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

Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium. Aix Marseille Université, INSERM, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), Centre de Recherche en CardioVasculaire et Nutrition (C2VN), Marseille, France. Research Laboratory, 3rd Department of Internal Medicine and Research Group of Immunology and Hematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary. Service d'Hématologie Biologique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris and EA3518, Institut de Recherche Saint Louis, Université de Paris, Paris, France. Aix Marseille Université, Assitance Publique-Hôpitaux de Marseille, INSERM, INRAE, C2VN, Hôpital de la Conception, Service de Médecine Interne, Marseille, France. Department of Internal Medicine and. INSERM U1096, University of Rouen Institute for Biochemical Research (IFRMP), Rouen University Hospital, Rouen, France. Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Department of Pathophysiology and Transplantation-Fondazione Luigi Villa, Milan, Italy. Institute of Clinical Chemistry and Laboratory Medicine. Center for Thrombosis and Hemostasis, and. Department of Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. Transfusion Research Center, Belgian Red Cross-Flanders, Ghent, Belgium. Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. Department of Haematology and Stem Cell Transplantation, Apheresis and Stem Cell Processing Unit, Central Hospital of Southern Pest, National Institute of Haematology and Infectious Diseases, Szent László Hospital Campus, Budapest, Hungary. Department of Molecular and Cellular Hemostasis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Institute for Immunology and Transfusion Medicine, University Medicine, Greifswald, Germany. Department for Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. Department of Hematology and Central Hematology Laboratory, Bern University Hospital, University of Bern, Bern, Switzerland. Haemostasis Research Unit, University College London, London, United Kingdom; and. Centre de Référence des Microangiopathies Thrombotiques, Service d'Hématologie, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris and Sorbonne Université, Paris, France.

Blood. 2020;(3):353-361
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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.

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Publication Type : Clinical Trial ; Multicenter Study

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