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

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.