Type 3 Von Willebrand International Registries Inhibitor Prospective Study
Type 3 Von Willebrand International Registries Inhibitor Prospective Study
International Registries and Prospective Study on Type 3 Von Willebrand's Disease (VWD3),
 aimed to assess number, types and risk factors for bleeding and the efficacy and safety of
 plasma-derived and/or recombinant Von Willebrand Factor (VWF) concentrates used to treat VWD
 patients.
Von Willebrand's Disease (VWD) is the most common inherited bleeding disorder, characterized
 by a quantitative and/or qualitative deficiency of Von Willebrand Factor (VWF), that plays a
 major role in early phases of hemostasis. Type 3 Von Willebrand's Disease (VWD3) is due to
 virtually complete deficiency of VWF and, for this reason, has been also described as "severe
 VWD". Recurrent Gastro-Intestinal Bleeds (GIB) is one of the most challenging complications
 encountered in the management of patients with VWD. The commonest cause is angiodysplasia
 (ANGDYS), but often no cause is identified due to the difficulty in making the diagnosis. In
 recent years, research from several laboratories has identified multiple roles for VWF in the
 control of vascular function. Globally, these findings provide the first possible explanation
 for the presence of ANGDYS in patients with VWD. These vascular malformations in the
 gastrointestinal (GI) tract are characterized by fragile, leaky mucosal vessels. Combined
 with the hemostatic dysfunction, these can lead to severe intractable bleeding including GIB.
 VWD3 is inherited as a recessive trait and heterozygous relatives have mild or no bleeding
 symptoms. Even if the prevalence of VWD3 is very low, 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 of its severe clinical presentation, the need for replacement
 therapy with plasma-derived and/or recombinant VWF concentrates and the risk of occurrence of
 anti-VWF inhibitors after the infusion of VWF concentrates, for which risk factors have not
 been systematically determined.

 The major objectives of the study are: to create an international network among European and
 Iranian Centers (ratio 1:1), the prospective enrollment of at least 250 VWD3 patients using a
 common database online, the collection of detailed information about previous bleedings and
 exposure to plasma-derived and/or recombinant VWF concentrates, the use of bleeding severity
 score of VWD3 calculated with a common questionnaire, the collection of plasma and DNA
 samples from all the identified VWD3 patients enrolled for centralized analyses, the
 confirmation of the local VWD3 diagnosis using centralized tests, Evaluation of VWF gene
 defects, VWF phenotype and risk of anti-VWF inhibitors through common methods, the evaluation
 of potential correlations between phenotypic results (including markers of angiogenesis) and
 GIB occurrence, the objective evaluation of severity of GIB in VWD3 patients, the assessment
 of frequency and sites of bleeding in VWD3 patients followed-up for 2 prospective observation
 periods (2 years each: 2017-2018 and 2020-2022), the efficacy assessment of the
 plasma-derived and/or recombinant VWF concentrates used to treat VWD3 (on demand versus
 prophylaxis) using the most objective criteria for efficacy during 2 prospective observation
 periods (2 years each: 2017-2018 and 2020-2022), the evaluation of the efficacy and safety of
 plasma-derived and/or recombinant VWF concentrates in the treatment of GIB during 2
 prospective observation periods (2 years each: 2017-2018 and 2020-2022), in comparison to the
 use of anti-angiogenetic agents within the standard clinical setting.

 To these purposes, a cohort of at least 250 patients with diagnosis of VWD3 will be enrolled
 using homogenous and standardized criteria.

 The work planned to achieve the objectives of the project will be divided in three parts:

 -  the first part deals with standardized criteria for enrolment and collection of
 retrospective clinical and laboratory data, to be confirmed by centralized laboratories;

 -  the second part involves a further characterization of clinical and laboratory
 parameters, collected in the retrospective phase, including prevalence of anti-VWF
 inhibitors, advanced laboratory tests to further identify VWD3, mutations analyses of
 the VWF gene;

 -  the third part of the study is divided in two parts: a first prospective observation and
 a second prospective observation. The third part for the first time deals with the
 prospective clinical observation in a large cohort of VWD3 patients all previously well
 characterized by an international panel of experts.
Inclusion Criteria:

 -  Male and female of any age, including infants, children, adolescent and adults

 -  Informed Consent obtained (parents should sign for patients < 18 y.o.)

 -  Previous Diagnosis of VWD3 (VWF Antigen: undetectable or <5 U/dL)

 -  Detailed information on inherited pattern, history of bleeding, previous exposure to
 blood products

 -  Availability of plasma and DNA samples

 Exclusion Criteria:

 • VWD3 patients who may not be available for follow-up