ATHN 9: Severe VWD Natural History Study

The overarching objective of this longitudinal, observational and prospective study is to
characterize the safety and effectiveness of factor replacement in participants with
clinically severe congenital VWD (VWF:Ag, VWF:GPlbM or VWF:RCo of ≤30% or ≤40% of normal with
severe bleeding phenotype defined as requiring recurrent use of factor concentrates) enrolled
in the ATHNdataset.

This is a longitudinal, observational cohort study being conducted at up to 30
ATHN-affiliated sites. Participants will be followed for 2 years from time of study
enrolment. The total study duration is 3 years.

Safety will be measured by the number of reported events defined by the European Haemophilia
Safety Surveillance (EUHASS) program. In addition, although not specifically defined by
EUHASS, treatment-emergent side effects of therapy will be included as reportable events
including: hypersensitivity/allergic reactions, thrombotic events, VW Factor inhibitor
development, treatment-emergent side effects of therapy, transfusion-transmitted infections,
malignancy, cardiovascular events, neurological events, unexpected poor efficacy and death.

Secondary objectives of ATHN 9 are:

- to enrich and analyze the data from currently enrolled participants with clinically
severe congenital VWD in the ATHNdataset via the collection of laboratory data
consisting of a standardized diagnostic battery using an ELISA based VWF activity assay,
and genetic sequence analysis of VWF coding regions and adjacent non-coding regions;

- to establish a platform for sub-studies for participants with congenital severe VWD,
that are treated with VWF products on demand or have started on or switched to a
particular VWF containing product for prophylaxis;

- to evaluate the use of factor replacement as prophylaxis in participants over 6-month
time periods;

- to describe bleeding events, changes in overall bleeding and annualized bleeding rate
(ABR) over the course of the study as measured by individual bleeding components; and

- to describe real-world effectiveness of VWD treatment as measured by health care
utilization and quality of life.

Inclusion Criteria:

1. Participants with severe Von Willebrand Disease with Type 3 VWD or VWF:RCo, VWF:GPlbM
or VWF:Ag ≤30% of pooled normal control plasma on more than one occasion;

2. Participants with clinically severe VWD as defined by VWF:RCo, VWF:GPlbM or VWF:Ag
≤40% of normal with severe bleeding phenotype defined as requiring recurrent use of
factor concentrates; and

3. Co-enrollment in the ATHNdataset.

Exclusion Criteria:

1. Diagnosis of platelet-type VWD;

2. Diagnosis of acquired VWD (clinical diagnosis based on association with
hypothyroidism, lymphoproliferative and myeloproliferative disorders, malignancies and
cardiovascular disease, typically aortic stenosis or LVAD).