Groningen Antithrombin Study

Rationale: Antithrombin deficiency is a rare autosomal dominant prothrombotic
disorder. Prevalence of heterozygous antithrombin deficiency is estimated
between 1 in 500 and 1 in 5000 persons. (Patnaik et al) Annual incidence of VTE
in antithrombin deficient family members of patients with VTE is 1,94% (*1),
the risk of recurrent VTE about 10% per year (*2).

Antithombin deficiency can either result from a lack of circulating
antithrombin molecules (type 1 deficiency) or from a lack of function of the
circulation molecules (type 2 deficiency). The type 2 deficiencies are
subdivided according to the localisation of the mutation: type 2 RE (reactive
site), type 2 HBS (heparin binding site), type 2 PE (pleiotrophic effects).
Patients with a type 2 HBS may have a lower risk of VTE, and therefore this
subdivision has clinical impact. (*3)

The antithrombin molecule is encoded in the SERPINC1 gene. Various mutations in
patients with antithrombin deficiency were found, most heterozygous, and even
some homozygous (Luxembourg et al). Homozygous antithrombin patients are
extremely rare, as most homozygous antithrombin mutations are lethal in utero.
The exact protrombotic nature of each mutation however is unknown. The link
between genotype and phenotype is often only supported by antithrombine
activity measurements in vitro, but not by the study of large families and/or
functional studies of the found mutations. Computer models of conformational
changes due to mutations are also used, but conflicting in their predictions of
clinical importance of mutations (In the study of Luxembourg et al: conflicting
results in 8 of 29 analyses). Because of this, no risk can be attributed to a
certain mutation.

In the patients and antithrombin-mutated family members studied in our centre
(*1,2,4), we found striking differences in our historical data between families
and the occurrence of VTE. For example, in one family, in 7 antithrombin
deficient family members, no VTE*s occurred, whilst in another family in 10
antithrombin deficient family members 8 VTE*s occurred.
The question arises whether these differences after several years still hold,
and - if present - why these differences have occurred. Is this due to
antithrombin deficiency subtype, or are there differences within subtypes due
to different mutations? Is it possible to describe the exact link between a
mutation and clinical behaviour? To investigate these questions, we have
formulated the following objectives:

Objectives:
1. To investigate the types of antitrombin deficiency in these families
2. To find the mutations in our families/patients with antitrombin deficiency.
3. To establish the risk of VTE due to these mutations and subtypes.(comparing
antithrombin deficient family members with non-deficient family members)

a retrospective family cohort study

The amount and number of blood samples: 1 blood sample,
* 10 ml in EDTA (sequencing, MPLA)
* 1x6ml in citrate in previously tested patients (needed for antithrombin
activity and antigen measurements)
* 2x6ml in citrate in patients not previously tested (extra tube needed to test
other thrombofilic factors which may influence VTE-risk)
the number of site visits: 1
questionnaires or diaries which have to be filled in: 1 questionnaire
physical and physiological discomfort associated with participation: 1
venapuncture,