Thrombotic Thrombocytopenic Purpura (TTP) Treatment & Management

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.