www.thelancet.com/haematology Published online April 15, 2016 http://dx.doi.org/10.1016/S2352-3026(16)30018-7 1 Articles Lancet Haematol 2016 Published Online April 15, 2016 http://dx.doi.org/10.1016/ S2352-3026(16)30018-7 See Online/Comment http://dx.doi.org/10.1016/ S2352-3026(16)30028-X *Members listed in the appendix Service de Réanimation médicale (E Mariotte MD, Prof E Azoulay MD) and Service d’Immunologie clinique (L Galicier MD), Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France; Service de Néphrologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France (Prof E Rondeau MD); Service d’Hématologie biologique, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Université Paris Sud, Clamart, France (F Zouiti MD); Service de Génétique moléculaire, Hôpital Hôtel Dieu, CHU de Nantes, Nantes, France (P Boisseau PhD); Service d’Hémaphérèse, CHU La Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France (P Poullin MD); Service d’Hématologie biologique, CHU de Dijon, Dijon, France (E de Maistre MD); Service de Néphrologie, CHRU de Lille, Lille, France (F Provôt MD); Service de Néphrologie, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France (Y Delmas MD); Service de Réanimation, Hôpital de Vandoeuvre, CHU de Nancy, Nancy, France (P Perez MD); Service de Médecine interne, Hôpital Charles Nicolle, CHU de Epidemiology and pathophysiology of adulthood-onset thrombotic microangiopathy with severe ADAMTS13 deficiency (thrombotic thrombocytopenic purpura): a cross-sectional analysis of the French national registry for thrombotic microangiopathy Eric Mariotte, Elie Azoulay, Lionel Galicier, Eric Rondeau, Fouzia Zouiti, Pierre Boisseau, Pascale Poullin, Emmanuel de Maistre, François Provôt, Yahsou Delmas, Pierre Perez, Ygal Benhamou, Alain Stepanian, Paul Coppo, Agnès Veyradier, for the French Reference Center for Thrombotic Microangiopathies* Summary Background Thrombotic thrombocytopenic purpura is a thrombotic microangiopathy related to a severe deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13; activity <10%). We aimed to investigate the association between mechanisms for ADAMTS13 deficiency and the epidemiology and pathophysiology of thrombotic thrombocytopenic purpura at initial presentation. Methods Between Jan 1, 1999, and Dec 31, 2013, we did a cross-sectional analysis of the French national registry for thrombotic microangiopathy to identify all patients with adult-onset thrombotic microangiopathy (first episode after age 18 years) who had severe ADAMTS13 deficiency at presentation. ADAMTS13 activity, anti-ADAMTS13 IgG, and ADAMTS13 gene mutations were investigated by a central laboratory. We collected patients’ clinical data for correlation with their ADAMTS13 phenotype and genotype. We used logistic regression analysis to identify variables significantly associated with idiopathic thrombotic thrombocytopenic purpura, as measured by estimated odds ratios (ORs) and 95% CIs. This study is registered with ClinicalTrials.gov, number NCT00426686. Findings We enrolled 939 patients with adult-onset thrombotic thrombocytopenic purpura, of whom 772 (82%) patients had available data and samples at presentation and comprised the cohort of interest. The prevalence of thrombotic thrombocytopenic purpura in France was 13 cases per million people. At presentation, 378 (49%) patients had idiopathic thrombotic thrombocytopenic purpura, whereas 394 (51%) patients had disease associated with miscellaneous clinical situations (infections, autoimmunity, pregnancy, cancer, organ transplantation, and drugs). Pathophysiologically, three distinct forms of thrombotic thrombocytopenic purpura were observed: 585 (75%) patients had autoimmune disease with anti-ADAMTS13 IgG, 166 (22%) patients had acquired disease of unknown cause and 21 (3%) patients had inherited disease (Upshaw-Schulman syndrome) with mutations of the ADAMTS13 gene. Idiopathic thrombotic thrombocytopenic purpura were mainly autoimmune (345 [91%] cases), whereas non-idiopathic diseases were heterogeneous, including a high rate of unexplained mechanisms for ADAMTS13 deficiency (133 [34%] cases). Obstetrical thrombotic thrombocytopenic purpura cases (n=62) were specifically remarkable because of the high rate of patients with Upshaw-Schulman syndrome (21 [34%] patients). Interpretation Our study shows that thrombotic thrombocytopenic purpura is a heterogeneous syndrome, and that features of the disease at presentation are strongly associated with the mechanisms of ADAMTS13 deficiency. In addition to mechanistic insight, our findings could have implications for the initial therapeutic management of patients with this disorder. Funding Assistance Publique-Hôpitaux de Paris. Introduction Thrombotic microangiopathies are rare (roughly ten cases per million people per year) 1 but life-threatening diseases. 1 The estimated mortality rate of these diseases is 20% despite appropriate treatment, consisting mainly of plasma therapy sometimes with immunomodulators. 1 Most thrombotic microangiopathies are characterised by recurrent episodes separated by remission periods. The episodes are defined by the presence of a mechanical haemolytic anaemia and a thrombocytopenia sometimes associated with visceral ischaemic manifestations. Thrombotic microangiopathies include several clinical syndromes, such as thrombotic thrombocytopenic purpura, in which the ischaemic process is multivisceral, and the haemolytic uraemic syndrome, in which the process is kidney related. 1 Some thrombotic micro- angiopathies are idiopathic, whereas others occur with pre-existing or concomitant clinical context