ADAMTS13 conformation and immunoprofiles in Japanese patients with immune-mediated thrombotic thrombocytopenic purpura

Abstract

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare thrombotic disease caused by autoantibody induced ADAMTS13 deficiency. Open ADAMST13 conformation, induced by autoantibodies, was identified as a novel biomarker for iTTP. Determining immunoprofiles in iTTP patients was shown to guide the development of novel targeted therapies. However, these studies were done in mainly Caucasian iTTP cohorts. To validate those findings across other ethnic cohorts, we investigated 195 acute TTP plasma samples from the Japanese iTTP registry. Seventy-six of the 195 samples had detectable ADAMTS13 antigen levels of which 94.7% were shown to have an open ADAMTS13 conformation. A positive correlation was observed between ADAMTS13 inhibitor titers (diagnostic parameter in Japan) and anti-ADAMTS13 IgG autoantibody titers. Studying anti-M, -DT; -CS, -T2-T5, -T6-T8, -CUB1-2 autoantibodies and the corresponding immunoprofile showed that 73.0% of the patients had anti-CS autoantibodies and 25.8% anti-M autoantibodies, with the latter being higher than in Caucasians. Stratifying patients according to their immunoprofile revealed that the profile with only anti-CS autoantibodies alone was the most common immunoprofile like in Caucasians (28.9%). While this profile did not impact the one-year TTP-related mortality rate, patients with autoantibodies against all 6 ADAMTS13 fragments had a higher risk for TTP-related death than other patients (p=0.02). We here validated open ADAMTS13 as a novel biomarker for acute iTTP and determined the dominant immunoprofiling in the Japanese cohort, contributing to setting up the diagnosis and managing guidelines across different ethnic cohorts and to developing ADAMTS13 variants that do not bind to the anti-CS autoantibodies.

Anti-ADAMTS13 Autoantibodies: From Pathophysiology to Prognostic Impact—A Review for Clinicians

“…In both acute and remission phases, profile 1 was the dominant immunoprofile, suggesting that anti-CS autoAbs are the first to reappear or are the ones that persist during remission, while the other domain-specific autoAbs mainly appear in the acute phase. A similar analysis was performed on a Japanese iTTP cohort: more than 70% of patients had anti-CS autoAbs, in agreement with the Caucasian cohorts, but the Japanese cohort only showed one dominant immunoprofile, profile 1, with only autoAbs against the CS domain [22].…”

ADAMTS13 and Non-ADAMTS13 Biomarkers in Immune-Mediated Thrombotic Thrombocytopenic Purpura

“…Despite the polyclonal immune response in iTTP, dominant immunoprofiles suggest that nearly all patients display antibodies targeted against immunogenic hotspots mainly located in the ADAMTS13 Spacer (S) and Cysteine-rich (C) domains (hereafter referred to as anti-CS antibodies) [34,[38][39][40][41][42]. However, the domain specificity of presenting anti-ADAMTS13 antibodies does not differ between surviving and deceased iTTP patients.…”

“…However, the domain specificity of presenting anti-ADAMTS13 antibodies does not differ between surviving and deceased iTTP patients. Moreover, disease severity, prognosis, or patient management to enable remission could not be linked to antibody domain specificity nor to the three most dominant patient immunoprofiles [34,39,42]. Aberrantly high antibody titers, typically found when multiple domains are targeted by anti-ADAMTS13 antibodies [42], are displayed in over 90% of presenting patients, even though elevated titers could often only be measured at the later stages of relapse episodes [35].…”

“…Moreover, disease severity, prognosis, or patient management to enable remission could not be linked to antibody domain specificity nor to the three most dominant patient immunoprofiles [34,39,42]. Aberrantly high antibody titers, typically found when multiple domains are targeted by anti-ADAMTS13 antibodies [42], are displayed in over 90% of presenting patients, even though elevated titers could often only be measured at the later stages of relapse episodes [35]. Interestingly, patients with antibody titers in the highest quartile showed a three-fold increased mortality rate when compared to those in the lowest quartile.…”

“…Additionally, elevated troponin levels, a lowered Glasgow Coma Scale (GCS) score, and a larger number of plasma exchange sessions were associated with patients in the highest quartile [35]. Therefore, both ADAMTS13 antibody (i.e., titers of the highest quartile) and antigen (i.e., titers of the lowest quartile) are reported to adversely affect TTP outcome by means of elevated mortality rates as well as raised cardiac and neurological involvement [34,35,42].…”