Clinical trial NCT01257269: Genotype and Phenotype Correlation in Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome)
Official title: Thrombotic Thrombocytopenic Purpura Registry - A Prospective Observational Study for Patients Suffering From Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Thrombotic Thrombocytopenic Purpura
Congenital Thrombotic Thrombocytopenic Purpura
Familial Thrombotic Thrombocytopenic Purpura
Thrombotic Thrombocytopenic Purpura, Congenital
Upshaw-Schulman Syndrome
Keywords: Thrombotic thrombocytopenic purpura
ADAMTS13
Von Willebrand factor
Von Willebrand factor cleaving protease
Thrombocytopenia
Hemolytic anemia
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
name: Mach Gaensslen Foundation
name: Baxalta Innovations GmbH, Wien, Austria
First posted: 2010-12-09
Enrollment: 450
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with either confirmed or with suspected hereditary TTP and their family members are eligible for enrollment

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.

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

Primary outcomes:
measure: Clinical presentation and disease course in hereditary TTP
timeFrame: every year until death
Secondary outcomes:
measure: Identification of disease-modifying factors, including genotype-phenotype correlation
timeFrame: every year until death
measure: Treatment requirements in hereditary TTP patients
timeFrame: every year until death
measure: Documentation of potential adversary effects of (long-term) plasma treatment
timeFrame: every year until death
measure: Mortality of hereditary TTP
timeFrame: every year until death
measure: Clinical course in family members
timeFrame: every year until death
Other outcomes:
Locations:
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center, Department of Medicine, PO Box 26901
state: Oklahoma
city: Vienna
country: Austria
facility: Medical University of Vienna, Department of Medicine 1, Div. Hematology and Hemostasis Waehringer Guertel 18-20
city: Prague 2
country: Czechia
facility: Institute of Hematology and Blood Transfusion, Coagulation Laboratory, U nemocnice 1
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf, Department of Pediatric Hematology and Oncology, Martinistr 52
city: Kashihara city
country: Japan
facility: Nara Medical University, Department of Blood Transfusion Medicine, Shijyo-cho 840
state: Nara
city: Trondheim
country: Norway
facility: Trondheim University St Olavs Hospital, Department of Hematology, PO Box 3250 Sluppen
city: Bern
country: Switzerland
facility: University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital and the University of Bern, Inselspital
Study officials:
affiliation: University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital and the University of Bern, Inselspital
name: Johanna A Kremer Hovinga, MD
role: STUDY_CHAIR
affiliation: University Medical Center, Center for Thrombosis and Hemostasis, Mainz, Germany
name: Bernhard Lämmle, M.D.
role: STUDY_CHAIR
affiliation: Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan
name: Yoshihiro Fujimura, M.D.
role: STUDY_CHAIR
affiliation: Institute of Hematology and Blood Transfusion, Coagulation Laboratory, Prague, Czech Republic
name: Ingrid Hrachovinova, Ph.D.
role: STUDY_CHAIR
affiliation: Department of Hematology, St Olavs Hospital, 7006 Trondheim, Norway
name: Petter Quist-Paulsen, M.D., Ph.D.
role: STUDY_CHAIR
affiliation: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
name: Reinhard Schneppenheim, M.D., Ph.D.
role: STUDY_CHAIR
affiliation: University of Oklahoma Health Sciences Center, Department of Medicine, United States of America
name: James N. George, MD
role: STUDY_CHAIR
affiliation: Medical University of Vienna, Div. Hematology and Hemostasis, Austria
name: Paul N Knoebl, MD
role: STUDY_CHAIR
References:
citation: Tarasco E, Butikofer L, Friedman KD, George JN, Hrachovinova I, Knobl PN, Matsumoto M, von Krogh AS, Aebi-Huber I, Cermakova Z, Gorska-Kosicka M, Jalowiec KA, Largiader CR, Prohaszka Z, Sinkovits G, Windyga J, Lammle B, Kremer Hovinga JA. Annual incidence and severity of acute episodes in hereditary thrombotic thrombocytopenic purpura. Blood. 2021 Jun 24;137(25):3563-3575. doi: 10.1182/blood.2020009801.
citation: van Dorland HA, Taleghani MM, Sakai K, Friedman KD, George JN, Hrachovinova I, Knobl PN, von Krogh AS, Schneppenheim R, Aebi-Huber I, Butikofer L, Largiader CR, Cermakova Z, Kokame K, Miyata T, Yagi H, Terrell DR, Vesely SK, Matsumoto M, Lammle B, Fujimura Y, Kremer Hovinga JA; Hereditary TTP Registry. The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017. Haematologica. 2019 Oct;104(10):2107-2115. doi: 10.3324/haematol.2019.216796. Epub 2019 Feb 21.
citation: Fan X, Kremer Hovinga JA, Shirotani-Ikejima H, Eura Y, Hirai H, Honda S, Kokame K, Taleghani MM, von Krogh AS, Yoshida Y, Fujimura Y, Lammle B, Miyata T. Genetic variations in complement factors in patients with congenital thrombotic thrombocytopenic purpura with renal insufficiency. Int J Hematol. 2016 Mar;103(3):283-91. doi: 10.1007/s12185-015-1933-7. Epub 2016 Feb 1.
citation: Lammle B. VWF and complement. Blood. 2015 Feb 5;125(6):896-8. doi: 10.1182/blood-2014-12-612556. No abstract available.
citation: Mansouri Taleghani M, von Krogh AS, Fujimura Y, George JN, Hrachovinova I, Knobl PN, Quist-Paulsen P, Schneppenheim R, Lammle B, Kremer Hovinga JA. Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry. Hamostaseologie. 2013 May 29;33(2):138-43. doi: 10.5482/HAMO-13-04-0026.