VON WILLEBRAND DISEASE PROPHYLAXIS NETWORK (vWD PN)
The VWD International Prophylaxis (VIP) Study

Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that is
synthesized in megakaryocytes and endothelial cells. It circulates in plasma
in the form of multimers with a size ranging from 500 to approximately 20,000
kDa. VWF mediates and contributes to platelet aggregation and the adhesion of
the initial platelet plug to the subendothelium of the injured blood vessels.
It also serves as the plasma carrier protein for factor VIII (FVIII) [Handin &
Wagner, 1989], with which it forms a non-covalently bound complex (FVIII/VWF
complex) [Hoyer, 1981].

Abnormalities of VWF (deficiency or dysfunction) result in von Willebrand
disease (VWD), a common hereditary bleeding disorder that may affect as much as
1% of the general population [Rodeghiero et al., 1987]. The inheritance modus
is mostly autosomal dominant, but sometimes is autosomal recessive or double
heterozygous; the disorder affects both sexes. The impaired formation and
adhesion of the initial platelet plug is reflected in the prolonged platelet
function assay (PFA) test or skin bleeding time (BT). In addition, reduced
levels of von Willebrand factor ristocetin cofactor (VWF:RCo) activity, von
Willebrand factor antigen (VWF:Ag), factor VIII coagulation activity (FVIII:C),
factor VIII antigen (FVIII:Ag), and abnormalities of the multimeric structure
of VWF are variably found among the several types and subtypes of VWD.

Clinically, the leading symptom in VWD is bleeding, chiefly of mucosal type,
e.g. epistaxis, gingival or GI bleeding, and menorrhagia. In severe forms of
VWD with secondary deficiency of FVIII, spontaneous joint and muscular
bleeding, resembling those observed in severe hemophilia A, may also be
observed.

The objectives are to:
A. Identify subjects with VWD who may benefit from prophylaxis by determining
patterns of bleeding prior to evaluation for enrollment
B. Study the effect of prophylaxis on bleeding frequency
C. Establish optimal treatment regimens for joint bleeding, GI bleeding,
epistaxis, and menorrhagia
D. Determine how quality of life at baseline is related to bleeding history
prior to enrollment and whether changes in bleeding frequency during follow-up
are associated with changes in quality of life at the conclusion of follow-up
E. Identify the frequency of development of inhibitory antibodies to VWF
F. Study the frequency and indications for hospitalizations
G. Evaluate the safety of prophylaxis by tracking study-related adverse events

Other goals include a retrospective study of the effect of prophylaxis on
bleeding frequency, and a retrospective natural history study of GI bleeding in
VWD.

The VIP study is observational in design. Participants will not be randomized.
VWF/FVIII products labeled for VWD will be chosen for use at the discretion of
the participating investigator. Products used to treat study participants will
not be provided as part of the study. Treatment of acute bleeding episodes and
management of treatment failure, such as severe breakthrough bleeding not
adequately controlled by the dose escalation schedule will be at the discretion
of the investigator. Participants enrolled in the prospective phase will
undergo an escalation of treatment from one to three dose levels of VWD
product. It is assumed that all subjects enrolled will begin treatment on the
level one dose and remain on this dose for the duration of follow-up, or until
they meet the criteria for escalation to level two or three (if indeed they do
meet the criteria).

Participants enrolled in the prospective phase will undergo an escalation of
treatment from one to three dose levels of VWD product. It is assumed that all
subjects enrolled will begin treatment on the level one dose and remain on this
dose for the duration of follow-up, or until they meet the criteria for
escalation to level two or three (if indeed they do meet the criteria).

The additional burden for the patients is limited because profylactic use of
coagulation factor concentrates in patients with VWD is already widely used in
the Netherlands. The criteria for start of prophylaxis are however not clearly
defined. This is also the case for dosage and frequncy of coagulation factor
ceonccentrate infusions. This is the main research question of this study. The
risk are small and are mainly the occurrence of inhibitory antibodies (only in
type 3 patients) against VWF (< 5%), athough the real incidence in type 3 VWD
is unknown.