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

Genotype and Phenotype Correlation in Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome)
Thrombotic Thrombocytopenic Purpura Registry - A Prospective Observational Study for Patients Suffering From Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome)

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.

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 IgG (Immunoglobulin G), inhibiting ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) activity. In contrast, hereditary TTP, also known as Upshaw-Schulman syndrome (USS); OMIM #274150 (Online Mendelian Inheritance in Man), 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 has been reported. It is the aim of the hereditary TTP Registry to provide information on the clinical course of the disease in as many patients as possible and therefore help to establish recommendations on the necessity, modalities, and risks of prophylactic plasma therapy in patients with hereditary TTP. Furthermore, it will help to gain detailed insight into triggers and risk factors of acute bouts of TTP.

Moreover, the hereditary TTP Registry will provide information for family members on their risk to develop TTP-like or TTP-related disorders.

Objective

Primary objective: Collection of as much information as possible on the clinical presentation, disease course, disease-modifying factors, and treatment modalities of patients suffering from hereditary thrombotic thrombocytopenic purpura (TTP).

Secondary objective: To document potential adversary effects of (long-term) plasma treatment in patients with hereditary thrombotic thrombocytopenic purpura (TTP).

Methods

The TTP Registry is designed to collect both retrospective and prospective clinical, molecular, and observational data on patients with confirmed or suspected hereditary TTP. Additionally, the Registry will collect data from family members of TTP patients enrolled in the Registry. The Registry will enroll as many confirmed or suspected hereditary TTP patients and their family members as possible; there is no cap on enrollment. The Registry enrollment and follow-up periods are open-ended. The endpoints for patients with confirmed or suspected hereditary TTP and family members are death or withdrawal of consent.

N/A
Observational
Observational Model: Case-Only
Clinical presentation and disease course in hereditary TTP
Identification of disease-modifying factors, including genotype-phenotype correlation
  • Thrombotic Thrombocytopenic Purpura
  • Congenital Thrombotic Thrombocytopenic Purpura
  • Familial Thrombotic Thrombocytopenic Purpura
  • Thrombotic Thrombocytopenic Purpura, Congenital
  • Upshaw-Schulman Syndrome
OtherObservation
  • 1

    Patients with confirmed hereditary TTP due to congenital ADAMTS13 deficiency

  • 2

    Family members of patients with confirmed hereditary TTP

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Other
180
October 2006
October 2030

Inclusion Criteria:

  • Severe ADAMTS13 deficiency ( ≤ 10% activity) and no ADAMTS 13 inhibitor on two or more occasions at least one month apart

  • Being a family member of a confirmed or suspected patient

  • Molecular analysis of ADAMTS13 gene with one or more mutations and/or positive infusion trial (full recovered ADAMTS13 activity after infused FFP with a plasma half-life of 2-4 days)

Both
N/A - N/A
No
  • Johanna A Kremer Hovinga, M. D., +41 31 632 90 22, johanna.kremer@insel.ch
  • Magnus Mansouri, M.D., +41 31 632 96 19, magnus.mansouri@insel.ch
Austria, Czech Republic, Germany, Japan, Norway, Switzerland, United States,
NCT01257269
031/06
Kremer Hovinga Johanna / M.D., University Clinic of Hematology and Central Hematology Laboratory, University Hospital and the University of Bern, Inselspital, CH-3010 Bern Switzerland
University Hospital Inselspital, Berne
  • Swiss National Science Foundation
  • Mach-Gaensslen Foundation Switzerland
  • Baxter Healthcare Corporation
Study Chair: Johanna A Kremer Hovinga, M.D., University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital and the University of Bern, Inselspital
University Hospital Inselspital, Berne
June 2014
December 6, 2010
June 17, 2014
Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.