Type 3 Von Willebrand International Registries Inhibitor Prospective Study Extended.

Von Willebrand Disease (VWD) is the most common inherited bleeding disorder,
characterized by a quantitative (VWD types 1 and 3) and/or qualitative (VWD
types 2A, 2B, 2M and 2N) deficiency of von Willebrand factor (VWF), the large
multifunctional plasma glycoprotein that plays a major role in early phases of
haemostasis. VWD type 3 (VWD3) is due to virtually complete deficiency of VWF
and, for this reason, has also been described as 'severe VWD'. In fact, VWD3
patients by definition are characterized by undetectable levels of VWF antigen
(VWF:Ag) in plasma and reduced concentrations (<10 IU/dL) of factor VIII
(FVIII). These baseline levels usually do not increase in plasma following
desmopressin (DDAVP), the drug which can release VWF from endothelium. VWD3 is
inherited as a recessive trait and heterozygous relatives have mild or no
bleeding symptoms. The prevalence of VWD3 is very low, ranging from 0.1-5.3 per
million and differing considerably between countries. The highest rate is found
in Iran and the lowest in southern Europe. However, the actual prevalence of
VWD3 is still unknown in most countries, due to the lack of retrospective or
prospective studies. Although rare, VWD3 is of major interest because its
severe clinical presentation, the need for replacement therapy with VWF
concentrates (until now only plasma-derived VWF concentrates are available but
a recombinant VWF is under clinical trial) and the risk of occurence of
anti-VWF inhibitors after the infusion of VWF concentrates, for which risk
factors have not been systematically determined.

- International network among European (125 cases) and Iranian (125 cases)
centers
- Prospective enrollment of the 250 VWD3 patients using a common database online
- Detailed information about previous bleedings and exposure to VWF concentrates
- Bleeding severity score of VWD3 calculated with a common questionnaire
- Plasma and DNA samples from all 250 patients for centralized analyses
- Confirmation of the diagnoses using centralized tests
- VWF gene defects with VWF phenotype and risk of anti-VWF inhibitors
- Common methods for anti-VWF antibody determination and for gene analyses in
VWD3
- Frequency and sites of bleeding in VWD3 followed-up for 2 years
- Efficacy assessment of the VWF concentrates used to treat VWD3 using the mos
objective criteria for efficacy

A no-profit, investigators initiated, multicenter, European-Iranian,
observational, retrospective and prospective study on patients with diagnosis
VWD3.

If the patient agrees to participate in the trial, an appointment will be made
at the treatment center for the first part of the trial. A medical doctor
involved in this research will explain the study to the patient, ask some
questions concerning the medical history, bleeding history, all the treatments
received and will ask to provide previous laboratory assessments and results
and finally have a sample of blood taken. All these procedures will be done in
a single visit.
In the second part of the study, if the patient is centrally confirmed to be
VWD3 subject, he or she will be asked to attend the medical center according to
the visits scheme foreseen by the center standards for a total of 4 years.
There are not pre-scheduled visit required by this study and visits at the
center will be agreed between the patient and the doctor according to the
standard care of the center, at least once per year. At each visit
(independently on when it occurs), the patient will be asked to provide
information on concomitant medications and treatments used, bleedings and other
adverse experiences occurred since the last visit.
The patient will not be asked to take any medication. The blood sampling will
take short time and involve a small amount of pain.
Hopefully the study will lead to a more accurate way of diagnosis and
management of VWD3. This will help the patient directly in being confirmed
whether he or she has VWD with a higher degree of certainty and will also allow
for a more accurate and easier way of diagnosing the disease in other patients.