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

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.

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)