Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura
2 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
3 MTA - Hungarian Academy of Sciences
4 Service d’Hématologie Biologique [CHU Lariboisière]
5 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
6 Hôpital Charles Nicolle [Rouen]
7 UNIMIB - Università degli Studi di Milano-Bicocca = University of Milano-Bicocca
8 JGU - Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University
9 Ghent University Hospital
10 CEU - Central European University [Budapest, Hongrie]
11 UvA - Universiteit van Amsterdam = University of Amsterdam
12 Greifswald University Hospital
13 UMCU - University Medical Center [Utrecht]
14 Department of Physics [Budapest]
15 CEREST-TC [CHU Saint-Antoine]
16 Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré]
- Fonction : Auteur
- PersonId : 794434
- ORCID : 0000-0002-9078-9070
- Fonction : Auteur
- PersonId : 1234659
- IdHAL : edwige-tellier
- ORCID : 0000-0003-3044-5388
- Fonction : Auteur
- PersonId : 1387539
- ORCID : 0000-0001-8890-7341
- Fonction : Auteur
- PersonId : 772305
- ORCID : 0000-0001-7773-5003
- Fonction : Auteur
- PersonId : 794433
- ORCID : 0000-0003-2288-8277
Résumé
Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was <50%. The open ADAMTS13 conformation was found during acute iTTP, as well as in patients in remission with ADAMTS13 activity <50% and in half of the patients with ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.