Type 3 Von Willebrand International Registries Inhibitor Prospective Study

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.

• Von Willebrand Factor (Drug), also known as Plasma-derived and/or recombinantVon Willebrand Factor (VWF) concentrates: Replacement therapy with plasma-derived and/or recombinant VWF concentrates on-demand or under prophylaxis therapeutic scheme.

Primary outcomes

• Centralized Factor VIII (FVIII) Procoagulant Activity (FVIII:C) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis [12 months (confirmatory phase)]: Measurement of the Factor VIII (FVIII) Procoagulant Activity (FVIII:C) in the blood through one-stage clotting test. Only patients with FVIII:C less or equal to 5 IU/dL were considered for the analysis.
• Centralized Von Willebrand Factor Antigen (VWF:Ag) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis [12 months (confirmatory phase)]: Measurement of the amount of Von Willebrand Factor (VWF) protein in the blood through Von Willebrand Factor Antigen (VWF:Ag) test. Only patients with VWF:Ag less or equal to 5 IU/dL were considered for the analysis.
• Centralized Factor VIII (FVIII) Amidolytic Activity (FVIII:Am) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis [12 months (confirmatory phase)]: Measurement of Factor VIII (FVIII) Amidolytic Activity (FVIII:Am) in the blood through chromogenic test. Only patients with FVIII:Am less or equal to 5 IU/dL were considered for the analysis.
• Centralized Factor VIII (FVIII) Antigen (FVIII:Ag) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis [12 months (confirmatory phase)]: Measurement of the amount of Factor VIII (FVIII) protein in the blood through FVIII:Ag test. Only patients with FVIII:Ag less or equal to 5 IU/dL were considered for the analysis.
• Centralized Von Willebrand Factor (VWF) Multimer Analysis for Type 3 Von Willebrand's Disease (VWD3) Diagnosis [12 months (confirmatory phase)]: Multimer analysis of Von Willebrand Factor (VWF) was carried out by electrophoresis of blood samples collected by investigational sites. The number of patients belonging of each multimer profile group (1 - Homozygotes / 2 - Only Protomers / 3 - 2-4 Bands) was calculated. The qualitative evaluation of VWF multimers is part of the diagnostic process of VWD3.
• Centralized Von Willebrand Factor (VWF) Propeptide Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis [12 months (confirmatory phase)]: Measurement of Von Willebrand Factor (VWF) Propeptide levels in the blood through VWF Propeptide test. This test has been performed according to the most recent methods and the results are important to characterize the molecular aspects of VWD patients.
• Centralized Molecular Type 3 Von Willebrand's Disease (VWD3) Diagnosis Through DNA Analysis [12 months (confirmatory phase)]: Evaluation of the presence of Von Willebrand Factor (VWF) gene defects (confirmation or screening for the first time).
• Record of Bleeding Episodes [24 months (first prospective phase) + 24 months (second prospective phase)]: Record of all bleedings occurred during the prospective phase of the study.
• Adverse Events [24 months (first prospective phase) + 24 months (second prospective phase)]: Record of all adverse events occurred during the prospective phase of the study.
• Type of Von Willebrand Factor / Factor VIII (VWF/FVIII)-Containing Concentrates in Use [24 months (first prospective phase) + 24 months (second prospective phase)]: Record of any Von Willebrand Factor / Factor VIII (VWF/FVIII)-containing concentrates used and currently in use, including the current schedule type of treatment.

Secondary outcomes

• Patients Experiencing Allergic Reactions During Use of Von Willebrand Factor (VWF)-Containing Concentrates [24 months (retrospective phase)]: Record of any allergic and anaphylactic reactions occurred in the past due to the use of any Von Willebrand Factor (VWF) concentrate and the date of onset.
• Number of Participants With Previous Use of Blood Products [24 months (retrospective phase)]: Record of any product used during the retrospective phase (collected type of blood products/Von Willebrand Factor (VWF) concentrate, year of first exposure, units used).
• Number of Patients With Available Local Laboratory Test for Anti-Von Willebrand Factor (Anti-VWF) Antibodies [24 months (retrospective phase)]: Evaluation of the titre of Anti-Von Willebrand Factor (anti-VWF) Antibodies through Bethesda Test.
• Local Laboratory Tests for Type 3 Von Willebrand's Disease (VWD3) Diagnosis (Composite) [24 months (retrospective phase)]: Number of patients for who the following tests have been performed: Hemoglobin (mmol/L), Hemagglutination Titer (HT) (%), Mean Corpuscular Volume (MVC) (fl), Leucocytes (E9/L), Neutrophils (%), Basophils (%), Eosinophils (%), Lymphocytes (%), Platelet Count (E9/L), Mean Platelet Volume (MPV) (fl), Prothrombin Time (sec), Partial Thromboplastin Time (PTT) (sec), Partial Thromboplastin Time Mix 50:50 (PTT mix 50:50) (sec), Ferritin (ug/l), Bleeding Time (min:sec), Closure Time (sec), Collagen/ADP (sec), Collagen/Epinephrine (sec); Factor VIII Procoagulant Activity (FVIII:C) (IU/mL), Von Willebrand Factor Ristocetin Cofactor (VWF:RCo) (IU/mL), Won Willebrand Factor Antigen (VWF:Ag) (IU/mL).

Sex: All

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

Participant flow

Outcome results

• Centralized Factor VIII (FVIII) Procoagulant Activity (FVIII:C) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis (Primary), Mean, IU/dL: Type 3 Von Willebrand's Disease (VWD3) 2.42 +/- 0.88
• Centralized Von Willebrand Factor Antigen (VWF:Ag) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis (Primary), Mean, IU/dL: Type 3 Von Willebrand's Disease (VWD3) 1.01 +/- 1.03
• Centralized Factor VIII (FVIII) Amidolytic Activity (FVIII:Am) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis (Primary), Mean, IU/dL: Type 3 Von Willebrand's Disease (VWD3) 1.54 +/- 0.91
• Centralized Factor VIII (FVIII) Antigen (FVIII:Ag) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis (Primary), Mean, IU/dL: Type 3 Von Willebrand's Disease (VWD3) 3.63 +/- 0.83
• Centralized Von Willebrand Factor (VWF) Multimer Analysis for Type 3 Von Willebrand's Disease (VWD3) Diagnosis (Primary), Count of participants, Participants: Type 3 Von Willebrand's Disease (VWD3) 174
• Centralized Von Willebrand Factor (VWF) Propeptide Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis (Primary), Mean, IU/dL: Type 3 Von Willebrand's Disease (VWD3) 6.44 +/- 13.98
• Centralized Molecular Type 3 Von Willebrand's Disease (VWD3) Diagnosis Through DNA Analysis (Primary), Count of participants, Participants: Type 3 Von Willebrand's Disease (VWD3) 219
• Record of Bleeding Episodes (Primary), Number, bleeding episodes: Type 3 Von Willebrand's Disease (VWD3) 713
• Adverse Events (Primary), Number, AE: Type 3 Von Willebrand's Disease (VWD3) 47
• Type of Von Willebrand Factor / Factor VIII (VWF/FVIII)-Containing Concentrates in Use (Primary), Number, participants: Type 3 Von Willebrand's Disease (VWD3) 1
• Patients Experiencing Allergic Reactions During Use of Von Willebrand Factor (VWF)-Containing Concentrates (Secondary), Count of participants, Participants: Type 3 Von Willebrand's Disease (VWD3) 41
• Number of Participants With Previous Use of Blood Products (Secondary), Count of participants, Participants: Type 3 Von Willebrand's Disease (VWD3) 24
• Number of Patients With Available Local Laboratory Test for Anti-Von Willebrand Factor (Anti-VWF) Antibodies (Secondary), Count of participants, Participants: Type 3 Von Willebrand's Disease (VWD3) 4
• Local Laboratory Tests for Type 3 Von Willebrand's Disease (VWD3) Diagnosis (Composite) (Secondary), Count of participants, Participants: Type 3 Von Willebrand's Disease (VWD3) 265

Adverse events

Time frame: Data about adverse events occurring to participants will be collected throughout the whole study period (retrospective phase + prospective phase).

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Lack of data due to issues with samples. Some samples were not collected properly or properly stored, resulting impossible to be analyzed.

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• Study Protocol and Statistical Analysis Plan (PDF, 2020-01-28)

• Augusto B. Federici, MD, Study director, Hematology and Transfusion Medicine, L. Sacco University Hospital, University of Milan, Via G. B. Grassi, 74 20157 Milan, Italy