Journal
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 16, Issue 2, Pages 378-388Publisher
WILEY
DOI: 10.1111/jth.13922
Keywords
ADAMTS-13 protein; antibodies; epitopes; protein conformation; thrombotic thrombocytopenic purpura
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Funding
- KU Leuven [OT/14/071, PF/10/014]
- European Framework Program for Research and Innovation (Horizon2020 Marie Sklodowska Curie Innovative training network PROFILE grant) [675746]
- LSBR program grant
- Delegation Regionale a la Recherche Clinique
- Assistance Publique-Hopitaux de Paris (PHRC) [AOM05012]
- Academische Stichting Leuven
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Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is an autoimmune disorder characterized by absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies. Recently, it was shown that ADAMTS-13 adopts a folded or an open conformation. Objectives: As conformational changes in self-antigens play a role in the pathophysiology of different autoimmune diseases, we hypothesized that the conformation of ADAMTS-13 changes during acute aTTP. Methods: Antibodies recognizing cryptic epitopes in the spacer domain were generated. Next, the conformation of ADAMTS-13 in 40 healthy donors HDs), 99 aTTP patients (63 in the acute phase versus 36 in remission), 12 hemolytic-uremic syndrome (HUS) patients and 63 sepsis patients was determined with ELISA. Results: The antibody 1C4 recognizes a cryptic epitope in ADAMTS-13. Therefore, we were able to discriminate between a folded and an open ADAMTS-13 conformation. We showed that ADAMTS-13 in HDs does not bind to 1C4, indicating that ADAMTS13 circulates in a folded conformation. Similar results were obtained for HUS and sepsis patients. In contrast, ADAMTS-13 of acute aTTP patients bound to 1C4 in 92% of the cases, whereas, in most cases, this binding was abolished during remission, showing that the conformation of ADAMTS-13 is open during an acute aTTP episode. Conclusions: Our study shows that, besides absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies, an open ADAMTS-13 conformation is also a hallmark of acute aTTP. Demonstrating this altered ADAMTS-13 conformation in acute aTTP will help to further unravel the pathophysiology of aTTP and lead to improved therapy and diagnosis.
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