Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura

Elien Roose, An Sofie Schelpe, Edwige Tellier, György Sinkovits, Bérangère S. Joly, Charlotte Dekimpe, Gilles Kaplanski, Maelle Le Besnerais, Ilaria Mancini, Tanja Falter, Charis Von Auer, Hendrik B. Feys, Marienn Reti, Heidi Rossmann, Aline Vandenbulcke, Inge Pareyn, Jan Voorberg, Andreas Greinacher, Ygal Benhamou, Hans DeckmynRob Fijnheer, Zoltan Prohászka, Flora Peyvandi, Bernhard Lämmle, Paul Coppo, Simon F. De Meyer, Agnès Veyradier, Karen Vanhoorelbeke

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)353-361
Number of pages9
JournalBlood
Volume136
Issue number3
DOIs
Publication statusPublished - Jul 16 2020

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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