TY - JOUR
T1 - Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura
AU - Roose, Elien
AU - Schelpe, An-Sofie
AU - Tellier, Edwige
AU - Sinkovits, György
AU - Joly, B. rangère S.
AU - Dekimpe, Charlotte
AU - Kaplanski, Gilles
AU - le Besnerais, Maelle
AU - Mancini, Ilaria
AU - Falter, Tanja
AU - von Auer, Charis
AU - Feys, Hendrik B.
AU - Reti, Marienn
AU - Rossmann, Heidi
AU - Vandenbulcke, Aline
AU - Pareyn, Inge
AU - Voorberg, Jan
AU - Greinacher, Andreas
AU - Benhamou, Ygal
AU - Deckmyn, Hans
AU - Fijnheer, Rob
AU - Prohászka, Zoltan
AU - Peyvandi, Flora
AU - Lämmle, Bernhard
AU - Coppo, Paul
AU - de Meyer, Simon F.
AU - Veyradier, Agnès
AU - Vanhoorelbeke, Karen
N1 - Funding Information: This work was supported by The European Framework Program for Research and Innovation (Horizon2020 Marie Sklodowska Curie Innovative Training Network PROFILE Grant 675746), Semmelweis University/KU Leuven (CELSA Research Grant 2018), KU Leuven (OT/14/071), a Projet National de Recherche Clinique 2007 (2007/23) (Marseille, France) and the Centre Constitutif des Microangiopathies Thrombotiques, Région PACA. The Mainz cohort study on iTTP patients was funded by the Bundesmi-nisterium für Bildung und Forschung. A.-S.S. is supported by a PhD grant from the Agency for Innovation and Entrepreneurship (Flanders, Belgium; 141136). Publisher Copyright: © 2020 by The American Society of Hematology Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7/16
Y1 - 2020/7/16
N2 - 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 5 197) 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.
AB - 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 5 197) 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.
UR - http://www.scopus.com/inward/record.url?scp=85088155007&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/blood.2019004221
DO - https://doi.org/10.1182/blood.2019004221
M3 - Article
C2 - 32356859
SN - 0006-4971
VL - 136
SP - 353
EP - 361
JO - Blood
JF - Blood
IS - 3
ER -