title: Child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency: a cohort study of the French national registry for thrombotic microangiopathy.
abstract: BACKGROUND
  Thrombotic thrombocytopenic purpura is a rare thrombotic microangiopathy, related to a severe ADAMTS13 deficiency (a disintegrin and metalloprotease with thromboSpondin type 1 repeats, member 13; activity <10% of normal). Childhood-onset thrombotic thrombocytopenic purpura is very rare and initially often misdiagnosed, especially when ADAMTS13 deficiency is acquired (ie, not linked to inherited mutations of the ADAMTS13 gene). We aimed to investigate initial presentation, management, and outcome of acquired thrombotic thrombocytopenic purpura in children.
  
  
  METHODS
  Between Jan 1, 2000, and Dec 31, 2015, we studied a cohort of patients with child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura included in the French national registry for thrombotic microangiopathies at presentation and during follow up. The inclusion criteria were: first episode before age 18 years; ADAMTS13 activity less than 10% of normal at presentation; positive anti-ADAMTS13 autoantibodies during an episode, or a recovery of ADAMTS13 activity in remission, or both. ADAMTS13 activity and anti-ADAMTS13 autoantibodies were investigated by a central laboratory, and medical records were extensively reviewed to collect clinical and biological features with a standardised form. This study is registered with ClinicalTrials.gov, number NCT00426686.
  
  
  RESULTS
  We enrolled 973 patients with childhood-onset thrombotic microangiopathy, of whom 74 had a severe ADAMTS13 deficiency (activity <10%) at presentation. 24 patients had an inherited thrombotic thrombocytopenic purpura also known as Upshaw-Schulman syndrome and five did not have follow-up data available, thus 45 children had acquired thrombotic thrombocytopenic purpura and were included in our database at presentation. 25 (56%) patients had idiopathic disease and 20 (44%) had miscellaneous associated clinical conditions. At diagnosis, median age was 13 years (IQR 7-16, range 4 months-17 years), with a sex ratio of 2·5 girls to 1 boy. Anti-ADAMTS13 autoantibodies were positive in 37 (82%) of 45 patients (24 [96%] of 25 idiopathic cases and 13 [65%] of 20 non-idiopathic cases). 39 (87%) of 45 patients were given plasma therapy and 21 (47%) received additional rituximab. Four (9%) children died after the first thrombotic thrombocytopenic purpura episode. Long-term follow up of the 41 survivors showed that ten (24%) patients relapsed and systemic lupus erythematosus occurred in two (5%) patients. Preemptive rituximab was used in seven (17%) of 41 patients with acquired thrombotic thrombocytopenic purpura.
  
  
  CONCLUSIONS
  Our study shows that child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura have specific clinical, biological and therapeutic features. Long-term follow-up is crucial to prevent relapses of the disease, to identify the occurrence of autoimmune disorders, and to evaluate consequences on social life. Child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura is a crucial diagnosis in the field of paediatric haematologic cytopenias because it is a life-threatening disease requiring a specific management.
  
  
  BACKGROUND
  Assistance Publique-Hôpitaux de Paris, France.
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: Bérangère S
authors.initials: BS
authors.lastname: Joly
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: Service d'Hématologie clinique, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Leblanc
authors.affiliation: Département d'Epidémiologie et recherche clinique, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Hajage
authors.affiliation: Service d'Hématologie clinique pédiatrique, Hôpital La Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Chambost
authors.affiliation: Service de Pédiatrie, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Harambat
authors.affiliation: Département d'Oncologie et d'Hématologie Pédiatriques et de Thérapie Cellulaire, CHU de Nancy, Hôpital d'Enfants, Vandoeuvre-lès-Nancy, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Fouyssac
authors.affiliation: Service de Pédiatrie, CHU de Limoges, Limoges, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Guigonis
authors.affiliation: Service d'Oncologie pédiatrique, Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Leverger
authors.affiliation: Service de Néphrologie pédiatrique, Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.
authors.forename: Tim
authors.initials: T
authors.lastname: Ulinski
authors.affiliation: Service de Néphrologie pédiatrique, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France.
authors.forename: Thérésa
authors.initials: T
authors.lastname: Kwon
authors.affiliation: Service de Néphrologie pédiatrique, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Loirat
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 / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D000293:Adolescent; D000367:Age Factors; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D012042:Registries; D000069283:Rituximab / Q000627:therapeutic use
chemical_list: D000069283:Rituximab; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human