Clinical Trial: Genotype and Phenotype Correlation in Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome)

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational

Official Title: Thrombotic Thrombocytopenic Purpura Registry - A Prospective Observational Study for Patients Suffering From Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndr

Brief Summary:

Hereditary thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) is a rare disorder characterized by thrombocytopenia as a result of platelet consumption, microangiopathic hemolytic anemia, occlusion of the microvasculature with von Willebrand factor-platelet-thrombic and ischemic end organ damage. The underlying patho-mechanism is a severe congenital ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) deficiency which is the result of compound heterozygous or homozygous ADAMTS13 gene mutations.

Although considered a monogenic disorder the clinical presentation in Upshaw-Schulman syndrome patients varies considerably without an apparent genotype-phenotype correlation. In 2006 we have initiated a registry for patients with Upshaw-Schulman syndrome and their family members to identify possible triggers of acute bouts of TTP, to document individual clinical courses and treatment requirements as well as possible side effects of long standing plasma substitution, e.g. alloantibody formation or viral infections.


Detailed Summary:

Background

Thrombocytopenia and microangiopathic hemolytic anemia together with a severely deficient ADAMTS13 activity confirm the diagnosis of acute thrombotic thrombocytopenic purpura (TTP). Today two forms of classical TTP are distinguished. The acquired form is caused by circulating auto-antibodies, mainly Immunoglobulin G (IgG), inhibiting ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) activity. In contrast, hereditary TTP, also known as Upshaw-Schulman syndrome (USS); #274150 Online Mendelian Inheritance in Man (OMIM), is the result of severe constitutional deficiency of ADAMTS13 due to compound heterozygous or homozygous mutations in the ADAMTS13 gene.

The clinical course of USS is variable with rather mild courses in some of the patients requiring plasma infusions only in special situations (i.e. pregnancy), while in others severe courses with important sequelae and even death in early childhood occur. The reasons for the variable clinical presentation and treatment requirements have not been elucidated. It seems likely, that additional, hitherto unidentified factors besides severe ADAMTS13 deficiency modify the clinical course.

At present, the clinical symptoms and laboratory values on which to base treatment regimens for hereditary TTP are poorly understood. Furthermore, increasing awareness of hereditary TTP results in rising numbers of patients in need of treatment and/or prophylaxis. However, currently very little is known on side effects of long standing plasma substitution. Alloimmunization with the formation of antibodies acting as inhibitors of treatment are well known in other congenital coagulation factor deficiencies (e.g. hemophilia A), but so far no case of treated hereditary TTP with subsequent antibody formation h
Sponsor: University Hospital Inselspital, Berne

Current Primary Outcome: Clinical presentation and disease course in hereditary TTP [ Time Frame: every year until death ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Identification of disease-modifying factors, including genotype-phenotype correlation [ Time Frame: every year until death ]
  • Treatment requirements in hereditary TTP patients [ Time Frame: every year until death ]
  • Documentation of potential adversary effects of (long-term) plasma treatment [ Time Frame: every year until death ]
  • Mortality of hereditary TTP [ Time Frame: every year until death ]
  • Clinical course in family members [ Time Frame: every year until death ]


Original Secondary Outcome:

  • Identification of disease-modifying factors [ Time Frame: every year until death ]
  • Treatment requirements in hereditary TTP patients [ Time Frame: every year until death ]
  • Documentation of potential adversary effects of (long-term) plasma treatment [ Time Frame: every year until death ]
  • Mortality of hereditary TTP [ Time Frame: every year until death ]
  • Clinical course in family members [ Time Frame: every year until death ]


Information By: University Hospital Inselspital, Berne

Dates:
Date Received: December 6, 2010
Date Started: October 2006
Date Completion: October 2030
Last Updated: September 1, 2016
Last Verified: September 2016