Thrombotic Thrombocytopenic Purpura (TTP)

In 1924, Eli Moschowitz, MD, described a girl who presented with an abrupt onset of petechiae and pallor followed rapidly by paralysis, coma, and death. Upon pathologic examination, the small arterioles and capillaries of the patient were found to have thrombi consisting mostly of platelets. Dr. Moschowitz hypothesized a "powerful poison which had both agglutinative and hemolytic properties" as the cause of the disease. The syndrome described by Moschowitz is now known as thrombotic thrombocytopenic purpura (TTP).[9]

A closely related disorder, hemolytic-uremic syndrome (HUS), shares many clinical characteristics of TTP but is more common in children. Renal abnormalities tend to be more severe in HUS. Although the two disorders were once considered variants of a single syndrome, current evidence suggests differing pathogenic mechanisms of TTP and HUS. The routine use of aggressive high-volume total plasma exchange (TPE) greatly reduces the mortality of TTP, whereas the effect of TPE on the outcome of patients with HUS is more controversial.

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]

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]   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.[12] 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, tends to occur in  older individuals, and patients more often have associated cancers and less often have accompanying autoimmune diseases.[13, 14]

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.[15]

Although the signs and symptoms of TTP overlap with those of classic , ADAMTS13 activity is normal in most patients with classic HUS. This suggests a differing pathogenesis of these closely related entities.[16]

Exact incidence figures for the United States are not available, although TTP is thought to be a rare disease. 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.[6]  The age-sex standardized incidence of TTP and HUS 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.[17]

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.[18]

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 diagnosis is approximately 40 years. However, in the authors' series of 126 consecutive patients, the median age was 52 years.

In general, HUS is diagnosed in children and TTP is diagnosed in adults; 90% of cases of HUS occur in children. Bouw et al have presented a review article of TTP in children.[19]

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

• Neurologic manifestations include alteration in mental status, seizures, hemiplegia, paresthesias, visual disturbance, and aphasia

• Fatigue may accompany the anemia

• Severe bleeding from thrombocytopenia is unusual, although petechiae are common

Clinical manifestations may also include the following:

• Fever occurs in approximately 50% of patients

• Patients may notice dark urine from hemoglobinuria.

Clinical differentiation of hemolytic-uremic syndrome (HUS) and TTP can be problematic. Differentiation is often based on the presence of CNS involvement in TTP and the more severe renal involvement in HUS. In HUS, an antecedent history of diarrheal illness is more often present. In fact, some investigators suggest a clinical classification of HUS based on the presence or absence of diarrhea.

In children, the distinction between HUS and TTP may be of more importance, as general supportive measures (with dialysis as needed) are the standard therapy for HUS, versus plasma exchange for TTP. However, albeit somewhat controversial, plasma exchange is performed in adults with HUS so the differentiation has less therapeutic implications at present.

Patients with TTP or HUS 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.

The exact etiology of HUS and TTP is not clear, although much recent data are available on the role of bacterial Shiga toxin in HUS and of a deficiency in a protease designated ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in TTP. HUS, and to some extent TTP, commonly occur following a diarrheal illness with enterohemorrhagic Escherichia coli O157:H7 and Shigella dysenteriae serotype I. These bacteria, besides causing bloody diarrhea, are able to secrete an exotoxin called Shiga toxin (in the case of Shigella) or Shigalike toxin (in the case of E coli).

These toxins can bind to certain cell membrane globotriaosylceramide receptors, which, depending on the cell in question, can lead to chemokine or cytokine secretion (colonic and renal epithelial cells), cellular activation (monocytes and platelets), or secretion of unusually large von Willebrand multimers (glomerular endothelial cells). Evidence for activation of the coagulation cascade in HUS also exists. The relative specificity of the toxin for renal endothelial cells versus other types of endothelial cells is unknown.

Drugs such as mitomycin, cyclosporine, cisplatin, bleomycin, quinine, and ticlopidine have been associated with HUS and TTP. 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.

Formation of endothelial cell autoantibodies may underlie the association of thrombotic microangiopathies and pregnancy.

Most sporadic cases of TTP appear to be associated with severe deficiency of ADAMTS13 activity due to autoantibodies against this protease.[5] Normally, ADAMTS13 cleaves the large multimers of von Willebrand factor when they are secreted from endothelial cells. In most patients with active TTP, unusually large von Willebrand multimers are found in plasma. These multimers can bind to platelets in the absence of physiologic stimulus, and this mechanism might underlie the white clot seen in pathologic specimens from patients with TTP.

Congenital TTP results from mutations in the gene for ADAMTS13. Why individuals with such mutations do not always have clinically apparent TTP remains unknown.

Pregnancy can precipitate TTP. Onset of TTP during pregnancy may represent acute acquired TTP or the first episode of congenital TTP. In a prospective study of pregnancy-associated TTP from the United Kingdom, TTP presented primarily in the third trimester or postpartum.[18]

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

• Total white blood cell count is normal or slightly elevated

• Hemoglobin concentration is moderately depressed at 8-9 g/dL

• Platelet count generally ranges from 20,000-50,000/μL

Peripheral blood smears reveal moderate-to-severe schistocytosis.

Early in the course of illness, schistocytes may not be seen, but, eventually, they will be present. Some 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:

• D-dimers are indicative of fibrinolysis and thus, thrombin activation, which usually is normal or mildly elevated in patients with TTP

• Fibrinogen typically is in the high to high-normal range

• These tests are useful in differentiating TTP/HUS from disseminated intravascular coagulation (DIC), in which most of these coagulation parameters are abnormal

Evaluation of renal function with a blood urea nitrogen (BUN) and creatinine level is necessary to establish the presence and severity of renal impairment. 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 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.[21]

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.

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.

Therapy should be initiated if the diagnosis of thrombotic thrombocytopenic purpura (TTP) is seriously considered.[22] 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.[23]

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.[24]

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.[25]

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.[26]

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. 

Approval was based on results from the phase 3 HERCULES trial (n = 145), in which platelet counts normalized significantly faster when caplacizumab was added to plasma exchange and immunosuppression (hazard ratio [HR] 1.55; 95% CI, 1.1-2.2; P = 0.01). Additionally, the rate of aTTP-related death, recurrence of aTTP, or a major thromboembolic event was significantly reduced with the addition of caplacizumab compared with plasma exchange and immunosuppression alone (12.7% vs 49.3%; P < 0.0001). Recurrence of aTTP at any point during the trial occurred signficantly less often in the caplacizumab-treated patients (13% vs 38%; P < 0.001).[7]

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:

• Resolution of neurologic symptoms
• Normalization of hemoglobin, platelet count, LDH, and bilirubin levels
• Normalization of creatinine concentration

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.[27] 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.[27] 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).[27]

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.[27] 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.[28]

Corticosteroids are commonly given to patients with TTP. Responses to corticosteroid therapy alone have been documented.

Increasing evidence supports the use of the anti-CD20 monoclonal antibody rituximab in cases of TTP refractory to plasma exchange, with resolution of acute disease and prolonged remission.[18, 29, 30, 31] British guidelines recommend offering rituximab to patients with refractory or relapsing immune-mediated TTP, and considering rituximab as part of first-line therapy, along with plasma exchange and steroids, in acute idiopathic TTP with neurological/cardiac pathology, as those cases are associated with high mortality.[23]

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.[32]  

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.[33]

A pair of case reports by van den Berg et al describes successful treatment of immune TTP with daratumumab, a humanized anti-CD38 antibody that is approved for the treatment of multiple myeloma. One patient had frequently relapsing TTP and the other, a treatment-refractory first episode. Initiation of daratumumab led to eradication of persistent ADAMTS13 inhibitory autoantibodies and restoration of normal ADAMTS13 activity; no relevant adverse effects occurred.[34]

The use of aspirin and dipyridamole, although part of standard therapy in the past, has fallen out of favor. Vincristine, a vinca alkaloid generally used as chemotherapy, also has been shown to be useful in refractory cases. Complete response has been reported in one patient with TTP treated with vincristine alone. Finally, reports have shown patients improving with therapy using a staphylococcal protein A column (Prosorba), which presumably acts by removing immune complexes.

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.[35]

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.[36]

Consultations to consider include the following:

• Hematologist

• Apheresis service, if different from the hematologist

• Surgical colleagues, for placement of a central venous access device adequate for apheresis; and for splenectomy, which has been used in refractory cases of TTP

• Nephrologist, if renal impairment warrants dialysis

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

British Committee for Standards in Haematology

Guidelines on the diagnosis and treatment of thrombotic thrombocytopenic purpura (TTP) were published by the British Society for Haematology in 2012.[23] Recommendations regarding diagnosis include the following:

• The diagnosis of TTP should be treated as a medical emergency.
• The initial diagnosis of TTP should be made on the basis of the patient's clinical history, examination, and routine laboratory parameters, including blood film review.
• Because of the high risk of preventable early deaths in TTP, treatment with plasma exchange should be initiated as soon as possible, preferably within 4–8 h, if a patient presents with a microangiopathic hemolytic anemia (MAHA) and thrombocytopenia in the absence of any other identifiable clinical cause.
• Pre-treatment samples should be obtained to measure ADAMTS13 activity levels and to detect anti-ADAMTS13 antibodies. Measurement of ADAMTS13 antigen levels is also useful in congenital TTP cases.

Additional recommended laboratory tests for patients with a suspected diagnosis of TTP, with samples taken before the first plasma exchange, and expected results, include the following:

• Complete blood cell count and peripheral smear - Anemia, thrombocytopenia, fragments on smear
• Reticulocyte count - Raised
• Haptoglobin - Reduced
• Coagulation screen, including fibrinogen - Normal
• Liver function tests - Usually normal
• Lactate dehydrogenase - Raised due to hemolysis
• Direct antiglobullin test - Negative
• Hepatitis A, B, and C and HIV serology
• Blood type and crossmatch - To permit transfusions

Assessment of organ involvement may involve the following:

• Heart - Troponin T and I, electrocardiogram
• Kidneys - Blood urea nitrogen and electrolytes, urinalysis
• Brain - CT/MRI

Tests to consider for a possible underlying cause include the following:

• Thyroid function tests - To exclude Graves disease
• Autoantibody screen (antinuclear antibody, rheumatoid factor, lupus antibody, anticardiolipin antibodies) - To exclude associated automimmune disease
• Stool culture - For pathogenic Escherichia coli, in patients with diarrhea
• CT of chest/abdomen/pelvis (if indicated, with or without tumor markers - To exclude underlying malignancy

Congenital TTP:

• Consider congenital TTP in neonates presenting with severe jaundice, but be aware that patients may not present until later in childhood or adulthood.
• Consider the diagnosis of congenital TTP in children and adults with unexplained thrombocytopenia.
• The diagnosis of congenital TTP is confirmed by ADAMTS13 activity < 5%, absence of antibody, and confirmation of homozygous or compound heterozygous defects of the ADAMTS13 gene.

Treatment:

• Start plasma exchange with 1.5 plasma volume (PV) exchanges, using solvent/detergent-treated fresh frozen plasma in all age groups and reassessed daily.
• The volume of exchange can be reduced to 1.0 PV when the patient's clinical condition and laboratory test results are stabilizing.
• Intensification in frequency and or volume of plasma exchange procedures should be considered in life-threatening cases.
• Daily plasma exchanges should continue for a minimum of 2 d after platelet count has been > 150 × 10 ⁹/L and should then be stopped.
• Intravenous daily methylprednisolone (eg, 1 g/d for three consecutive days – adult dose) or high-dose oral prednisolone (eg, 1 mg/kg/d) should be considered in addition to plasma exchanges.
• In patients with acute idiopathic TTP who have neurological/cardiac pathology, treatment with rituximab should be considered on admission, in conjunction with plasma exchange and steroids. Rituximab should also be offered to patients with refractory or relapsing immune-mediated TTP.
• Cyclosporine may be considered for second-line therapy in patients with acute or chronic relapsing acquired TTP.
• Splenectomy may rarely be considered in the non-acute period of immune-mediated TTP but has limited proven benefit.
• Low-dose aspirin (75 mg OD) may be given during platelet recovery (platelet count > 50 × 10 ⁹/L).

Supportive therapy recommendations include the following:

• Red cell transfusions should be administered according to clinical need, especially in patients  with cardiac involvement. 
• Folate supplementation is required during active hemolysis.
• Platelet transfusions are contraindicated in TTP unless the patient has life-threatening hemorrhage.
• Thromboprophylaxis with low molecular weight heparin is recommended once the platelet count has reached > 50 × 10 ⁹ /L).

For treatment of congenital TTP, the guidelines recommend infusion of solvent/detergent-treated plasma or intermediate-purity plasma-derived factor VIII (FVIII) concentrates, although there is no guaranteed constant quantity of ADAMTS13 in such concentrates. 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.

International Society on Thrombosis and Haemostasis

The International Society on Thrombosis and Haemostasis (ISTH) issued guidelines on the treatment of TTP in 2020.[11] Recommendations for treatment of acute events in patients with immune-related TTP ( iTTP) are as follows:

• For treatment of a first acute event, the ISTH panel recommends therapeutic plasma exchange (TPE) plus corticosteroids over TPE alone.
• For treatment of a first acute event, the panel suggests the addition of rituximab to corticosteroids and TPE.
• For treatment of relapse, the panel recommends TPE plus corticosteroids over TPE alone.
• For treatment of relapse, the panel suggests the addition of rituximab to corticosteroids and TPE.
• For treatment of a first acute event or a relapse, the panel suggests using caplacizumab.

ISTH recommendations for management of patients with TTP who are in remission are as follows:

• For patients with iTTP who are in remission, but still have low plasma ADAMTS13 activity with no clinical signs/symptoms, the panel suggests the use of rituximab for prophylaxis.
• For patients with hereditary or congenital TTP (cTTP) who are in remission, the panel suggests either plasma infusion or a watch and wait strategy.
• For patients with cTTP who are in remission, the panel suggests against the use of FVIII concentrate.

ISTH recommendations for management of TTP in pregnant patients are as follows:

• For patients with iTTP who are pregnant and have decreased plasma ADAMTS13 activity but no clinical signs/symptoms, and for those with cTTP, the panel recommends prophylactic treatment. For prophylaxis in pregnant patients with cTTP, the panel suggests plasma infusion rather than FVIII products.

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.[7]

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. 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.[37] Although used in the past, aspirin and dipyridamole are no longer used in treating TTP.

The anti-CD20 monoclonal antibody rituximab has been reported to have activity in TTP that is refractory to plasma exchange. 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.[38] A study by Froissart and colleagues, in 22 adult patients who had responded poorly to plasma exchange, found that treatment with rituximab resulted in shorter overall treatment duration and reduced 1-year relapses, compared with historical controls.[29]

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.[23]

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.[7]

Caplacizumab (Cablivi, caplacizumab-yhdp)

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 (Rituxan)

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.

Class Summary

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

Fresh frozen plasma (FFP, Octaplas)

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

These agents are used as an adjunct to plasma exchange.

Vincristine (Oncovin, Vincasar)

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

Prednisone (Sterapred)

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.

The necessary outpatient follow-up for patients with thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) 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.[39] 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 the follow-up 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. Comparon et al report successful use of cyclosporine for preemptive therapy in such cases.[40, 15, 41]

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

• Resolution of altered mental status
• Improved platelet count
• Reduced LDH level
• Stable hemoglobin level

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

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 renal 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.

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% if comorbid conditions were present.

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[42] :

• Prolonged activated partial thromboplastin time
• High fibrinogen level
• Elevated serum lactate dehydrogenase level
• Elevated complement activation marker Bb
• Elevated complement activation marker sC5b-9

Other findings predictive of higher mortality included the following[42] :

• Failure to normalize platelet counts within 7 days
• Failure to markedly reduce serum lactate dehydrogenase by day 5
• Low total serum protein or albumin
• High troponin levels prior to total plasma exchange

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.[43] 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.[44]