Abstract
Background
TTP is a thrombotic microangiopathy characterized by reduced activity of the von Willebrand factor (VWF)-cleaving protease ADAMTS13. It can occur due to congenital (mutation of ADAMTS13), immune-mediated (antibody inhibiting or causing clearance of ADAMTS13, iTTP), or unknown (other mechanisms altering the balance between ADAMTS13 activity and unusually large VWF) causes. Studies suggest that the persistence of severe ADAMTS13 deficiency and/or circulating antibodies during clinical remission increases the risk of recurrence. However, there are limited data comparing the initial clinical presentation and treatment outcomes of patients with and without ADAMTS13 inhibitor. The aim of our study was to compare the clinical presentation and outcome of iTTP patients with (iTTPI) and without (iTTPΦ) ADAMTS13 inhibitor at the time of presentation.
Methods
We utilized the USTMA registry (n=181) to identify iTTP patients (ADAMTS13 activity <10% or <20% in the presence of an inhibitor at initial diagnosis). We included only those who had ADAMTS13 inhibitor testing performed. We described the presenting laboratory findings and precipitating events at presentation. Treatment outcomes of interest included: 1) duration of total daily plasma exchange (TPE); 2) time to platelet recovery (platelet count >150,000 for two days) from initiation of TPE; 3) duration of prednisone use at a dose of 1 mg/kg/day; and 4) time to exacerbation or first relapse. Exacerbation was defined as the need to restart daily TPE within the first 30 days after last TPE while relapse was defined as the need to restart daily TPE after 30 days. Event-free survival (exacerbation, relapse and death) was analyzed by Kaplan-Meir methods and survival data were censored at 2 years.
Results
138 patients underwent ADAMTS13 inhibitor testing and 115 (83.3%) had a detectable ADAMTS13 inhibitor. 21 patients with iTTPI and 3 patients with iTTPΦ had a history of iTTP prior to enrolling in the USTMA registry. iTTPI were more likely to have a precipitating event (Table 1). There was no significant difference in sex, race, and presenting laboratory values between the two groups (Table 2). 105/115 (91.3%) of iTTPI had platelet recovery with initial TPE compared to 19/23 (82.6%) of iTTPΦ (P=0.018). iTTPI were treated with TPE for a longer duration and achieved platelet recovery later than iTTPΦ (Table 3). TTPI were more likely to be treated with prednisone at a starting dose of 1 mg/kg/day compared to iTTPΦ [94/115 (81.7%) vs 13/23 [56.5%], (P=0.008). 5/23 (21.7%) of iTTPΦ and 51/115 (44.3%) of iTTPI underwent taper of TPE. Rituximab was used in 35/115 (30.4%) and 3/23 (13.0%) patients in iTTPI and iTTPΦ, respectively (p=0.076). There were 12 (10.4%) and 6 (26.9%) exacerbations in iTTPI and iTTPΦ, respectively (p:0.06). There were a total of 21 first time relapses (19 and 2 in iTTPI and iTTPΦ, respectively). In iTTPΦ, both patients had one relapse within follow-up time. In iTTPI, 12 (10.4%) patients had one, three (2.6%) patients had two, and four (3.5%) patients had > 3 relapse events. 2-year event free survival was similar between the two groups (73.0. % vs 60.9. % in iTTPI and iTTPΦ, respectively; P=0.087).
Conclusions
About 1/5 of patients with iTTP do not have a detectable ADAMTS13 inhibitor. While the presenting demographics and laboratory findings were similar, there were clinical differences between the two groups. Compared to iTTPΦ, iTTPI were more likely to have a precipitating event, longer daily TPE duration, longer time to platelet recovery, and treatment with high dose prednisone. Further studies are necessary to determine the optimal treatment strategies for iTTP patients with and without an ADAMTS13 inhibitor.
Sadler: Ablynx: Consultancy; BioMarin: Consultancy; Genentech: Consultancy; 23andMe: Consultancy.
