ADAMTS13 in Thrombotic Thrombocytopenic Purpura

Thrombotic Thrombocytopenic Purpura Clinical Trial

— ADAMTS13  

Official title:

ADAMTS13-related Prognostic Factors in Adult and Pediatric Thrombotic Thrombocytopenic Purpura

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00426686
• Other study ID #: PO51064
• Status: Completed
• Phase: N/A
• First received: January 24, 2007
• Last updated: December 11, 2012
• Start date: November 2006
• Est. completion date: April 2011

Study information

• Verified date: April 2011
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 153
• Est. completion date: April 2011
• Est. primary completion date: March 2009
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: N/A and older

Eligibility

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

Study Design

Observational Model: Case-Only

Related Conditions & MeSH terms

• Purpura
• Purpura, Thrombocytopenic
• Purpura, Thrombotic Thrombocytopenic
• Thrombotic Thrombocytopenic Purpura

Locations

Country	Name	City	State
France	Hôpital Antoine Béclère	Clamart

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (8)

Fakhouri F, Vernant JP, Veyradier A, Wolf M, Kaplanski G, Binaut R, Rieger M, Scheiflinger F, Poullin P, Deroure B, Delarue R, Lesavre P, Vanhille P, Hermine O, Remuzzi G, Grünfeld JP. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood. 2005 Sep 15;106(6):1932-7. Epub 2005 Jun 2. — View Citation

Ferrari S, Scheiflinger F, Rieger M, Mudde G, Wolf M, Coppo P, Girma JP, Azoulay E, Brun-Buisson C, Fakhouri F, Mira JP, Oksenhendler E, Poullin P, Rondeau E, Schleinitz N, Schlemmer B, Teboul JL, Vanhille P, Vernant JP, Meyer D, Veyradier A; French Clini — View Citation

Hommais A, Rayes J, Houllier A, Obert B, Legendre P, Veyradier A, Girma JP, Ribba AS. Molecular characterization of four ADAMTS13 mutations responsible for congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). Thromb Haemost. 2007 Sep — View Citation

Loirat C, Girma JP, Desconclois C, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatr Nephrol. 2009 Jan;24(1):19-29. doi: 10.1007/s00467-008-0863-5. Epub 2008 Jun 24. Review. — View Citation

Malak S, Wolf M, Millot GA, Mariotte E, Veyradier A, Meynard JL, Korach JM, Malot S, Bussel A, Azoulay E, Boulanger E, Galicier L, Devaux E, Eschwège V, Gallien S, Adrie C, Schlemmer B, Rondeau E, Coppo P; Réseau d'Etude des Microangiopathies Thrombotique — View Citation

Veyradier A, Lavergne JM, Ribba AS, Obert B, Loirat C, Meyer D, Girma JP. Ten candidate ADAMTS13 mutations in six French families with congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). J Thromb Haemost. 2004 Mar;2(3):424-9. — View Citation

Veyradier A, Obert B, Haddad E, Cloarec S, Nivet H, Foulard M, Lesure F, Delattre P, Lakhdari M, Meyer D, Girma JP, Loirat C. Severe deficiency of the specific von Willebrand factor-cleaving protease (ADAMTS 13) activity in a subgroup of children with atypical hemolytic uremic syndrome. J Pediatr. 2003 Mar;142(3):310-7. Erratum in: J Pediatr. 2003 Jun;142(6):616. Loriat, C [corrected to Loirat, C]. — View Citation

Veyradier A, Obert B, Houllier A, Meyer D, Girma JP. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood. 2001 Sep 15;98(6):1765-72. — View Citation