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

Thrombotic Thrombocytopenic Purpura Clinical Trial

— TTP registry  

Official title:

Thrombotic Thrombocytopenic Purpura Registry - A Prospective Observational Study for Patients Suffering From Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01257269
• Other study ID #: 031/06
• Status: Recruiting
• Start date: October 2006
• Est. completion date: October 2030

Study information

• Verified date: October 2023
• Source: Insel Gruppe AG, University Hospital Bern
• Contact: Johanna A Kremer Hovinga, MD
• Phone: +41 31 632 02 65
• Email: johanna.kremer[@]insel.ch
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 450
• Est. completion date: October 2030
• Est. primary completion date: October 2030
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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 fresh frozen plasma (FFP) with a plasma half-life of 2-4 days)

Related Conditions & MeSH terms

• Congenital Thrombotic Thrombocytopenic Purpura
• Eosinophilia
• Familial Thrombotic Thrombocytopenic Purpura
• Fasciitis
• Purpura
• Purpura, Thrombocytopenic
• Purpura, Thrombotic Thrombocytopenic
• Syndrome
• Thrombotic Thrombocytopenic Purpura
• Thrombotic Thrombocytopenic Purpura, Congenital
• Upshaw-Schulman Syndrome

Intervention

Other:
• Observation
No interventions planned: treatment of patients at the discretion of the treating/responsible physician

Locations

Country	Name	City	State
Austria	Medical University of Vienna, Department of Medicine 1, Div. Hematology and Hemostasis Waehringer Guertel 18-20	Vienna
Czechia	Institute of Hematology and Blood Transfusion, Coagulation Laboratory, U nemocnice 1	Prague 2
Germany	University Medical Center Hamburg-Eppendorf, Department of Pediatric Hematology and Oncology, Martinistr 52	Hamburg
Japan	Nara Medical University, Department of Blood Transfusion Medicine, Shijyo-cho 840	Kashihara city	Nara
Norway	Trondheim University St Olavs Hospital, Department of Hematology, PO Box 3250 Sluppen	Trondheim
Switzerland	University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital and the University of Bern, Inselspital	Bern
United States	University of Oklahoma Health Sciences Center, Department of Medicine, PO Box 26901	Oklahoma City	Oklahoma

Sponsors (4)

Lead Sponsor	Collaborator
Insel Gruppe AG, University Hospital Bern	Baxalta Innovations GmbH, Wien, Austria, Mach Gaensslen Foundation, Swiss National Science Foundation

Countries where clinical trial is conducted

United States,  Austria,  Czechia,  Germany,  Japan,  Norway,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical presentation and disease course in hereditary TTP		every year until death
Secondary	Identification of disease-modifying factors, including genotype-phenotype correlation		every year until death
Secondary	Treatment requirements in hereditary TTP patients		every year until death
Secondary	Documentation of potential adversary effects of (long-term) plasma treatment		every year until death
Secondary	Mortality of hereditary TTP		every year until death
Secondary	Clinical course in family members		every year until death

External Links

•   Additional information