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

• Published in: Blood Vol. 143; no. 25; pp. 2644 - 2653
• Main Authors: Prasannan, Nithya, Dragunaite, Bertina, Subhan, Maryam, Thomas, Mari, de Groot, Rens, Singh, Deepak, Vanhoorelbeke, Karen, Scully, Marie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-06-2024
• Subjects: ADAMTS13 Protein - immunology; ADAMTS13 Protein - metabolism; Adolescent; Adult; Aged; Female; Humans; Longitudinal Studies; Male; Middle Aged; Protein Conformation; Purpura, Thrombotic Thrombocytopenic - blood; Purpura, Thrombotic Thrombocytopenic - diagnosis; Purpura, Thrombotic Thrombocytopenic - immunology; Recurrence; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2023023269

•Closed ADAMTS13 conformation at peak ADAMTS13 activity significantly reduced relapse rates by eightfold in 1 year and fivefold 2 years.•Longitudinal data identifies ADAMTS13 conformation as a better predictor of relapse than the current ADAMTS13 assays.
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Previous studies have demonstrated that >38% of patients with immune-mediated thrombotic thrombocytopenic purpura in remission with activity >50% had an open ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) conformation. We assessed ADAMTS13 conformation in remission (ADAMTS13 activity >60%), focusing on peak ADAMTS13 activity levels and longitudinal assessment in 420 samples across 157 patients. Fewer cases had an open conformation at peak ADAMTS13 activity than unselected remission samples with ADAMTS13 activity >60% (23% vs 43%). Patients with a closed ADAMTS13 conformation at peak ADAMTS13 activity had an eightfold lower relapse rate in the subsequent year (9% vs 46%) and a fivefold lower relapse rate within 2 years (23% vs 62%) compared with cases with an open conformation. Patients with an open conformation at peak ADAMTS13 activity required preemptive anti-CD20 treatment earlier than those with a closed conformation (median, 10 vs 25 months). Longitudinally, an open conformation was evident at, and often preceded relapse. When the conformation was already open before relapse, an increase in the conformation index at relapse was seen despite the undetectable anti-ADAMTS13 immunoglobulin G (IgG) antibody. In cases with detectable anti-ADAMTS13 IgG antibody, these became undetectable before achieving a closed conformation, highlighting the relapse risk even with undetectable anti-ADAMTS13 IgG antibody and the clinical utility of open/closed during monitoring. To our knowledge, this is the first study to show an association between relapse risk and ADAMTS13 conformation when activity levels are at a peak. The open conformation identifies antibody-mediated subclinical disease that is not detectable by the current ADAMTS13 testing.
Patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) respond well to current therapies, but 40% relapse within 5 years. It has been described recently that the molecular configuration of ADAMTS13 in acute iTTP is open and not all patients in remission revert to a closed conformation. Prasannan et al examined the predictive value of continued open conformation in remission by assessing patients at peak ADAMTS13 levels postrecovery. Patients with a closed conformation had a much lower relapse rate at 1 year (9% vs 46%) and 2 years (23% vs 62%). ADAMTS13 conformation identifies patients requiring closer monitoring to optimize preemptive therapy.