Peak ADAMTS13 activity to assess ADAMTS13 conformation and risk of relapse in immune-mediated thrombotic thrombocytopenic purpura

Previous studies have demonstrated that more than 38% of immune-mediated thrombotic thrombocytopenic purpura (TTP) patients in remission with activity >50% had an open ADAMTS13 conformation. We assessed ADAMTS13 conformation in remission (ADAMTS13 activity >60%), focussing on peak ADAMTS13 activity levels and longitudinal assessment in 420 samples across 157 patients. Fewer cases had open conformation at peak ADAMTS13 activity compared to unselected remission samples with ADAMTS13 activity>60% (23% vs 43%). Patients with a closed ADAMTS13 conformation at peak ADAMTS13 activity had an 8-fold lower relapse rate in the subsequent year (9% vs 46%; OR 8.4, p=0.007) and a 5-fold lower relapse rate within 2 years (23% vs 62%; OR 5.3, p=0.02) compared to cases with an open conformation. Patients with an open conformation at peak ADAMTS13 activity required pre-emptive anti-CD20 treatment earlier than patients with a closed conformation (median 10 vs 25 months, p=0.02). Longitudinally, an open conformation was evident at, and often preceded relapse. Where the conformation was already open prior to relapse, an increase in conformation index at relapse was seen despite undetectable anti-ADAMTS13 IgG antibody. In cases with detectable anti-ADAMTS13 IgG antibody, these became undetectable prior to achieving closed conformation, highlighting the relapse risk even with undetectable anti-ADAMTS13 IgG antibody and the clinical utility of open/closed during monitoring. This is the first study to show an association between relapse risk and ADAMTS13 conformation when activity levels are at a peak. Open conformation identifies antibody mediated subclinical disease which is not detectable through current ADAMTS13 testing.