Molecular and Clinical Profile of Von Willebrand Disease in Spain

Von Willebrand Disease Clinical Trial

— PCM-EVW-ES  

Official title:

Molecular and Clinical Profile of Von Willebrand Disease (VWD) in Spain (PCM-EVW-ES). Recruitment Extension, Further Data Analysis, Improvement of Registry Platform, Diagnosis and Management of VWD Application Development

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02869074
• Other study ID #: PCM-EVW-ES.SPANISH REGISTRY
• Status: Recruiting
• Start date: October 3, 2017
• Est. completion date: August 31, 2021

Study information

• Verified date: March 2020
• Source: Spanish Society of Thrombosis and Haemostasis
• Contact: Francisco Javier BATLLE, PhD, MD
• Phone: +34 981 232174
• Email: Francisco.Javier.Batlle.Fonrodona[@]sergas.es
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

The present Project is a third phase of the previous PCM-EVW-ES Project (Batlle et al. Thromb & Haemost 2015) with the aim of its extension, further analysis with an innovation development in the field of von Willebrand disease (VWD) based in the newer recently available methodologies. The aim of this project is to help the physician in a more uniform characterization and therapy of VWD in clinical practice, at an international level. A reduction of the expenses in the diagnosis process by using the new methodologies is pursued.

Description:

The present Project is a third phase of the previous PCM-EVW-ES Project (Batlle et al. Thromb & Haemost 2015) with the aim of its extension, further analysis with an innovation development in the field of von Willebrand disease (VWD) based in the newer recently available methodologies. The aim of this project is to help the physician in a more uniform characterization and therapy of VWD in clinical practice, at an international level. A reduction of the expenses in the diagnosis process by using the new methodologies is pursued.

The specific objectives and corresponding tasks of the present project are as follows:

1. Extension of the central phenotypic and next generation sequencing (NGS) genotypic characterization of the VWD in Spain, through the prospective recruitment in the Spanish VWD cohort of approximately 500 new patients with local historical VWD diagnosis (from approximately 38 centres).

i. Improvement of the registry portal and database. ii. Recruitment criteria, phenotypic and genetic analysis of new recruited patients. In silico studies of novel von Willebrand factor gene (VWF) mutations iii. Analysis/investigation of the potential interrelationship between different clinical, phenotypic and genetic variations of the all recruited patients. iv. Validation/confirmation of the PCM-EVW-ES of the new initial diagnostic proposed algorithm including VWF NGS analysis. This project involves leading innovation and translational research with a direct impact on the quality of clinical care (applicability). To our knowledge there is no similar project in this field. Potential patents may derive from this project. It involves also development of e-learning and new information technologies (debates forum, ads, google search engine). This project may promote international collaboration.

Development of an algorithmic platform that facilitates diagnosis and therapy orientation of VWD in clinical practice using the selected data from the overwhelming amount of information that new technologies, such as NGS, are producing.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: August 31, 2021
• Est. primary completion date: August 31, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 2 Years to 80 Years

Eligibility

Inclusion Criteria: One or more of the following:

1. VWF = 30 IU/d, in 2 or more occasions.

2. Presence of multimeric abnormalities.

3. If isolated FVIII deficiency demonstration of decreased FVIII binding.

4. Presence of some VWF mutation.

5. ? RIPA at low concentrations of ristocetin.

Exclusion Criteria:

1. Presence of any data suggesting AVWS.

2. Absence of a signed patient informed consent

Related Conditions & MeSH terms

• Von Willebrand Disease
• Von Willebrand Diseases

Intervention

Genetic:
• VWF gene analysis
52 exons adjacent intronic regions and promotor of VWF will be analyzed

Locations

Country	Name	City	State
Spain	Hospital Universitario Central de Asturias	Oviedo	Asturias

Sponsors (6)

Lead Sponsor	Collaborator
Spanish Society of Thrombosis and Haemostasis	Almudena Pérez Rodríguez, Ana Rosa Cid Haro, Francisco Vidal Pérez, Irene Corrales Insa, Maria Fernanda López Fernández

Country where clinical trial is conducted

Spain, 

References & Publications (29)

Batlle J, López-Fernández MF, Fraga EL, Trillo AR, Pérez-Rodríguez MA. Von Willebrand factor/factor VIII concentrates in the treatment of von Willebrand disease. Blood Coagul Fibrinolysis. 2009 Mar;20(2):89-100. doi: 10.1097/MBC.0b013e3283254570. Review. — View Citation

Batlle J, Pérez-Rodríguez A, Corrales I, Borràs N, Costa Pinto J, López-Fernández MF, Vidal F; PCM-EVW-ES Investigators Team. Update on Molecular Testing in von Willebrand Disease. Semin Thromb Hemost. 2019 Oct;45(7):708-719. doi: 10.1055/s-0039-1679922. — View Citation

Batlle J, Pérez-Rodríguez A, Corrales I, López-Fernández MF, Rodríguez-Trillo Á, Lourés E, Cid AR, Bonanad S, Cabrera N, Moret A, Parra R, Mingot-Castellano ME, Balda I, Altisent C, Pérez-Montes R, Fisac RM, Iruín G, Herrero S, Soto I, de Rueda B, Jiménez — View Citation

Batlle J, Perez-Rodriguez A, Pinto JC, Fraga EL, Rodriguez-Trillo Tch A, Fernanda Lopez-Fernandez M. Diagnosis and management of von Willebrand disease in Spain. Semin Thromb Hemost. 2011 Jul;37(5):503-10. doi: 10.1055/s-0031-1281036. Epub 2011 Nov 18. — View Citation

Bellissimo DB, Christopherson PA, Flood VH, Gill JC, Friedman KD, Haberichter SL, Shapiro AD, Abshire TC, Leissinger C, Hoots WK, Lusher JM, Ragni MV, Montgomery RR. VWF mutations and new sequence variations identified in healthy controls are more frequen — View Citation

Borràs N, Batlle J, Pérez-Rodríguez A, López-Fernández MF, Rodríguez-Trillo Á, Lourés E, Cid AR, Bonanad S, Cabrera N, Moret A, Parra R, Mingot-Castellano ME, Balda I, Altisent C, Pérez-Montes R, Fisac RM, Iruín G, Herrero S, Soto I, de Rueda B, Jiménez-Y — View Citation

Borràs N, Garcia-Martínez I, Batlle J, Pérez-Rodríguez A, Parra R, Altisent C, López-Fernández MF, Costa Pinto J, Batlle-López F, Cid AR, Bonanad S, Cabrera N, Moret A, Mingot-Castellano ME, Navarro N, Pérez-Montes R, Marcellini S, Moreto A, Herrero S, So — View Citation

Borràs N, Orriols G, Batlle J, Pérez-Rodríguez A, Fidalgo T, Martinho P, López-Fernández MF, Rodríguez-Trillo Á, Lourés E, Parra R, Altisent C, Cid AR, Bonanad S, Cabrera N, Moret A, Mingot-Castellano ME, Navarro N, Pérez-Montes R, Marcellin S, Moreto A, — View Citation

Budde U, Schneppenheim R, Eikenboom J, Goodeve A, Will K, Drewke E, Castaman G, Rodeghiero F, Federici AB, Batlle J, Pérez A, Meyer D, Mazurier C, Goudemand J, Ingerslev J, Habart D, Vorlova Z, Holmberg L, Lethagen S, Pasi J, Hill F, Peake I. Detailed von — View Citation

Castaman G, Goodeve A, Eikenboom J; European Group on von Willebrand Disease. Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica. 2013 May;98(5):667-74. doi: 10.3324/haematol.2012.077263. Review. — View Citation

Corrales I, Ramírez L, Altisent C, Parra R, Vidal F. Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene. Thromb Haemost. 2009 Mar;101(3):570-6. — View Citation

Corrales I, Ramírez L, Altisent C, Parra R, Vidal F. The study of the effect of splicing mutations in von Willebrand factor using RNA isolated from patients' platelets and leukocytes. J Thromb Haemost. 2011 Apr;9(4):679-88. doi: 10.1111/j.1538-7836.2011.0 — View Citation

Corrales I, Ramírez L, Ayats J, Altisent C, Parra R, Vidal F. Integration of molecular and clinical data of 40 unrelated von Willebrand Disease families in a Spanish locus-specific mutation database: first release including 58 mutations. Haematologica. 20 — View Citation

Costa-Pinto J, Pérez-Rodríguez A, del C Goméz-del-Castillo M, Lourés E, Rodríguez-Trillo A, Batlle J, López-Fernández MF. Diagnosis of inherited von Willebrand disease: comparison of two methodologies and analysis of the discrepancies. Haemophilia. 2014 J — View Citation

Eikenboom J, Federici AB, Dirven RJ, Castaman G, Rodeghiero F, Budde U, Schneppenheim R, Batlle J, Canciani MT, Goudemand J, Peake I, Goodeve A; MCMDM-1VWD Study Group. VWF propeptide and ratios between VWF, VWF propeptide, and FVIII in the characterizati — View Citation

Eikenboom J, Hilbert L, Ribba AS, Hommais A, Habart D, Messenger S, Al-Buhairan A, Guilliatt A, Lester W, Mazurier C, Meyer D, Fressinaud E, Budde U, Will K, Schneppenheim R, Obser T, Marggraf O, Eckert E, Castaman G, Rodeghiero F, Federici AB, Batlle J, — View Citation

Eikenboom J, Van Marion V, Putter H, Goodeve A, Rodeghiero F, Castaman G, Federici AB, Batlle J, Meyer D, Mazurier C, Goudemand J, Schneppenheim R, Budde U, Ingerslev J, Vorlova Z, Habart D, Holmberg L, Lethagen S, Pasi J, Hill F, Peake I. Linkage analysi — View Citation

Flood VH, Gill JC, Christopherson PA, Bellissimo DB, Friedman KD, Haberichter SL, Lentz SR, Montgomery RR. Critical von Willebrand factor A1 domain residues influence type VI collagen binding. J Thromb Haemost. 2012 Jul;10(7):1417-24. doi: 10.1111/j.1538- — View Citation

Goodeve A, Eikenboom J, Castaman G, Rodeghiero F, Federici AB, Batlle J, Meyer D, Mazurier C, Goudemand J, Schneppenheim R, Budde U, Ingerslev J, Habart D, Vorlova Z, Holmberg L, Lethagen S, Pasi J, Hill F, Hashemi Soteh M, Baronciani L, Hallden C, Guilli — View Citation

Haberichter SL, Castaman G, Budde U, Peake I, Goodeve A, Rodeghiero F, Federici AB, Batlle J, Meyer D, Mazurier C, Goudemand J, Eikenboom J, Schneppenheim R, Ingerslev J, Vorlova Z, Habart D, Holmberg L, Lethagen S, Pasi J, Hill FG, Montgomery RR. Identif — View Citation

Hashemi Soteh M, Peake IR, Marsden L, Anson J, Batlle J, Meyer D, Fressinaud E, Mazurier C, Goudemand J, Eikenboom J, Goodeve A; MCMDM-1VWD Study Group. Mutational analysis of the von Willebrand factor gene in type 1 von Willebrand disease using conformat — View Citation

Lillicrap D. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. Hematology Am Soc Hematol Educ Program. 2013;2013:254-60. doi: 10.1182/asheducation-2013.1.254. Review. — View Citation

Mancuso DJ, Tuley EA, Westfield LA, Worrall NK, Shelton-Inloes BB, Sorace JM, Alevy YG, Sadler JE. Structure of the gene for human von Willebrand factor. J Biol Chem. 1989 Nov 25;264(33):19514-27. — View Citation

Penas N, Pérez-Rodríguez A, Torea JH, Lourés E, Noya MS, López-Fernández MF, Batlle J. von Willebrand disease R1374C: type 2A or 2M? A challenge to the revised classification. High frequency in the northwest of Spain (Galicia). Am J Hematol. 2005 Nov;80(3 — View Citation

Pérez-Rodríguez A, Batlle J, Corrales I, Borràs N, Rodríguez-Trillo Á, Lourés E, Cid AR, Bonanad S, Cabrera N, Moret A, Parra R, Mingot-Castellano ME, Navarro N, Altisent C, Pérez-Montes R, Marcellini S, Moreto A, Herrero S, Soto I, Fernández Mosteirín N, — View Citation

Rodeghiero F, Castaman G, Tosetto A, Batlle J, Baudo F, Cappelletti A, Casana P, De Bosch N, Eikenboom JC, Federici AB, Lethagen S, Linari S, Srivastava A. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an i — View Citation

Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB; W — View Citation

Tosetto A, Rodeghiero F, Castaman G, Goodeve A, Federici AB, Batlle J, Meyer D, Fressinaud E, Mazurier C, Goudemand J, Eikenboom J, Schneppenheim R, Budde U, Ingerslev J, Vorlova Z, Habart D, Holmberg L, Lethagen S, Pasi J, Hill F, Peake I. A quantitative — View Citation

Tosetto A, Rodeghiero F, Castaman G, Goodeve A, Federici AB, Batlle J, Meyer D, Goudemand J, Eikenboom J, Schneppenheim R, Budde U, Ingerslev J, Lethagen S, Hill FG, Peake I. A comparison between two semi-quantitative bleeding scales for the diagnosis and — View Citation

* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Central diagnosis of 400 new VWD Spanish patients	Phenotype and genetic central diagnosis of 400 new VWD Spanish patients. With determinations in samples obtained after patients recruitment, VWF NGS sequencing carried out in all patients, for exons 1 to 52, adjacent intronic regions and aproximately 1300 bp of promotor region.; A pheno-genotype will be made With a final diagnosis assignment Evaluation of pheno/genotype congruence	January 2019
Secondary	PCM-EVW-ES project algorithm validation/confirmation	Evaluation of the algorithm with data from the Spanish Registry patients. Mutation results will be used in the first line of VWD diagnosis Correlation between mutations and phenotype	January 2019
Secondary	Potential collaboration with the International Society on Thrombosis and Haemostasis	Proposal for evaluation of the PCM-EVW-ES algorithm with data from other international VWD patients cohorts	January 2019