Genotype and Phenotype Correlation in Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome)
- Conditions
- Upshaw-Schulman SyndromeThrombotic Thrombocytopenic Purpura, CongenitalFamilial Thrombotic Thrombocytopenic PurpuraThrombotic Thrombocytopenic PurpuraCongenital Thrombotic Thrombocytopenic Purpura
- Interventions
- Other: Observation
- Registration Number
- NCT01257269
- Lead Sponsor
- Insel Gruppe AG, University Hospital Bern
- 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 Description
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 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 450
- 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 fresh frozen plasma (FFP) with a plasma half-life of 2-4 days)
Not provided
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description 2 Observation Family members of patients with confirmed hereditary TTP 1 Observation Patients with confirmed hereditary TTP due to congenital ADAMTS13 deficiency
- Primary Outcome Measures
Name Time Method Clinical presentation and disease course in hereditary TTP every year until death
- Secondary Outcome Measures
Name Time Method Treatment requirements in hereditary TTP patients every year until death Mortality of hereditary TTP every year until death Identification of disease-modifying factors, including genotype-phenotype correlation every year until death Documentation of potential adversary effects of (long-term) plasma treatment every year until death Clinical course in family members every year until death
Trial Locations
- Locations (7)
Medical University of Vienna, Department of Medicine 1, Div. Hematology and Hemostasis Waehringer Guertel 18-20
🇦🇹Vienna, Austria
University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital and the University of Bern, Inselspital
🇨🇭Bern, Switzerland
University Medical Center Hamburg-Eppendorf, Department of Pediatric Hematology and Oncology, Martinistr 52
🇩🇪Hamburg, Germany
Trondheim University St Olavs Hospital, Department of Hematology, PO Box 3250 Sluppen
🇳🇴Trondheim, Norway
University of Oklahoma Health Sciences Center, Department of Medicine, PO Box 26901
🇺🇸Oklahoma City, Oklahoma, United States
Nara Medical University, Department of Blood Transfusion Medicine, Shijyo-cho 840
🇯🇵Kashihara city, Nara, Japan
Institute of Hematology and Blood Transfusion, Coagulation Laboratory, U nemocnice 1
🇨🇿Prague 2, Czechia