title: Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal involvement.
abstract: The significance of ADAMTS13 deficiency in adult thrombotic microangiopathy (TMA) remains controversial. In an attempt to define the characteristics of adult TMA with severe ADAMTS13 deficiency, we determined 2 groups of patients on the basis of ADAMTS13 activity (undetectable or detectable). Clinical presentation, laboratory values, autoimmune manifestations, and outcome were compared between the groups. Patients were included retrospectively from 12 centers. All fulfilled the diagnosis criteria of TMA. Patients with a history of transplantation, cancer and chemotherapy, and Centers for Disease Control and Prevention (CDC) stage C human immunodeficiency virus (HIV) infection were not included. Forty-six patients were included. Thirty-one patients had an undetectable ADAMTS13 activity (<5%), and the remaining 15 patients had ADAMTS13 activity of >25%. Severe ADAMTS13 deficiency was associated with a plasmatic inhibitor in 17 cases (55%), suggesting an immune-mediated mechanism. Patients with undetectable ADAMTS13 were more frequently of Afro-Caribbean origin than patients with detectable ADAMTS13 activity (48.4% vs 13.3%, respectively; p = 0.03). As opposed to patients with detectable ADAMTS13 activity, patients with severe ADAMTS13 deficiency displayed various autoimmune manifestations that consisted of nondestructive polyarthritis (4 cases) associated in 1 case with malar rash and extramembranous glomerulonephritis, discoid lupus (3 cases), and autoimmune endocrinopathies, Raynaud phenomenon, and sarcoidosis-like disease (1 case each). In patients with severe ADAMTS13 deficiency, antinuclear antibodies, anti-double-stranded DNA antibodies, and anticardiolipin antibodies were positive in 22 (71%) cases, 3 (9.7%) cases, and 1 (3.2%) case, respectively. One patient fulfilled the criteria for the diagnosis of systemic lupus erythematosus. During follow-up, 1 patient with severe ADAMTS13 deficiency developed antinuclear antibodies, and 3 others developed anti-double-stranded DNA antibodies, in association with neurologic manifestations and anticardiolipin antibodies in 1 case. Patients with severe ADAMTS13 deficiency also had a lower platelet count (12 x 10(9)/L; range, 2-69 x 10(9)/L) and less severe renal failure (estimated glomerular filtration rate: 78 mL/min; range, 9-157 mL/min) than patients with detectable ADAMTS13 activity (49.5 x 10(9)/L; range, 6-103 x 10(9)/L; p = 0.0004, and 15.8 mL/min; range, 5.6-80 mL/min; p < 0.0001, respectively). End-stage renal failure occurred in 1 patient with severe ADAMTS13 deficiency and in 3 patients with detectable ADAMTS13 activity (3.2% vs 21.4%, respectively; p = 0.08). Flare-up and relapse episodes and survival were comparable between the groups. Taken together, these data indicate that adult idiopathic thrombotic thrombocytopenic purpura, as defined by severe ADAMTS13 deficiency, may occur preferentially in a particular ethnic group, and is characterized by severe thrombocytopenia, mild renal involvement, and a wide spectrum of autoimmune manifestations that may be completed during follow-up. Indeed, apparently idiopathic thrombotic thrombocytopenic purpura may be considered a specific autoimmune disease.
authors.affiliation: From Service d'Hématologie et Faculté de Médecine (PC), Hôpital Saint-Antoine, Paris; Laboratoire d'Immunologie (D. Bengoufa), Unité de Thérapie Cellulaire et Transfusionnelle (AB), Service d'Immuno-Hématologie (EB, L. Galicier, SM), Laboratoire d'Hémostase (MLS), Service de Réanimation Médicale (DM, EA, BS), Hôpital Saint-Louis, Paris; Laboratoire d'Hématologie (AV, MW), Hôpital Antoine Béclère, Clamart; Service d'Immunologie (VG, KL), Faculté de Médecine d'Amiens, Amiens; Structure et Dynamique des Génomes (GAM), Institut Jacques Monod, Université Pierre et Marie Curie, Paris; Unité d'Hémaphérèse (FH), Service de Réanimation Médicale (JPM), Service de Médecine Interne (L. Guillevin), Hôpital Cochin, Paris; Laboratoire d'Immunologie (MADD, VFB), Hôpital Européen Georges Pompidou, Paris; Service de Réanimation Médicale (MR), CHU de Caen, Caen; Service de Néphrologie (AP), Centre Hospitalier de Meaux, Meaux; Service d'Hématologie (D. Bordessoule), CHU de Limoges, Limoges; Service d'Hématologie Adultes (JPV), Hôpital la Pitié-Salpétrière, Paris, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Coppo
authors.forename: Djaouida
authors.initials: D
authors.lastname: Bengoufa
authors.forename: Agnès
authors.initials: A
authors.lastname: Veyradier
authors.forename: Martine
authors.initials: M
authors.lastname: Wolf
authors.forename: Annette
authors.initials: A
authors.lastname: Bussel
authors.forename: Gaël Armel
authors.initials: GA
authors.lastname: Millot
authors.forename: Sandrine
authors.initials: S
authors.lastname: Malot
authors.forename: Farhad
authors.initials: F
authors.lastname: Heshmati
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Mira
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Boulanger
authors.forename: Lionel
authors.initials: L
authors.lastname: Galicier
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Durey-Dragon
authors.forename: Véronique
authors.initials: V
authors.lastname: Frémeaux-Bacchi
authors.forename: Michel
authors.initials: M
authors.lastname: Ramakers
authors.forename: André
authors.initials: A
authors.lastname: Pruna
authors.forename: Dominique
authors.initials: D
authors.lastname: Bordessoule
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouilleux
authors.forename: Marie-Lorraine
authors.initials: ML
authors.lastname: Scrobohaci
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vernant
authors.forename: Delphine
authors.initials: D
authors.lastname: Moreau
authors.forename: Elie
authors.initials: E
authors.lastname: Azoulay
authors.forename: Benoît
authors.initials: B
authors.lastname: Schlemmer
authors.forename: Loïc
authors.initials: L
authors.lastname: Guillevin
authors.forename: Kaïss
authors.initials: K
authors.lastname: Lassoued
mesh_terms: D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; D000293:Adolescent; D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases / Q000209:etiology*; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology*; D008297:Male; D008666:Metalloendopeptidases / Q000172:deficiency*; D008875:Middle Aged; D010976:Platelet Count; D011379:Prognosis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000209:etiology*; D013927:Thrombosis / Q000209:etiology*; D014841:von Willebrand Factor
chemical_list: D014841:von Willebrand Factor; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human