Clinical trial NCT00426686: ADAMTS13 in Thrombotic Thrombocytopenic Purpura
Official title: ADAMTS13-related Prognostic Factors in Adult and Pediatric Thrombotic Thrombocytopenic Purpura
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Thrombotic Thrombocytopenic Purpura
Keywords: thrombotic thrombocytopenic purpura
prognostic factors
ADAMTS13
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2007-01-25
Enrollment: 153
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_ONLY
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adult and pediatric patients with TTP related to a severe ADAMTS13 deficiency.

Brief summary: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy defined by the spontaneous formation of platelet thrombi in the microvessels. These platelet microthrombi are responsible for a mechanical hemolytic anemia, a thrombocytopenia and a multivisceral ischemia. TTP is a rare but life-threatening disease in the absence of appropriate treatment (PLASMATHERAPY). The onset of the disease usually occurs in adulthood (MOSCHCOVITZ syndrome) and rarely in childhood (UPSHAW-SCHULMAN syndrome). TTP is either sporadic or recurrent with multiple unpredictable relapses. TTP pathophysiology has remained obscure until a new metalloprotease, ADAMTS13, has been demonstrated to be involved in about 90% of all cases. Physiologically, ADAMTS13 function consists in limiting the size of von Willebrand factor (VWF) multimers and consequently, their hemostatic capacity. A large majority of TTP is associated with a severe deficiency of ADAMTS13. In most cases, ADAMTS13 severe deficiency is acquired via auto-antibodies to ADAMTS13; more rarely, ADAMTS13 deficiency is hereditary via ADAMTS13 gene mutations. ADAMTS13 auto-antibodies are either inhibitory of the catalytic activity or non inhibitory. ADAMTS13 mutations are spread all over the gene.

TTP prognosis is quite heterogeneous. Indeed, in about one third of the patients, TTP is refractory to PLASMATHERAPY and/or chronic relapsing. Until now, TTP prognosis factors are not known. Their identification is however crucial both to adapt the curative treatment of an acute episode (addition of first intention immunosuppressive agents to PLASMATHERAPY) and to prevent relapses.

In this context, the aim of the current project is to identify some ADAMTS13 related prognosis factors in TTP. A national prospective multicenter study including both adult and pediatric patients with TTP related to a severe ADAMTS13 deficiency will be designed over a three-year period. This study will involve our group as the French reference center for ADAMTS13 and 10 clinical departments from various French hospitals. Patients will be tested for ADAMTS13 activity and antigen, ADAMTS13 antibodies and ADAMTS13 gene sequencing. Our main hypothesis is that the inactivation of the ADAMTS13 domains crucial for its catalytic activity, either by inhibitory auto-antibodies (acquired TTP) or by genetic mutations (hereditary TTP) is a major bad prognosis factor.

Detailed description: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy defined by the spontaneous formation of platelet thrombi in the microvessels. These platelet microthrombi are responsible for a mechanical hemolytic anemia, a thrombocytopenia and a multivisceral ischemia. TTP is a rare but life-threatening disease in the absence of appropriate treatment (PLASMATHERAPY). The onset of the disease usually occurs in adulthood (MOSCHCOVITZ syndrome) and rarely in childhood (UPSHAW-SCHULMAN syndrome). TTP is either sporadic or recurrent with multiple unpredictable relapses. TTP pathophysiology has remained obscure until a new metalloprotease, ADAMTS13, has been demonstrated to be involved in about 90% of all cases. Physiologically, ADAMTS13 function consists in limiting the size of von WILLBRAND factor (VWF) multimers and consequently, their hemostatic capacity. A large majority of TTP is associated with a severe deficiency of ADAMTS13 activity leading to the accumulation of ultra large VWF multimers in plasma inducing the formation of platelet microthrombi in the microcirculation. In most cases, ADAMTS13 severe deficiency is acquired via auto-antibodies to ADAMTS13; more rarely, ADAMTS13 deficiency is hereditary via ADAMTS13 gene mutations. ADAMTS13 auto-antibodies are either inhibitory of the catalytic activity or non inhibitory. ADAMTS13 mutations are spread all over the gene.

TTP prognosis is quite heterogeneous. Indeed, in about one third of the patients, TTP is refractory to PLASMATHERAPY and/or chronic relapsing. Until now, TTP prognosis factors are not known. Their identification is however crucial both to adapt the curative treatment of an acute episode (addition of first intention immunosuppressive agents to PLASMATHERAPY) and to prevent relapses.

In this context, the aim of the current project is to identify some ADAMTS13 related prognosis factors in TTP. A national prospective multicenter study including both adult and pediatric patients with TTP related to a severe ADAMTS13 deficiency will be designed over a three-year period. This study will involve our group as the French reference center for ADAMTS13 and about 50 clinical departments from various French hospitals. Patients will be tested for ADAMTS13 activity and antigen, ADAMTS13 antibodies and ADAMTS13 gene sequencing. Our main hypothesis is that the inactivation of the ADAMTS13 domains crucial for its catalytic activity, either by inhibitory auto-antibodies (acquired TTP) or by genetic mutations (hereditary TTP) is a major bad prognosis factor.

Eligibility criteria: Inclusion Criteria:

* clinical suspicion of TTP
* Hemoglobin level \< 10 g/dl (adult) or \< 12 g/dl (child)
* Platelet level \< 150 giga/l
* ADAMTS13 activity \< 5%

Exclusion Criteria:

* Cancer
* Organ graft
* HIV infection

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Clamart
country: France
facility: Hôpital Antoine Béclère
Study officials:
affiliation: Hôpital Saint Antoire, PARIS
name: paul COPPO, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Saint Louis Paris
name: Elie AZOULAY, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital Saint Louis Paris
name: Benoît SCHLEMMER, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Saint Louis Paris
name: Eric OKSENHENDLER, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Necker, PARIS
name: Fadi FAKHOURI, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Cochin, PARIS
name: Jean-Paul MIRA, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital Tenon, PARIS
name: Eric RONDEAU, MD
role: STUDY_DIRECTOR
affiliation: Hôpital la Pitié Salpétrière, PARIS
name: Jean-paul VERNANT, MD
role: STUDY_DIRECTOR
affiliation: CHU Conception, MARSEILLE
name: Nicolas SCHLEINITZ, MD
role: STUDY_DIRECTOR
affiliation: CHU Conception, MARSEILLE
name: Gilles KAPLANSKI, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital Trousseau, PARIS
name: Albert BENSMAN, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Robert Debré, PARIS
name: Chantal LOIRAT, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Robert Debré, PARIS
name: Brigitte BADER-MEUNIER, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Dupuytren, LIMOGES
name: Christophe PIGUET, MD
role: STUDY_DIRECTOR
affiliation: Hospices civils de LYON, LYON
name: Guy PUTET, MD
role: STUDY_DIRECTOR
affiliation: INSERM U569 Kremlin Bicêtre, Paris
name: Béatrice DUCOT, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Antoine Béclère, CLAMART
name: Agnes VEYRADIER, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital Saint Louis Paris
name: Thierry LEBLANC, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Necker, PARIS
name: Patrick NIAUDET, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital Tenon, PARIS
name: Christophe RIDEL, MD
role: STUDY_DIRECTOR
affiliation: CHU de la Conception, MARSEILLE
name: Pascale POULLIN, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Bicêtre, LE KREMLIN BICETRE
name: arlos FRANGIE, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Bicêtre, LE KREMLIN BICETRE
name: Hélène FRANCOIS, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Bicêtre, LE KREMLIN BICETRE
name: Olivier LAMBOTTE, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Dupytren, LIMOGES
name: Dominique BORDESSOULE, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital Dupytren, LIMOGES
name: Stéphane GIRAULT, MD
role: STUDY_DIRECTOR
affiliation: Hôpital de la Timone Enfants, Marseilles
name: Hervé CHAMBOST, MD
role: STUDY_DIRECTOR
affiliation: Hôpital de Brabois-Hôpital d'Enfants, Vandoeuvre-lès-Nancy
name: Pierre BORDOGONI, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital de Brabois- hôpital d'enfants, Vandoeuvre-lès-Nancy
name: Alexandra SALMON, MD
role: STUDY_DIRECTOR
affiliation: Hôpital de Brabois-Hôpital d'enfants, Vandoeuvre-lès-Nancy
name: Laurence CLEMENT, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Pellegrin, Bordeaux
name: Christian COMBE, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital Edouard Heriot, Lyon
name: Sandrine MEUNIER, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Hotel Dieu, Nantes
name: Gwenaêlle ROUSSEY, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Hotel Dieu, Nantes
name: Mohammed HAMIDOU, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital du Bocage, Dijon
name: Bernard BONNOTTE, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital du Bocage, Dijon
name: Yves TANTER, MD
role: STUDY_DIRECTOR
affiliation: Hôpital de Rangueil, Toulouse
name: Jacques POURRAT, MD, PhD
role: STUDY_DIRECTOR
affiliation: CHU de l'Archet 2, Nice
name: Marie-Christine THOURET, MD
role: STUDY_DIRECTOR
affiliation: CH de Valenciennes, Valenciennes
name: Philippe VANHILLE, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Henri Mondor, Créteil
name: Nicolas LIMAL, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Henri Mondor, Créteil
name: Philippe REMY, MD
role: STUDY_DIRECTOR
affiliation: CHG Châlons-en-Champagne, Châlons-en-Champagne
name: Jean-Michel KORACH, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Haut-Lévêque, Pesac
name: Carine GREIB, MD
role: STUDY_DIRECTOR
affiliation: CHI André Grégoire, Montreuil
name: Jean-Louis PALLOT, MD
role: STUDY_DIRECTOR
affiliation: CHU de Reims, Reims
name: Alain WYNCKEL, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Sud, Rennes
name: Claire CAZALETS, MD
role: STUDY_DIRECTOR
affiliation: CHU d'Amiens, Amiens
name: Bertrand DE CAGNY, MD
role: STUDY_DIRECTOR
affiliation: CHU D'Amiens, Amiens
name: Claire PRESNE, MD
role: STUDY_DIRECTOR
affiliation: Hôpital de Haute-Pierre, Strasbourg
name: Cécile FOHRER, MD
role: STUDY_DIRECTOR
affiliation: Hôpital de Haute-Pierre, Strasbourg
name: Karin BILGER, MD
role: STUDY_DIRECTOR
affiliation: Hôpital de Haute-Pierre, Strasbourg
name: Bruno LIOURE, MD
role: STUDY_DIRECTOR
affiliation: Hôpital de Haute-Pierre, Strasbourg
name: Raoul HERBRECHT, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital Nord, Grenoble
name: Dominique PLANTAZ, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital Gatien de Clovheville, Tours
name: Hubert NIVET, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hôpital Saint Louis, La Rochelle
name: Emmanuel FLECK, MD
role: STUDY_DIRECTOR
affiliation: Centre Hospitalier du Mans, LE MANS
name: Jean-Philippe COINDRE, PH
role: STUDY_DIRECTOR
affiliation: Hôpital Sainte-Blandine Service de Médecine Interne, METZ
name: François MAURIER, PH
role: STUDY_DIRECTOR
affiliation: Centre Hospitalier Régional de MULHOUSE Hôpital Edouard Muller, Département d'Hématologie, Unité de thérapie cellulaire et greffes, MULHOUSE
name: Mario OJEDA-URIBE, PH
role: STUDY_DIRECTOR
affiliation: Hôpital Tenon, Service de Néphrologie et de Transplantation rénale, PARIS
name: Christophe RIDEL, PH
role: STUDY_DIRECTOR
affiliation: Hôpital Antoine Béclère, Service de réanimation médicale, CLAMART
name: François BRIVET, PH
role: STUDY_DIRECTOR
affiliation: CHU Pontchaillou, Service de maladies infectieuses et réanimation médicale, RENNES
name: Sylvain LAVOUÉ, PH
role: STUDY_DIRECTOR
affiliation: Centre Hospitalier de Perpignan, Hôpital Saint-Jean, Service de Néphrologie, Hémodialyse, PERPIGNAN
name: Sébastien CANET, PH
role: STUDY_DIRECTOR
affiliation: Centre Hospitalier Régional Universitaire de Lille, Hôpital Calmette, Pôle de Néphrologie, LILLE
name: François PROVOT, PH
role: STUDY_DIRECTOR
affiliation: CHU de Nantes, Hôpital de jour et d'Hémodialyse pédiatrique
name: Claude GUYOT, PH
role: STUDY_DIRECTOR
affiliation: CHI André Grégoire de Montreuil, Service de Néphrologie, Diabète et Dialyse, MONTREUIL
name: Xavier BELENFANT, PH
role: STUDY_DIRECTOR
affiliation: Hôpital Edouard Herriot, Service de Médecine Interne, LYON
name: Laurent PERARD, PH
role: STUDY_DIRECTOR
affiliation: CHR de Pontoise Hôpital René Dubos, Service de Médecine Interne- Néphrologie- Dialyse, PONTOISE
name: Edouard DEVAUD, PH
role: STUDY_DIRECTOR
affiliation: CH CHAMBERY, Service de Pédiatrie, CHAMBERY
name: Arnaud BUFFIN, PH
role: STUDY_DIRECTOR
affiliation: CHU Montpellier Hôpital Lapeyronie, Service d'Hématologie et Oncologie médicale, MONTPELLIER
name: Tarik KANOUNI, PH
role: STUDY_DIRECTOR
affiliation: Hôpital Avicenne, Service de Médecine Interne, BOBIGNY
name: Nicolas GAMBIER, PH
role: STUDY_DIRECTOR
affiliation: CH Sud-Francilien- Hôpital Gilles de Corbeil, Service d'Hématologie Clinique, CORBEIL-ESSONNES
name: Alain DEVIDAS, PH
role: STUDY_DIRECTOR
affiliation: CH Colmar- Hôpital Pasteur, Service de Médecine Interne, COLMAR
name: Laure FEDERICI, PH
role: STUDY_DIRECTOR
affiliation: CHRU de Lille- Hôpital Jeanne de Flandre, Service de Néphrologie pédiatrique, LILLE
name: Michel FOULARD, PH
role: STUDY_DIRECTOR
affiliation: Hôpital Brabois Adulte, Service d'Hématologie, VANDOEUVRE-LÈS-NANCYS
name: Serge BOLOGNA, PH
role: STUDY_DIRECTOR
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