Jan

12

2025

Journal Club – TTP

By Kevin Barnum, MD

Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med. 1991; 325(6): 393-397

Clinical Question

Does plasma exchange or plasma infusion result in superior outcomes for patients with thrombotic thrombocytopenic purpura (TTP)? 

Background

At the time of this study, the pathophysiologic mechanism of immune TTP was unknown. Mortality without treatment approached 90%, so an effective therapy was needed. Reports of plasma infusion (purported to replace a missing factor in the plasma) and plasma exchange (to remove a toxic substance) had shown similar efficacy in separate studies, but they had not been compared head-to-head in a trial. This phase III study was undertaken by the Canadian Apheresis Study Group to compare these two interventions for the management of acute TTP. 

Guidelines

Plasma exchange is the recommended first-line therapy for TTP by professional organizations including:

  • International Society on Thrombosis and Haemostasis (ISTH)1
  • American Society for Apheresis (ASFA)2
  • British Society for Haematology (BSH)3

Study Design:

  • Multicenter, randomized control trial 
  • n = 102, randomized to:
    • Plasma infusion: 51 
    • Plasma exchange: 51 
  • Setting: 16 sites in Canada 
  • Enrollment period: March 1982 though 1989 
  • Follow-up period: 6 months after enrollment 
  • Analysis: Intention-to-treat 
  • Outcomes: Assessed at Day 9 and after 6 months:
    • Survival 
    • Platelet count 
    • Platelet count increase 
    • Glasgow Coma Scale score 
    • Complete response: increase in platelet count to >150 x 109 per L for two consecutive days with no deterioration in neurologic status 

Population:

Inclusion Criteria:

  • Diagnosis of TTP: 
    • Thrombocytopenia (platelet count < 100 x 109 per L) 
    • Microangiopathic hemolytic anemia (indicated by red cell fragmentation on peripheral blood film) 
    • No identifiable cause of thrombocytopenia and microangiopathic hemolytic anemia (e.g., DIC, malignancy, eclampsia) 

Exclusion Criteria:

  • History of congestive heart failure or anuria that would render the patient unable to tolerate plasma infusion. 

Baseline Characteristics:

  • Sex: 67 women, 35 men 
  • Age: 40.5 ± 14.3 years (mean ± standard deviation) 
  • Prior TTP: 11 patients (11%) 

Interventions

  • Patients were randomized 1:1 to plasma exchange or plasma infusion:
    • Plasma exchange: 1.5 plasma volumes at least 7 times over the first 9 hospital days, then 1.0 plasma volume thereafter 
    • Plasma infusion: 30 mL/kg over the first 24 hours, then 15 mL/kg daily thereafter 
    • For responders: tapered to 5 procedures over the next 2 weeks 
  • Crossover was allowed from plasma infusion to plasma exchange.
  • All patients received aspirin 325 mg daily and dipyridamole 400 mg daily for at least 2 weeks. 

Outcomes

Treatments:

  • Patients in the plasma exchange group received a mean of 15.8 procedures (range 3-36) 
    • Average total plasma administered: 21.5 L 
  • Patients in the plasma infusion group underwent 7.7 procedures (range 1-31) 
    • Average total plasma administered: 6.7 L 
  • Thirty-one patients (12 by day 9, another 19 by 6 months) crossed over from plasma infusion to plasma exchange due to rapid deterioration.

Efficacy:

  • Early outcome (at day 9) (plasma exchange vs. plasma infusion
    • Complete response rate: 47% vs. 25% (P = 0.025) 
    • Survival: 96% vs. 84% (Difference: 12%, 95% confidence 2-23%) 
  • Late outcome (at 6 months) (plasma exchange vs. plasma infusion only vs. cross-over group) 
    • Complete response: 78% vs. 31% vs. 79% 
    • Survival: 78% vs. 50% vs. 71% 

Safety:

  • Complications were observed in <25% of procedures, but most patients experienced complications: 
    • Nausea: 41 patients 
    • Hives: 35 patients 
    • Hypotension 34 patients 
    • Increase in pulse and/or respiration: 27 patients 
    • Dizziness: 10 patients 
    • Chills: 17 patients 
    • Edema: 9 patients 
    • Bleeding: 8 patients (7 gastrointestinal (1 fatal), 1 hematuria) 

Commentary:

In this trial, plasma exchange resulted in a significantly improved rate of complete response (normalization of platelet count without neurologic decline) and overall survival when compared with plasma infusion. The crossover rate from the plasma infusion to plasma exchange group was high (31 of 51 patients), but even the intention-to-treat analysis showed improved outcomes for up-front plasma exchange. Treatment was generally safe, but rates of complications were not directly compared between the two groups. 

The results of the study are consistent with what we now know about the pathophysiology of TTP. Immune TTP is mediated by an antibody recognizing ADAMTS13, and the efficacy of TPE lies in both removal of the toxic antibody and replacement of ADAMTS13. In contrast, congenital TTP is due to insufficient ADAMTS13 activity, so plasma infusion is sufficient for supplementing functional ADAMTS13.

This study is limited by the fact that the diagnosis of TTP was based on clinical evaluation rather than ADAMTS13 level, as the role of ADAMTS13 in TTP was unknown at the time; there are therefore likely patients included in this trial who did not have TTP. Further limiting its interpretation in the modern era are the uniform treatment of patients with aspirin and dipyridamole (which are no longer widely used) and lack of treatment with corticosteroids and rituximab (which are considered standard of care). 

This trial established plasma exchange as the cornerstone of treatment of acute TTP, as reflected in multiple guidelines which recommend TPE for the management of acute immune TTP. 


Kevin Barnum, MD, PhD is a hematology/oncology fellow at Beth Israel Deaconess Medical Center. He completed medical and graduate school at the Icahn School of Medicine at Mount Sinai and then completed residency at Yale-New Haven Hospital, where he also served as Chief Resident. He loves all things hematology, in particular lymphoid malignancy and immune disorders of the hematologic system.