Open ADAMTS-13 conformation index predicts earlier relapse in immune-mediated thrombotic thrombocytopenic purpura

Laure De Waele; Kazuya Sakai; Ilaria Mancini; György Sinkovits; Tanja Falter; Takashi Inoue; Pasquale Agosti; Heidi Rossmann; Charis Von Auer; Claudia Tersteeg; Simon F De Meyer; Bérangère S Joly; Agnès Veyradier; Paul Coppo; Rob Fijnheer; Flora Peyvandi; Zoltán Prohászka; Bernhard Lämmle; Karen Vanhoorelbeke

doi:10.1016/j.jtha.2023.10.014

Open ADAMTS-13 conformation index predicts earlier relapse in immune-mediated thrombotic thrombocytopenic purpura

J Thromb Haemost. 2024 Feb;22(2):493-502. doi: 10.1016/j.jtha.2023.10.014. Epub 2023 Oct 20.

Authors

Laure De Waele¹, Kazuya Sakai², Ilaria Mancini³, György Sinkovits⁴, Tanja Falter⁵, Takashi Inoue⁶, Pasquale Agosti³, Heidi Rossmann⁵, Charis Von Auer⁷, Claudia Tersteeg¹, Simon F De Meyer¹, Bérangère S Joly⁸, Agnès Veyradier⁸, Paul Coppo⁹, Rob Fijnheer¹⁰, Flora Peyvandi³, Zoltán Prohászka⁴, Bernhard Lämmle¹¹, Karen Vanhoorelbeke¹²

Affiliations

¹ Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.
² Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium; Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan.
³ Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Department of Pathophysiology and Transplantation, and Fondazione Luigi Villa, Milan, Italy.
⁴ Department of Internal Medicine and Hematology, Semmelweis University and Research Group for Immunology and Haematology, Semmelweis University - Eötvös Loránd Research Network (Office for Supported Research Groups), Budapest, Hungary.
⁵ Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
⁶ Department of Evidence-Based Medicine, Nara Medical University, Kashihara, Japan.
⁷ Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Department of Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
⁸ Service d'Hématologie Biologique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris and EA3518, Institut de Recherche Saint Louis, Université de Paris, Paris, France.
⁹ Centre de Référence des Microangiopathies Thrombotiques, Service d'hématologie, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris and Sorbonne Université, Paris, France.
¹⁰ Department for Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
¹¹ Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Haemostasis Research Unit, University College London, London, United Kingdom.
¹² Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium. Electronic address: karen.vanhoorelbeke@kuleuven.be.

PMID: 37866519
DOI: 10.1016/j.jtha.2023.10.014

Abstract

Background: ADAMTS-13 adopts an open conformation in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in acute phase while being closed in healthy donors. We reported that a substantial number of patients with iTTP in remission with restored ADAMTS-13 activity (>50%) still had an open ADAMTS-13 conformation, although a closed conformation is expected given the extent of remission.

Objectives: To investigate whether open ADAMTS-13, represented by a conformation index >0.5, is associated with a risk of earlier ADAMTS-13 and/or clinical relapse.

Methods: We collected follow-up data (ADAMTS-13 parameters, ADAMTS-13 and clinical relapse, and treatment) from 81 patients with iTTP in remission with ADAMTS-13 activity >50%.

Results: During follow-up, 19 ADAMTS-13 and 10 clinical relapses were reported (median follow-up period, 20 months). First, open or closed ADAMTS-13 conformation was dichotomized based on the 0.5 conformation index cutoff. Open ADAMTS-13 (conformation index, >0.5) was not identified as a risk factor for ADAMTS-13 and clinical relapse (log-rank test and Cox regression model). In contrast, by identifying the optimal conformation index cutoff for relapse prediction, using classification and regression tree analysis, a conformation index >0.645 and >0.835 was shown to be a risk factor for ADAMTS-13 relapse (hazard ratio, 3.3; 95% CI, 1.3-8.3; P = .01) and clinical relapse (hazard ratio, 4.4; 95% CI, 1.3-15.3; P = .02), respectively.

Conclusion: Patients with open ADAMTS-13 with a conformation index >0.645 and >0.835 have a >3- and >4-fold higher risk of earlier ADAMTS-13 and clinical relapse, respectively. Hence, ADAMTS-13 conformation index could be used to complement ADAMTS-13 activity monitoring to timely notice ADAMTS-13 relapse and prevent clinical relapse.

Keywords: ADAMTS-13 activity; ADAMTS-13 conformation; autoantibodies; relapse; thrombotic thrombocytopenic purpura.

MeSH terms

ADAMTS13 Protein*
Autoantibodies
Humans
Proportional Hazards Models
Purpura, Thrombotic Thrombocytopenic* / diagnosis
Purpura, Thrombotic Thrombocytopenic* / therapy
Recurrence
Risk Factors

Substances

ADAMTS13 Protein
Autoantibodies