title: 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.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Assistance Publique-Hôpitaux de Paris.
authors.affiliation: Service de Réanimation médicale, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Mariotte
authors.affiliation: Service de Réanimation médicale, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Azoulay
authors.affiliation: Service d'Immunologie clinique, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Galicier
authors.affiliation: Service de Néphrologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Rondeau
authors.affiliation: Service d'Hématologie biologique, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Université Paris Sud, Clamart, France.
authors.forename: Fouzia
authors.initials: F
authors.lastname: Zouiti
authors.affiliation: Service de Génétique moléculaire, Hôpital Hôtel Dieu, CHU de Nantes, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Boisseau
authors.affiliation: Service d'Hémaphérèse, CHU La Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Poullin
authors.affiliation: Service d'Hématologie biologique, CHU de Dijon, Dijon, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: de Maistre
authors.affiliation: Service de Néphrologie, CHRU de Lille, Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Provôt
authors.affiliation: Service de Néphrologie, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France.
authors.forename: Yahsou
authors.initials: Y
authors.lastname: Delmas
authors.affiliation: Service de Réanimation, Hôpital de Vandoeuvre, CHU de Nancy, Nancy, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Perez
authors.affiliation: Service de Médecine interne, Hôpital Charles Nicolle, CHU de Rouen, Rouen, France.
authors.forename: Ygal
authors.initials: Y
authors.lastname: Benhamou
authors.affiliation: Service d'Hématologie biologique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris and EA3518, Institut Universitaire d'Hématologie-Hôpital Saint Louis, Université Paris Diderot, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Stepanian
authors.affiliation: Département d'Hématologie clinique, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Coppo
authors.affiliation: Service d'Hématologie biologique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris and EA3518, Institut Universitaire d'Hématologie-Hôpital Saint Louis, Université Paris Diderot, Paris, France. Electronic address: agnes.veyradier@aphp.fr.
authors.forename: Agnès
authors.initials: A
authors.lastname: Veyradier
mesh_terms: D000071120:ADAMTS13 Protein / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology*; D000328:Adult; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000150:complications / Q000209:etiology; D000077144:Clopidogrel; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004066:Digestive System Diseases / Q000150:complications; D005260:Female; D005334:Fever / Q000150:complications; D005602:France / Q000453:epidemiology; D005838:Genotype; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007239:Infections / Q000150:complications; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000150:complications; D009422:Nervous System Diseases / Q000150:complications; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology; D015995:Prevalence; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000150:complications / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology*; D011697:Purpura, Thrombotic Thrombocytopenic / Q000150:complications / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology*; D012042:Registries; D012307:Risk Factors; D012737:Sex Factors; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives; D014180:Transplantation / Q000009:adverse effects
chemical_list: D001323:Autoantibodies; D000077144:Clopidogrel; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D013988:Ticlopidine