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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by University Hospital Inselspital, Berne
Sponsor:
Collaborators:
Swiss National Science Foundation
Mach-Gaensslen Foundation Switzerland
Baxter Healthcare Corporation
Information provided by:
University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier:
NCT01257269
First received: December 6, 2010
Last updated: June 17, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention
Thrombotic Thrombocytopenic Purpura
Congenital Thrombotic Thrombocytopenic Purpura
Familial Thrombotic Thrombocytopenic Purpura
Thrombotic Thrombocytopenic Purpura, Congenital
Upshaw-Schulman Syndrome
Other: Observation

Study Type: Observational
Study Design: Observational Model: Case-Only
Official Title: Thrombotic Thrombocytopenic Purpura Registry - A Prospective Observational Study for Patients Suffering From Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome)

Resource links provided by NLM:


Further study details as provided by University Hospital Inselspital, Berne:

Primary Outcome Measures:
  • Clinical presentation and disease course in hereditary TTP [ Time Frame: every year until death ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Identification of disease-modifying factors, including genotype-phenotype correlation [ Time Frame: every year until death ] [ Designated as safety issue: No ]
  • Treatment requirements in hereditary TTP patients [ Time Frame: every year until death ] [ Designated as safety issue: No ]
  • Documentation of potential adversary effects of (long-term) plasma treatment [ Time Frame: every year until death ] [ Designated as safety issue: No ]
  • Mortality of hereditary TTP [ Time Frame: every year until death ] [ Designated as safety issue: No ]
  • Clinical course in family members [ Time Frame: every year until death ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

Whole blood and plasma


Estimated Enrollment: 180
Study Start Date: October 2006
Estimated Study Completion Date: October 2030
Groups/Cohorts Assigned Interventions
1
Patients with confirmed hereditary TTP due to congenital ADAMTS13 deficiency
Other: Observation
No interventions planned: treatment of patients at the discretion of the treating/responsible physician
2
Family members of patients with confirmed hereditary TTP
Other: Observation
No interventions planned: treatment of patients at the discretion of the treating/responsible physician

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 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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Patients with either confirmed or with suspected hereditary TTP and their family members are eligible for enrollment

Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01257269

Contacts
Contact: Johanna A Kremer Hovinga, M. D. +41 31 632 90 22 johanna.kremer@insel.ch
Contact: Magnus Mansouri, M.D. +41 31 632 96 19 magnus.mansouri@insel.ch

Locations
United States, Oklahoma
University of Oklahoma Health Sciences Center, Department of Medicine, PO Box 26901 Recruiting
Oklahoma City, Oklahoma, United States, 73126-0901
Contact: James N. George, M.D.    405-271-4222    james-george@ouhsc.edu   
Principal Investigator: James N. George, M.D.         
Austria
Medical University of Vienna, Department of Medicine 1, Div. Hematology and Hemostasis Waehringer Guertel 18-20 Recruiting
Vienna, Austria, A-1090
Contact: Paul N. Knoebl, M.D.    +43 1 40400 4410    paul.knoebl@meduniwien.ac.at   
Principal Investigator: Paul N. Knoebl, M.D.         
Czech Republic
Institute of Hematology and Blood Transfusion, Coagulation Laboratory, U nemocnice 1 Recruiting
Prague 2, Czech Republic, CZ-12820
Contact: Ingrid Hrachovinova, Ph.D.    +420 2 2197 271    Ingrid.Hrachovinova@uhkt.cz   
Principal Investigator: Ingrid Hrachovinova, Ph.D.         
Germany
University Medical Center Hamburg-Eppendorf, Department of Pediatric Hematology and Oncology, Martinistr 52 Not yet recruiting
Hamburg, Germany, D-20246
Contact: Reinhard Schneppenheim, M.D., Ph.D.    +49 40 7410 54270    schneppenheim@uke.de   
Principal Investigator: Reinhard Schneppenheim, M.D., Ph.D.         
Japan
Nara Medical University, Department of Blood Transfusion Medicine, Shijyo-cho 840 Recruiting
Kashihara city, Nara, Japan, 634-8522
Contact: Yoshihiro Fujimura, M.D.    +81 744 22 3051 ext 3289    yoshifuji325@naramed-u.ac.jp   
Principal Investigator: Yoshihiro Fujimura, M.D.         
Norway
Trondheim University St Olavs Hospital, Department of Hematology, PO Box 3250 Sluppen Recruiting
Trondheim, Norway, NO-7006
Contact: Petter Quist-Paulsen, M.D., Ph.D.    +47 815 55 850    Petter.Quist-Paulsen@stolav.no   
Contact: Anne-Sophie von Krogh, M.D.    +47 815 55 850    Anne-Sophie.von.Krogh@stolav.no   
Principal Investigator: Petter Quist-Paulsen, M.D.,Ph.D.         
Sub-Investigator: Anne-Sophie von Krogh, M.D.         
Switzerland
University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital and the University of Bern, Inselspital Recruiting
Bern, Switzerland, 3010
Contact: Johanna A Kremer Hovinga, M.D.    +41 31 632 90 22    johanna.kremer@insel.ch   
Contact: Bernhard Lämmle, M.D.    +41 31 632 33 02    bernhard.laemmle@insel.ch   
Principal Investigator: Johanna A Kremer Hovinga, M.D.         
Sub-Investigator: Bernhard Lämmle, M.D.         
Sponsors and Collaborators
University Hospital Inselspital, Berne
Swiss National Science Foundation
Mach-Gaensslen Foundation Switzerland
Baxter Healthcare Corporation
Investigators
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
Study Chair: Bernhard Lämmle, M.D. University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital and the University of Bern, Inselspital
Study Chair: Yoshihiro Fujimura, M.D. Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan
Study Chair: Ingrid Hrachovinova, Ph.D. Institute of Hematology and Blood Transfusion, Coagulation Laboratory, Prague, Czech Republic
Study Chair: Petter Quist-Paulsen, M.D., Ph.D. Department of Hematology, St Olavs Hospital, 7006 Trondheim, Norway
Study Chair: Reinhard Schneppenheim, M.D., Ph.D. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Study Chair: James N. George, MD University of Oklahoma Health Sciences Center, Department of Medicine, United States of America
Study Chair: Paul N Knoebl, MD Medical University of Vienna, Div. Hematology and Hemostasis, Austria
  More Information

Additional Information:
No publications provided

Responsible Party: 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
ClinicalTrials.gov Identifier: NCT01257269     History of Changes
Other Study ID Numbers: 031/06
Study First Received: December 6, 2010
Last Updated: June 17, 2014
Health Authority: Switzerland: Ethikkommission

Keywords provided by University Hospital Inselspital, Berne:
Thrombotic thrombocytopenic purpura
ADAMTS13
Von Willebrand factor
Von Willebrand factor cleaving protease
Thrombocytopenia
Hemolytic anemia

Additional relevant MeSH terms:
Purpura
Purpura, Thrombocytopenic
Purpura, Thrombotic Thrombocytopenic
Eosinophilia
Fasciitis
Blood Coagulation Disorders
Hematologic Diseases
Hemorrhage
Pathologic Processes
Skin Manifestations
Signs and Symptoms
Thrombotic Microangiopathies
Thrombocytopenia
Blood Platelet Disorders
Immune System Diseases
Thrombophilia
Leukocyte Disorders
Musculoskeletal Diseases

ClinicalTrials.gov processed this record on August 20, 2014