function was found in 36% of patients, 93% (52/56) had an excellent response to the therapy, of whom 86% (48 patients) reached complete remission (platelet count > 100 × 109/L).[37]

There were four deaths soon after plasma exchange therapy was initiated (post one to three procedures), and in the follow-up period, of six patients who had achieved complete remission and subsequently had one to five relapses each year, one died of acute hemolytic reaction during tapering of the therapy. Splenectomy was performed on three patients.[37] Overall, Marn Pernat et al did not find serious side effects with plasma exchange therapy in their cohort of 1066 patients.

In patients whose TTP is refractory to plasma exchange, using cryopoor plasma (or cryosupernatant) has sometimes led to a response. This is fresh frozen plasma that has had the cryoprecipitate removed and is thus depleted of high-molecular-weight von Willebrand multimers, which have a pathogenic role in TTP. However, a meta-analysis of three trials that compared plasma exchange using cryosupernatant plasma with plasma exchange using fresh frozen plasma showed no difference between the two.[38]

Corticosteroids are given to patients with TTP along with plasma exchange. Responses to corticosteroid therapy alone have been documented. The International Society on Thrombosis and Haemostasis (ISTH) strongly recommends the addition of corticosteroids to plasma exchange in patients experiencing a first acute episode or a relapse of immune TTP, despite very low certainty of evidence.[11] Corticosteroids are generally given in a dose of 1 mg/kg per day of prednisone in neurologically intact patients; or methylprednisolone, 1000 mg intravenously (IV) daily for three days or 125 mg two to four times daily.[2] A randomized trial by the Italian TTP Study Group reported higher rates of remission with IV methylprednisolone given in a dose of 10 mg/kg/day for 3 days, compared with 1 mg.kg/day.[39]

In 2019 the US Food and Drug Administration (FDA) approved caplacizumab (Cablivi) for adults with acquired TTP (aTTP), in combination with plasma exchange and immunosuppressive therapy. It is an antibody fragment that targets the A1-domain of von Willebrand factor (vWF), and inhibits the interaction between vWF and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption.[9]

Kühne et al reported on successful use of a regimen aimed at avoiding plasma exchange if the platelet count increased after the first caplacizumab dose. In 38 of their 42 patients with immune TTP, caplacizumab and immunosuppression alone rapidly controlled thrombotic microangiopathy and resulted in a sustained clinical response.[40]

Increasing evidence supports the use of the anti-CD20 monoclonal antibody rituximab in cases of immune TTP refractory to plasma exchange, with resolution of acute disease and prolonged remission.[11, 30, 22, 41, 42, 43, 44]  Rituximab may also be considered as part of first-line therapy, along with plasma exchange and steroids, in acute immune TTP.[11, 30]  A study by Scully et al found that weekly rituximab given within 3 days of acute admission for TTP was safe and effective, with reduced stay and relapse.[44]

Rituximab may also be considered for maintaining remission of TTP.[11] Jestin et al reported that in patients with immune-mediated TTP in remission who have severe ADAMTS13 deficiency (activity < 10%), preemptive treatment with rituximab can often spur recovery of ADAMTS13 and reduce the frequency of relapses. Patients in whom severe ADAMTS13 deficiency failed to respond to an initial course of rituximab, or recurred after initial improvement, typically responded to retreatment with rituximab.[45]  

Patriquin et al reported successful use of the proteasome inhibitor bortezomib in patients with TTP refractory to intensive therapy. Five of the six patients in this study achieved complete remission with bortezomib; one died of cardiac arrest due to underlying disease. No treatment-related adverse events were observed.[46]

Case reports and a case series describe successful treatment of initial or refractory immune TTP with daratumumab, a humanized anti-CD38 antibody that is approved for the treatment of multiple myeloma. Initiation of daratumumab led to eradication of persistent ADAMTS13 inhibitory autoantibodies and restoration of normal ADAMTS13 activity; no relevant adverse effects occurred.[47, 48]

Other immunosuppressive agents that may be considered in patients with TTP refractory to plasma exchange, corticosteroids, and rituximab include vincristine and cyclophosphamide (either one alone, or the two in combination).[49] Case reports have suggested that cyclosporine may be beneficial in patients with refractory disease, even though this drug has been incriminated as a potential trigger of TTP.[50]

The addition of high-dose N-acetylcysteine (150 mg/kg/day) to standard TTP therapy has proved effective and well tolerated in case series.[51, 52] N-acetylcysteine rapidly degrades the ultralarge von Willebrand factor multimers that promote thrombosis in TTP.[49]

The use of aspirin and dipyridamole, although part of standard therapy in the past, has fallen out of favor. 

Platelet transfusions should be avoided unless life-threatening (usually central nervous system) bleeding is present. Anecdotal reports have documented myocardial infarction and stroke following platelet transfusion in patients with TTP. In a single-institution review, Zhou et al found that of 233 patients with TTP, 15 patients had received platelet transfusions, with variable responses; in general, platelet transfusion was not detrimental, but its efficacy was uncertain.[53]

In TTP triggered by underlying infection, treatment of the infection may help improve the outcome. Gringauz et al report a case of refractory TTP, in a patient with active chronic gastritis positive for Helicobacter pylori, in which the TTP resolved completely after eradication of the infection.[54]

Inpatient care

Patients with TTP should remain hospitalized until at least a partial response is achieved. Criteria for discharge include the following:

In some patients, intravenous access for plasma exchange will become a concern. Large-bore dual-lumen apheresis catheters are readily available and often can be placed by interventional radiology services. The patient and/or a caregiver can be instructed in the proper care of these catheters after discharge.

Surgical Care

In rare cases, splenectomy has been used for the treatment of TTP refractory to medical measures. Response rates have been variable, and the advent of new medical options has further limited its appeal; the most recent case series was published in 2010.[55] The potential benefits of splenectomy must be weighed against the risks of the surgical procedure and the long-term risk of infections.[49]

Consultations

Consultations to consider include the following:

Diet and Activity

Other than a renal diet if the patient is azotemic or uremic, no special diet is indicated for this condition. Activity should be restricted if the patient has altered mental status or bleeding.

Complications

If patients recover from the acute episode of TTP or HUS, generally, no long-term complications occur. Complications can be divided into disease-related and treatment-related.

Disease-related complications are rare. Persistent neurologic abnormalities can occur after otherwise successful treatment of TTP. Abnormalities may result from actual stroke. Persistent kidney impairment to the point of requiring dialysis is rare, although mild renal impairment may persist for weeks to months.

Treatment-related complications include fluid overload or allergic reactions from plasma infusion. Apheresis catheters can become thrombosed or infected. During the apheresis, hypotension can occur. Paresthesias are related to hypocalcemia from the anticoagulant acid-citrate dextrose (ACD) most commonly used in apheresis procedures; however, this is transient. Long-term complications include the small risk of a bloodborne infection.

Long-Term Monitoring

The necessary outpatient follow-up for patients with TTP who have entered a complete or partial response is not well defined. After recovery from an acute episode of immune TTP, patients are at risk of both relapse and long-term complications that include neurocognitive deficits and cardiovascular events.[56] Anecdotal reports of increased relapse rates upon abrupt cessation of plasma exchange have resulted in many apheresis services tapering off plasma exchange over the course of 2-3 weeks. However, this practice has not been validated in any prospective or retrospective analysis.

Recommendations are that the patient be seen every week for 2 weeks and, if stable, every 2 weeks for a month. During this time, weekly measurement of a complete blood count and lactate dehydrogenase (LDH) are performed. If the platelet count drops or the LDH level starts to rise, another course of five plasma exchanges is reinstituted. If the patient remains stable for a month, the frequency of follow-up visits is decreased.The relapse rate is 13-36%, and recurrences as many as 9 years later have been reported.

Regular monitoring of ADAMTS13 activity is also recommended during follow‐up of patients with TTP in remission. A decrease in ADAMTS13 activity to less than 10 IU/dL is generally considered an indication for preemptive therapy to prevent clinical relapse. Rituximab is typically used for preemptive therapy; however, approximately 15% of patients experience refractoriness or intolerance to rituximab.[16, 57] Comparon et al report successful use of cyclosporine for preemptive therapy in such cases.[58]

Medication Summary

The therapy of choice is plasma exchange with fresh frozen plasma and immunosuppression.

The US Food and Drug Administration (FDA) has approved caplacizumab (Cablivi) for adults with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy. It has been shown to reduce time to platelet count response and also to reduce aTTP-related death, recurrence, or major thromboembolic events.[9]

A recombinant ADMTS13 (Adzynma) was approved by the FDA in 2023 for prophylactic or on-demand enzyme replacement therapy in adults and children with congenital thrombotic thrombocytopenic purpura (cTTP).[34, 35]  

The anti-CD20 monoclonal antibody rituximab is recommended for use in TTP that is refractory to plasma exchange. It may be considered as part of first-line therapy, and as preemptive treatment to maintain remission in patients with.  Rituximab is typically given in a dosage of 375 mg/m2 weekly for 4 weeks. Ideally, at least 4 hours should elapse between administration of rituximab and plasma exchange.[30]

The chemotherapeutic agent vincristine has been used as an adjunct to plasma exchange in patients with refractory disease, but its routine use has not been validated.

Caplacizumab (Cablivi, Caplacizumab-yhdp)

Clinical Context:  Antibody fragment that targets the A1-domain of von Willebrand factor (vWF), and inhibits the interaction between vWF and platelets; thereby, reducing both vWF-mediated platelet adhesion and platelet consumption. It is indicated for aTTP in combination with plasma exchange and immunosuppressive therapy.

Rituximab (Riabni, Rituxan, Rituximab-abbs)

Clinical Context:  Anti-CD20 chimeric monoclonal antibody initially approved for therapy of follicular lymphoma. Has been shown to have activity in several autoimmune disorders such as immune thrombocytopenia, systemic lupus erythematosus, autoimmune hemolytic anemia, and rheumatoid arthritis, as well as in immune thrombocytopenic purpura.

Class Summary

These agents have shown efficacy in the treatment of autoimmune disorders. Caplacizumab has been shown to reduce time to platelet count response and also to reduce aTTP-related death, recurrence, or major thromboembolic events.[9]

Fresh frozen plasma (FFP, Octaplas)

Clinical Context:  Plasma provides all plasma proteins and clotting factors to support adequate hemostasis to treat or prevent bleeding or to treat other protein deficiencies that cannot be replaced with protein specific concentrates. It is indicated for plasma exchange in patients with TTP. Octaplas is a solvent detergent treated, pooled FFP.

Class Summary

Plasma exchange with FFP is the therapy of choice for TTP.Fresh frozen plasma (FFP, Octaplas)

Vincristine (Oncovin, Vincasar)

Clinical Context:  Mechanism of action uncertain. May involve a decrease in reticuloendothelial cell function or increase in platelet production. However, neither of these mechanisms fully explains the effect in TTP and HUS.

Class Summary

These agents are used as an adjunct to plasma exchange.

Prednisone (Deltasone, Prednisone Intensol, Rayos)

Clinical Context:  May work by decreasing activity of reticuloendothelial system. In light of the evidence that patients with acquired TTP have an inhibitor to vWF-cleaving protease, steroids may decrease production of autoantibody.

Class Summary

These agents are used to treat idiopathic and acquired autoimmune disorders. They are also used as an adjunct to plasma exchange.

ADAMTS13, recombinant (ADAMTS13, recombinant-krhn, Adzynma)

Clinical Context:  Indicated for prophylactic or on-demand enzyme replacement therapy in adult and pediatric patients with congenital thrombotic thrombocytopenic purpura (cTTP). 

Class Summary

Congenital thrombotic thrombocytopenic purpura (cTTP), is an ADAM metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13) gene deficiency disorder. ADAMTS13 enzyme splices von Willebrand factor to regulate its interaction with platelets; this action is involved in platelet adhesion to form temporary clots at the site of an injury. 

What is thrombotic thrombocytopenic purpura (TTP)?Which clinical history findings are characteristic of thrombotic thrombocytopenic purpura (TTP)?How is thrombotic thrombocytopenic purpura (TTP) diagnosed?What is the role of plasma exchange in the treatment of thrombotic thrombocytopenic purpura (TTP)?What is the role of caplacizumab (Cablivi) in the treatment of thrombotic thrombocytopenic purpura (TTP)?What is the role of octaplas (Octapharma) in the treatment of thrombotic thrombocytopenic purpura (TTP)?How is refractory thrombotic thrombocytopenic purpura (TTP) treated?When was thrombotic thrombocytopenic purpura (TTP) first identified?What are the differences between thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS)?What is the pathophysiology of thrombotic thrombocytopenic purpura (TTP)?What is the prevalence of thrombotic thrombocytopenic purpura (TTP)?What is the mortality and morbidity associated with thrombotic thrombocytopenic purpura (TTP)?Which patient groups have the highest prevalence of thrombotic thrombocytopenic purpura (TTP)?What are the signs and symptoms of thrombotic thrombocytopenic purpura (TTP)?How is thrombotic thrombocytopenic purpura (TTP) differentiated from hemolytic-uremic syndrome (HUS)?Which physical findings are characteristic of thrombotic thrombocytopenic purpura (TTP)?What causes thrombotic thrombocytopenic purpura (TTP)?Which conditions are included in the differential diagnoses of thrombotic thrombocytopenic purpura (TTP)?What are the differential diagnoses for Thrombotic Thrombocytopenic Purpura (TTP)?Which CBC findings are characteristic of thrombotic thrombocytopenic purpura (TTP)?Which peripheral blood smear finding suggests thrombotic thrombocytopenic purpura (TTP)?Which prothrombin time (PT) and partial thromboplastin time (PTT) results are characteristic of thrombotic thrombocytopenic purpura (TTP)?Which D-dimer and fibrinogen assay findings are characteristic of thrombotic thrombocytopenic purpura (TTP)?How is renal function evaluated in the workup of thrombotic thrombocytopenic purpura (TTP)?How is hemolysis assessed in the workup of thrombotic thrombocytopenic purpura (TTP)?Why is HIV testing included in the workup of thrombotic thrombocytopenic purpura (TTP)?What is the role of von Willebrand factor–cleaving protease (ADAMTS13) measurement in the workup of thrombotic thrombocytopenic purpura (TTP)?What is the role of imaging studies in the workup of thrombotic thrombocytopenic purpura (TTP)?Which histologic findings are characteristic of thrombotic thrombocytopenic purpura (TTP)?How is thrombotic thrombocytopenic purpura (TTP) treated?How is complete treatment response determined for thrombotic thrombocytopenic purpura (TTP)?What is the efficacy of plasma exchange for thrombotic thrombocytopenic purpura (TTP) treatment?What is the role of cryopoor plasma (or cryosupernatant) in the treatment of thrombotic thrombocytopenic purpura (TTP)?What is the role of corticosteroids in the treatment of thrombotic thrombocytopenic purpura (TTP)?What is the role of rituximab in the treatment of thrombotic thrombocytopenic purpura (TTP)?What is the role of bortezomib in the treatment of thrombotic thrombocytopenic purpura (TTP)?What is the role of vincristine in the treatment of thrombotic thrombocytopenic purpura (TTP)?What is the role of platelet transfusion in the treatment of thrombotic thrombocytopenic purpura (TTP)?What is the effect of infections on the treatment of thrombotic thrombocytopenic purpura (TTP)?Which specialist consultations are beneficial to patients with thrombotic thrombocytopenic purpura (TTP)?Which dietary and activity modifications are used in the treatment of thrombotic thrombocytopenic purpura (TTP)?Which medications are used in the treatment of thrombotic thrombocytopenic purpura (TTP)?Which medications in the drug class Corticosteroids are used in the treatment of Thrombotic Thrombocytopenic Purpura (TTP)?Which medications in the drug class Chemotherapy agents are used in the treatment of Thrombotic Thrombocytopenic Purpura (TTP)?Which medications in the drug class Blood Products are used in the treatment of Thrombotic Thrombocytopenic Purpura (TTP)?Which medications in the drug class Monoclonal antibody are used in the treatment of Thrombotic Thrombocytopenic Purpura (TTP)?

Author

Theodore Wun, MD, FACP, Professor of Medicine, Professor of Pathology and Laboratory Medicine, University of California Davis School of Medicine; Chief of Hematology/Oncology, Program Director, Veterans Affairs Northern California Health Care System; Medical Director, University of California Davis CCRC

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD, Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Srikanth Nagalla, MD, MS, FACP, Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion; Sanofi; Dova; Apellis; Pharmacosmos<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sobi; Sanofi; Rigel.

Acknowledgements

Wadie F Bahou, MD Chief, Division of Hematology, Hematology/Oncology Fellowship Director, Professor, Department of Internal Medicine, State University of New York at Stony Brook

Wadie F Bahou, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

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Differential diagnosis of immune thrombocytopenia (ITP), thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC).

Differential diagnosis of immune thrombocytopenia (ITP), thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC).

Differential diagnosis of immune thrombocytopenia (ITP), thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC).