National study of moderate and severe von Willebrand disease in the Netherlands

In the Netherlands the population with hemophilia is well known, and several
studies (Hemophilia in the Netherlands, HIN1-5 studies) have been performed to
obtain insight in the disease, treatment and complications of treatment. This
does not apply for patients with von Willebrand disease. The incidence of von
Willebrand disease in the Netherlands is unknown, but the occurrence of all
types of von Willebrand disease together is estimated at 1:100-1:200
individuals. Most patients have mild von Willebrand disease, mostly type 1.
For the more severe forms of von Willebrand disease the incidence in unclear,
but the expectation is, that there are at least 500-1500 patients. In the
Netherlands, an unique situation exists for the treatment of patients with
hemophilia and related coagulation disorders.
In 2000 a hemophilia management policy was set up by the Ministry of Health,
which stated that the care for these patients should be concentrated in 13
Hemophilia Treatment Centers (HTC). The representatives of the attending
centers, the hemophilia specialists, have been organized in the NVHB, the Dutch
society of Hemophilia treaters. In the hemophilia management policy is stated
that all patients with a coagulation disorder dependent of replacement products
must be treated in a HTC or under responsibility of a HTC. These patients will
be followed and seen in a HTC at least once a year and all patients have a
maintenance program.

Because all moderate and severe von Willebrand patients in the Netherlands are
known in HTC, it is possible for this study to register this population. This
is imperative to the research of von Willebrand disease. Because the moderate
and severe forms of von Willebrand disease are rare, it is impossible for an
individual center to perform research of moderate severe and severe von
Willebrand disease. Therefore a national approach is necessary. A similar
national study done for hemophilia patients (HIN-study), resulted in important
information about diagnosis, treatment, related diseases and social
consequences. The HIN-study facilitated national research, in which hemophilia
patients participate. For this WIN-study, expertise of the HIN-study can be
used.

For optimal care of patients with the moderate and severe form of von
Willebrand disease a better understanding of symptoms, diagnostics, treatment
and complications of treatment is necessary. The present study aims to register
and investigate all patients in the Netherlands with moderate and severe von
Willebrand disease.

The objective of this study is to assess the clinical presentation, the
treatment and the complications of treatment in moderate and severe von
Willebrand disease. Another goal is to investigate the influence of von
Willebrand disease on quality of life.

To perform this study a number of study topics are formulated:

1. Clinical presentation
a. What is the frequency and severity of bleeding symptoms in patients with
von
Willebrand disease, measured with the Bleeding Score of Tosetto et al.
completed with hematuria and bleedings in children
b. Which proportion of women with von Willebrand disease has menorrhagia. Do
they have iron deficiency anemia, do they need treatment with drugs or
surgical interventions
c. Which proportion of patients with von Willebrand disease has joint
bleedings.
What is the frequency of joints bleedings. Which proportion of patients
with
von Willebrand disease has arthropathy. Which joints are
damaged
d. Which proportion of patients with von Willebrand disease has irreversible
damage of organs because of the bleedings and the treatment bleedings (for
instance: arthropathy, brain damage, fertility problems due to
hysterectomy).
What is the nature of organ damage. What are the risk factors of
irreversible
organ damage (vWF levels, age, treatment et cetera)

2. Treatment
a. Which drugs (DDAVP, antifibrinolytics or coagulation factor concentrates)
has
been used as treatment of von Willebrand
disease and based on which indication
b. Have patients been treated prophylactic with coagulation factor
concentrates

3. Complications of treatment
a. Which proportion of patients has inhibitors against vWF due to treatment
with
coagulation factor concentrates
b. Which proportion of patients has had an allergic reaction after treatment
with
coagulation factor concentrates
c. Which proportion of patients has had venous thromboembolism or pulmonary
embolism during treatment with coagulation factor concentrates
d. Which proportion of patients is tested for hepatitis B, C or HIV. Which
proportion of patients is infected with hepatitis B, C or HIV. Are they
treated
because of this transmission
3. Which risk factors can be identified

4. Heart and blood vessel disease
a. Which proportion of patients has had arterial thrombotic complications such
as
cerebral ischemia, myocardial infarction or peripheral arterial disease

5. Social implications of von Willebrand disease
a. What is de influence of von Willebrand disease on quality of life, measured
with
the RAND-36 questionnaire in patients older than 11 years. In children the
Haemo-QoL questionnaire is used
b. What are the effects of von Willebrand disease on social participation
(education, work, sports, family planning)
c. Which factors have an influence on quality of life in von Willebrand disease
patients (for instance: amount of bleeding episodes, irreversible organ
damage
due to bleedings, age, living with a partner)

6. Mutation analysis
a. Which mutations in the von Willebrand-gene are responsible for von
Willebrand disease
b. What is the correlation between the different mutations of the von
Willebrand-gene and the Bleeding Score

To answer these questions a questionnaire is developed, which will be sent to
the study population. Blood will be taken and result in a plasma and DNA bank.

Amendment Unravellingen von Willebrand disease: a new genetic bleeding disorder:
The aim is to gain more knowledge on the genetic background of von Willebrand
disease. Mutations in von Willebrand-factor gene are not always found in
patients, and different family members with the same mutations an have
different phenotypes. We will perform mutation analysis in both the von
Willebrand factor gene and other genes in patients already included and family
members with mild disease and unaffected family members and compare their
phenotype.

The study population will be sent a questionnaire, it will take approximately
50 minutes to fill in this questionnaire. Furthermore a venapunction will take
place once, four blood tubes (18ml) will be obtained in adults. In children
this will be two blood tubes (9 ml).