ADAMTS13 in Thrombotic Thrombocytopenic Purpura
ADAMTS13 in Thrombotic Thrombocytopenic Purpura
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.
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.
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