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
Conditions: Von Willebrand Disease
Sponsor: Spanish Society of Thrombosis and Haemostasis

 
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1. Project information 
1.1. Principal investigators 
Dr. Francisco Javier Batlle Fonrodona 
INIBIC-Complexo Hospitalario Universitario A Coruña (Edificio Materno Infantil) 
Carretera del Pasaje s/n; 15006-A Coruña, Spain. 
Dr. Francisco Vidal Pérez 
Unitat de Diagnòstic i Teràpia Molecular 
Ed Dr. Frederic Duran i Jordà 
Passeig Taulat 106-116 
08005 Barcelona, Spain. 
1.2. Co-investigator name, title & Institution  
Dr. María Fernanda López-Fernandez / Dr. Almudena Pérez-Rodríguez 
Complexo Hospitalario Universitario A Coruña (Edificio Materno Infantil) 
Servicio de Hematología y Hemoterapia 
Carretera dcel Pasaje s/n; 15006-A Coruña, Spain. 
Dr. Almudena Pérez Rodríguez  
Complexo Hospitalario Universitario A Coruña (Edificio Materno Infantil) 
Servicio de Hematología y Hemoterapia 
Carretera dcel Pasaje s/n; 15006-A Coruña, Spain. 
Dr. Irene Corrales Insa 
Unitat de Diagnòstic i Teràpia Molecular 
Ed Dr. Frederic Duran i Jordà 
Passeig Taulat 106-116 
08005 Barcelona, Spain. 
 
Dr. Ana Rosa Cid Haro 
 
Hospital Universitari i Politecnic La Fe 
Bulevar s/n 
46026-Valencia (Spain) 
1.3. Duration 
 3 years. 

 
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1.4. Keywords 
von Willebrand disease, von Willebrand factor, diagnosis, genetic testing, diagnostic platform, registry 
database, LOPD, NGS, custom panel, Data encryption and security, Cloud computing, Software usability, 
API, IaaS, e-Learning, BPM, Translational research, Software usability, Software scalability, Data modeling, 
Iterative and Incremental Development, e-Training, Web 2.0, Machine Learning. 
 
1.5. Correspondence to 
Dr. María Fernanda López Fernández 
Chairman Servicio de Hematología. 
Complexo Hospitalario Universitario A Coruña (Edificio Materno Infantil) 
Servicio de Hematología y Hemoterapia 
Carretera del Pasaje s/n; 15006-A Coruña (Spain) 
E mail: Francisco.Javier.Batlle.Fonrodona@sergas.es 
 
 
 
 

 
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2. Summary of grant request 
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 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:  
Main objective is:  
1. Extension of the central phenotypic and 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).  
 
Secondary objective is: 
1. Development of an electronic platform using this proposed algorithm. In a second step, some 
other mutation-oriented tests or investigations could be carried out for confirmation.  
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 
(debate 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. 
3. State of art/study background 
VWD overview in Spain  
A previous published multicenter study on the situation of VWD in Spain showed a frequency of this 
disease and distribution of the different types similar to that observed in some other European countries. 
The results of a concise survey on the diagnosis of VWD showed a frequency fivefold greater in Spain than 
that expected from epidemiological studies in other European countries; this may result from 
overdiagnosis and/or a higher prevalence of VWD. These results clearly reinforce the need for the Spanish 
VWD registry. The rate of response to our questionnaire was 66.6% (36 centers, including the 5 
Hemophilia Treating Centers), which is very similar to the mean responses indicated in the study of 
Rodeghiero et al (65%) [30]. From an epidemiological point of view, the entire population analyzed, 
corresponding to the responding centers, was 22.8 million inhabitants; this represents 49% of the global 
Spain population. When also taking the wide geographic distribution of the participating centers into 
account, we believe it is possible to extrapolate our findings to the entire country.  
It is particularly noteworthy that in classified patients the distribution of VWD types is quite similar to that 
observed by Rodeghiero et al [30], especially for types 1 and 2.  
Globally, participant investigators experienced difficulty in characterizing about a third of the patients 
with a definite diagnosis of VWD. 
 

 
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Diagnostic strategy  
The data obtained in that survey for diagnostic parameters indicated that the more widely used tests are 
FVIII activity (FVIII:C), VWF:RCo, and VWF:Ag, and, to a lesser extent, VWF:CB. The RIPA at low ristocetin 
concentration (that allow identified the type 2B), the plasma VWF capacity to bind exogenous FVIII 
(VWF:FVIIIB) (that can distinguish between hemophilia and type 2N VWD) and the multimeric analysis 
were test very little used due to their complexity. The limited use of these methods may lead to 
underdiagnosis of some patients. Also, the complexity, high cost, and experience required to perform a 
molecular study constitute the main reasons for that only five centers carried out this study by Sanger and 
the 50% of participants never request this study its low use. One of the conclusions of this the Spanish 
study was that because of the complexity and/or difficulty in performing some of the tests used in the 
diagnosis of VWD, supporting the centralization of these tests in laboratories that have the experience 
necessary to achieve a more uniform characterization. 
The Molecular and Clinical Profile of von Willebrand Disease in Spain (PCM-EVW-ES) Project. 
Spanish Registry 
Motivated by the success and experience of the European Project MCMDM-1VWD, a Spanish Registry on 
VWD has been initiated. Several European countries already have their own registry. In order to achieve 
a better comprehension of this complex pathology, it is necessary to rely on a patient database that must 
be as much extensive and detailed as possible [31].  
A main feature of the PCM-EVW-ES is that the analysis of the samples has been centralized in three 
laboratories that have the experience necessary to achieve a more uniform characterization. It should be 
emphasized that this study was not intended as a prevalence study or as a quality assessment of the 
participant laboratories. The main goals of the study are:  
i. 
An assessment of the real diagnosis and therapeutic situation of VWD in Spain in normal clinical 
practice;  
ii. The achievement of a platform of recruited patients with the best possible characterization;  
iii. The development of a Spanish Working Group on VWD (recently created);  
iv. Participation in international projects on VWD (European Union VWD Group, Zimmerman Project, 
Type 3 VWD International “Registry Inhibitor Prospective Study (3WINTERS-IPS)”;  
v. Elaboration of practical guidelines on diagnosis and therapy of VWD in Spain.  
 
There are several additional aims to the study, summarized as follows:  
1. To ascertain the clinical profile of those patients diagnosed with VWD who had been referred to 
the Spanish centers and were in active follow-up in 2011. The bleeding score is used to establish 
the bleeding history.  
2. To characterize the diagnosis of types and subtypes up to the most complete hierarchical level, 
based on the revised and updated classification of the ISTH-SSC VWF.  
3. To know the modality of therapy used.  
4. To register and analyze any genetic abnormality.  
5. To register patients with bloodborne diseases, such as human immunodeficiency virus, hepatitis 
B, and hepatitis C infected patients, and under retroviral therapy.  
6. To develop knowledge on alloantibodies against VWF and to evaluate any corresponding 
treatments.  
7. To record the history of major surgeries and types of treatment.  

 
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Study Cohort  
Patients of any age previously diagnosed locally with VWD or referred from any hospital department or 
from family care that fulfill one or more of the following inclusion criteria: 1) VWF:Ag, VWF:RCo and/or 
VWF:CB ≤30 UI/dL (%), observed on two or more occasions; 2)detection of multimeric abnormalities; 3) 
in case of isolated FVIII deficiency it will be necessary to provide demonstration of a decreased VWF:FVIIIB; 
4) presence of VWF mutations; 5) presence of RIPA at a low ristocetin concentration. 
Exclusion criteria: Presence of any data suggesting acquired Von Willebrand syndrome. The definitive 
diagnosis will be performed centrally.  
Genetic analysis: Initially it was planned to analyze by using the expensive Sanger method either some 
exons or the whole VWF in some patients with types 2 and 3 VWD. However, thanks to the availability of 
the new methodology based on NGS, much less expensive, the genetic analysis was extended to all the 
recruited patients. 
3.1. Previous results from the PCM-EVW-ES Project. 
A cohort of 556 patients from 330 families previously diagnosed as VWD at the local centres were analyzed 
centrally. VWD was confirmed in 480 [31]. NGS of the whole coding VWF was carried out in all recruited 
patients, compared with the phenotype, and a final diagnosis was established. A total of 238 different 
VWF mutations were found, 154 were not included in the Leiden Open Variation Database (LOVD). Of 
these patients, 463 were found to have VWF mutation/s. A good phenotypic/genotypic association was 
estimated in 96.5% of the patients. One hundred and seventy-four patients had two or more mutations. 
Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred and 
sixteen patients presented with mutations that had previously been associated with increased VWF 
clearance. RIPA unavailability, central phenotypic results disagreement and difficult distinction between 
severe type 1 and type 3 VWD prevented a clear diagnosis in 70 patients. The NGS study facilitated an 
appropriate classification in 63 of them. The remaining seven patients presented a VWF novel mutation 
pending further investigation. In five patients with a type 3 and two with a type 2A or 2B phenotype with 
no mutation, an acquired von Willebrand syndrome (AVWS) was suspected/confirmed.  
A 42.3% local/central phenotypic diagnosis discrepancy was observed indicating the practical 
difficulties/drawbacks of VWD diagnosis.  A 96.5% phenotypic/NGS genotypic association was observed, 
suggesting the possibility of incorporating the NGS in the initial VWD work-up. Comparative analysis of 
sensitivity and specificity with traditional gold standard sequencing method showed values of nearly 99% 
and 98% respectively. 
These data seem to support the NGS as a first line efficient and faster paradigm in VWD diagnosis. Anew 
algorithm for the initial study of VWD was proposed. It includes family history, bleeding score, VWF:Ag, 
VWF:RCo/VWF:GPIbα assay, platelet count and peripheral blood smear, and VWF molecular study by NGS, 
using a cut-off for VWF:Ag of ≤ 30 IU/dL in type 1 VWD, considering all of them as  essential information 
to predict and manage the severity of the clinical bleeding phenotype. In a second step, some other 
mutation-oriented tests or investigations could be carried out for confirmation.  
Thus, this does not intend at all to transmit the message of molecular analysis as a surrogate approach of 
a phenotypic study. We are now developing an algorithm platform as a software based on these 
parameters that will help in the diagnostic process in the clinical setting. It includes a VWF mutations 
database that will be updated regularly, taking into account the VWF sequence variants that are known 
not to influence VWF levels or cause a clinical disease.  

 
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Recently a similar study in a Portuguese cohort has been published [32] confirming the NGS value in VWD 
diagnosis. 
4. Hypothesis 
i. 
Homogeneous characterization of patients with VWD is not generally accomplished in Spain and 
also in many countries. There is considerable confusion between variant and non-variants forms. 
The methods, which would allow us a better characterization of the patients, are not available in 
all centers due to the fact that they lack the necessary infrastructure to carry them out.  
ii. The possibility to enlarge the number of patients by the reopening of the project will allow the 
validation of the proposed algorithm (phenotype study and NGS of the VWF as a first line 
diagnostic approach) enriching our knowledge of VWD spectrum in our population. 
iii. The feasibility to develop linkage analysis and expression studies of certain mutations can help to 
establish their possible common origin and explain how the mutation affect the protein synthesis 
or secretion deeping in the molecular basis of VWD at the population or individual level 
iv. Currently the new diagnostic methodologies are very helpful but generating overwhelming 
amount of information impossible to manage at clinical setting. The creation of an algorithmic 
platform with a regularly updated database that includes processed information in regard to 
mutations and approved international criteria, to guide   the physician in the VWD diagnostic 
process and recommended therapy should be extremely helpful in facilitating a more uniform 
characterization and therapy of VWD patients in clinical practice at an international level. Also 
another main point might be a reduction of the cost (work effort and expenses) in the diagnosis 
process by using the new methodologies as it is the NGS.  
5. Specific objectives description, rationale, methodology and 
corresponding tasks 
The present project was already approved by the Galicia Ethical Committee (CEIC) (Annex I). 
5.1. Specific main objective 
Extension of the central phenotypic and 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) 
5.2. Secondary objective 
Development of an electronic platform using this proposed algorithm. In a second step, some 
other mutation-oriented tests or investigations could be carried out for confirmation.  
Overwhelming information provided from VWD phenotypical and genetic data requires the help of 
electronic applications.  
6. Limitations of the study 
i. 
A higher number of cases for simulation than that available at this moment desirable  ` the future 
inclusion of newer cases will facilitate the platform improvement.   

 
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ii. Existence of some complex cases that fail in the algorithm process (such as complex genetic 
changes) ` they are not frequent and, again, with their better knowledge will help to improve and 
refine the platform.  
iii. Potential legal problems with the corresponding foreign LOPDs in regard to the possibility of 
collaborative platform use ` an authorization from each particular country should be obtained by 
the collaborator research team in its country.  
iv. Nomenclature of the mutations and diagnostic assignment not always uniformly followed 
according the international standards and recommendations (for instance from ISTH-SSC VWF) ` 
the present project includes a regular revision of the international information and the adaptation 
in case of controversy or non-uniform report.   
v. The utility of the machine learning approach will require the future participation of cohorts of 
patients from other countries to achieve solid information in regard to the meaning of some VWF 
genetic variations.  
7. Expected achievements 
I. 
To improve the database for the Spanish Registry on VWD to save the already available data from 
the records of PCM-VWD-ES project, that allows interconnection with newer future electronic 
applications, facilitating further studies.  
II. Enlargement of the Spanish VWD patients cohort uniformly well characterized at the phenotypic 
and genetic levels. Future incorporation of new patients potentiating the development of this 
registry. 
III. Achievement of a platform maintainable, potentially scalable, extensible, usable in clinical 
practice, validated and accepted at an international level that allows a more accurate and uniform 
diagnosis and therapy of the VWD patients.  
IV. Potential ISTH acceptance of this platform to be used internationally.   
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9. Experience and suitability of the proposed investigator team   
9.1. Medical Team 1 
This Team is deeply involved in the Medical Institute of Research A Coruña (INIBIC) and   Foundation 
Professor Novoa Santos of Xerencia de Xestion Integrada Area de A Coruña (XXIAC), Spain.  
Composition 
1. Dr. Francisco Javier Batlle Fonrodona (Chairman of Service Hematology and Hemotherapy). 
2. Dr. María Fernanda López Fernández (Head of Unit in Hemostasia and Thrombosis, Hematology 
Department). 
3. Dr. Almudena Pérez Rodríguez (Post-doctoral Investigator,Hematology Department). 
4. María Joana Costa Pinto Prego de Faria (Pre-doctoral Investigator, Hematology Department. 
Doctoral Thesis ongoing in the PCM-EVW-ES Project ). 
5. Ángela Rodríguez Trillo (Pre-doctoral Investigator, Hematology  Department. Doctoral Thesis 
ongoing in the PCM-EVW-ES Project). 
6. Dr. María del Carmen Gómez del Castillo Solano (Assistant Physician and Pre-doctoral 
Investigator, Hematology Department. Doctoral Thesis ongoing in the PCM-EVW-ES Project). 
7. Dr. Marta Fernández Docampo (Assistant Physician and Pre-doctoral Investigator, Hematology 
Department. Doctoral Thesis ongoing in the PCM-EVW-ES Project) 
Experience 
1. Continuous development of a line of research on VWF and VWD started in the Department of 
Molecular Immunology, Scripps Clinic and Research Foundation, La Jolla, California, USA (Dr. 
Theodore S. Zimmerman). It was funded by different institutions such as FIS (Instituto Carlos III, 
Spain), European Union (project MCMDM-1VWD), Xunta de Galicia and North American 
Committee for Scientific and Technological Collaboration. 
2. Our group participated as expert group in the project of standardization and evaluation of 
patients with VWD sponsored by the Subcommittee on von Willebrand Factor of the ISTH-SSC 
VWF. The objective was to assess the minimum required methodology for the study of the VWD 
in clinical practice. Thirty-two laboratories from around the world participated. 
3. Since the year 2000, the Team is part of the European Group of VWD, participating in several 
projects such as: 
i. 
European Project “MCMDM-1VWD”. It is a European Union (EU)–funded survey on type 
1 VWD. Fourteen VWD treatment centers in 9 European countries participated. The study 
aimed at recruiting the full spectrum of type 1 VWD families, including milder cases to 
mimic the clinical situation as much as possible and not to have bias toward the more 
severe, highly penetrant type 1 VWD. Also, affected and unaffected family members were 
recruited. (2000-2003). 
ii. 
Member of the European Group on VWD.  

 
P a g e  13 | 24 
 
iii. 
International Project “3WINTERS-IPS”. It is an European-Iranian study based in the study 
of the type 3 von Willebrand disease (a total of 16 investigational sites are involved in this 
project in 8 European countries). (2012-to the present). 
iv. 
Coordinator center for the project “PCM-VWD-ES". Thirty-eight Spanish hospitals are 
participating in this project. Currently, a total of 557 have recruited and studied in a 
centralized way. 
v. 
Coordinating center for the initial analysis of VWD in Spain that was published in Seminars 
in Thrombosis and Hemostasis.  
4. Six Doctoral Thesis, two of them currently under development, related to the field of VWD. 
5. Reference Laboratory for the study of many patients with VWD from Spain including their 
phenotypic and genetic characterization.  
6. Initiation of Translational Research and Innovation and Development by cooperation with the 
enterprise LapiSoft   in the field of VWD.  
Recent publications related to the field of the present proposal 
1. Pérez-Rodríguez A, Batlle-López A, Blanco R, Varela I, León J, Delgado MD, et al. A novel mutation 
in the ADAMTS13 of a child with Upshaw-Schulman Syndrome. Thromb Haemost, 2014 [ahead of 
print]. 
2.  Costa-Pinto J, Pérez-Rodríguez A, Gómez-del-Castillo M del C, Lourés E, Ródríguez-Trillo A, Batlle 
J, López-Fernández MF. Diagnosis of inherited von Willebrand disease: comparison of two 
methodologies and analysis of the discrepancies. Haemophilia 2014;20:559–567. 
3. 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;98:667-74.  
4. Eikenboom J, Federici AB, Dirven RJ, Castaman G, Rodeghiero F, Budde U,et al. VWF propeptide 
and ratios between VWF, VWF propeptide, and FVIII in the characterization of type 1 von 
Willebrand disease. Blood. 2013;121(12):2336-9.  
5. Batlle J, Perez-Rodriguez A, Pinto JC, Fraga EL, Rodriguez-Trillo A, Lopez-Fernandez MF. Diagnosis 
and management of von Willebrand disease in Spain. Semin Thromb Hemost. 2011;37:503-10.  
6. Pérez-Rodríguez A, Pinto JC, Lourés E, Rodríguez-Trillo A, Cuenca JJ, Batlle J, López-Fernández MF. 
Acquired von Willebrand syndrome and mitral valve prosthesis leakage. A pilot study. Eur J 
Haematol. 2011;87:448-56.  
7. Tosetto A, Rodeghiero F, Castaman G, Goodeve A, Federici AB, Batlle J, et al. A comparison 
between two semi-quantitative bleeding scales for the diagnosis and assessment of bleeding 
severity in type 1 von Willebrand disease. Haemophilia. 2011;17:165-6.  
8. Castaman G, Tosetto A, Goodeve A, Federici AB, Lethagen S, Budde U, et al. The impact of bleeding 
history, von Willebrand factor and PFA-100(®) on the diagnosis of type 1 von Willebrand disease: 
results from the European study MCMDM-1VWD. Br J Haematol. 2010;151:245-51.  
9. Castaman G, Tosetto A, Cappelletti A, Goodeve A, Federici AB, Batlle J, et al. Validation of a rapid 
test (VWF-LIA) for the quantitative determination of von Willebrand factor antigen in type 1 von 

 
P a g e  14 | 24 
 
Willebrand disease diagnosis within the European multicenter study MCMDM-1VWD. Thromb 
Res. 2010;126:227-31.  
10. 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;20:89-100. 
11.  Eikenboom J, Hilbert L, Ribba AS, Hommais A, Habart D, Messenger S, et al A. Expression of 14 
von Willebrand factor mutations identified in patients with type 1 von Willebrand disease from 
the MCMDM-1VWD study. J Thromb Haemost. 2009;7:1304-12.  
12. Hermans C, Batlle J. Autosomal dominant von Willebrand disease type 2M. Acta Haematol. 
2009;121:139-44.  
13. Pérez-Rodríguez A, García-Rivero A, Lourés E, López-Fernández MF, Rodríguez-Trillo A, Batlle J. 
Autosomal dominant C1149R von Willebrand disease: phenotypic findings and their implications. 
Haematologica. 2009;94:679-86. 
14. Haberichter SL, Castaman G, Budde U, Peake I, Goodeve A, Rodeghiero F, et al. Identification of 
type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of 
the VWF propeptide in the European study: molecular and clinical markers for the diagnosis and 
management of type 1 VWD (MCMDM-1VWD). Blood. 2008;111:4979-85.  
15. Budde U, Schneppenheim R, Eikenboom J, Goodeve A, Will K, Drewke E, et al. Detailed von 
Willebrand factor multimer analysis in patients with von Willebrand disease in the European 
study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand 
disease (MCMDM-1VWD). J Thromb Haemost. 2008;6:762-71.  
16. Castaman G, Lethagen S, Federici AB, Tosetto A, Goodeve A, Budde U, et al. Response to 
desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease 
(VWD): results from the European Study MCMDM-1VWD. Blood. 2008;111:3531-9.  
17. Batlle J, Pérez-Rodríguez A, Franqueira MD, López-Fernández MF. Type 2M von Willebrand 
disease: a variant of type 2A? J Thromb Haemost. 2008;6:388-90. 
18. Hashemi Soteh M, Peake IR, Marsden L, Anson J, Batlle J, et al. Mutational analysis of the von 
Willebrand factor gene in type 1 von Willebrand disease using conformation sensitive gel 
electrophoresis: a comparison of fluorescent and manual techniques. Haematologica. 
2007;92:550-3.  
19. Tosetto A, Rodeghiero F, Castaman G, Bernardi M, Bertoncello K, Goodeve A, et al. Impact of 
plasma von Willebrand factor levels in the diagnosis of type 1 von Willebrand disease: results from 
a multicenter European study (MCMDM-1VWD). J Thromb Haemost 2007;5:715-21. 
20.  Goodeve A, Eikenboom J, Castaman G, Rodeghiero F, Federici AB, Batlle J, et al. Phenotype and 
genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the 
European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von 
Willebrand Disease (MCMDM-1VWD). Blood. 2007;109:112-21. 
21. Eikenboom J, Van Marion V, Putter H, Goodeve A, Rodeghiero F, Castaman G, et al. Linkage 
analysis in families diagnosed with type 1 von Willebrand disease in the European study, 
molecular and clinical markers for the diagnosis and management of type 1 VWD. J Thromb 
Haemost. 2006;4:774-82.  

 
P a g e  15 | 24 
 
22. Tosetto A, Rodeghiero F, Castaman G, Goodeve A, Federici AB, Batlle J, et al. A quantitative 
analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter 
European study (MCMDM-1 VWD). J Thromb Haemost. 2006;4:766-73.  
23. Rodeghiero F, Castaman G, Tosetto A, Batlle J, Baudo F, Cappelletti A, et al. The discriminant 
power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, 
multicenter study. J Thromb Haemost. 2005;3:2619-26. Erratum in: J Thromb Haemost. 
2006;4:925 
24. Penas N, Pérez-Rodríguez A, Torea JH, Lourés E, Noya MS, López-Fernández MF, et al. 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;80:188-96.  
25. Penas N, Pérez A, González-Boullosa R, Batlle J. C1272S: a new candidate mutation in type 2A von 
Willebrand disease that disrupts the disulfide loop responsible for the interaction of VWF with 
platelet GP Ib-IX. Am J Hematol. 2004;75:73-7.  
26. 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-Yuste V, Alonso N, Vilariño D, Arija O, 
Campos R, Paloma MJ, Bermejo N, Toll T, Mateo J, Arribalzaga K, Marco P, Palomo Á, Sarmiento 
L, Iñigo  B, Nieto Mdel M, Vidal R, Martínez MP, Aguinaco R, César JM, Ferreiro M, García-Frade J, 
Rodríguez-Huerta AM, Cuesta J, Rodríguez-González R, García-Candel F, Cornudella R, Aguilar C, 
Borràs N, Vidal F. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): 
Proposal for a new diagnostic paradigm. Thromb Haemost. 2015 Dec 22;115(1):40-50. 
9.2. Medical Team 2. Banc de Sang I Teixits, Barcelona.  
Composition 
Molecular Diagnosis and Therapy Unit (UDTM) of the Blood and Tissue Bank (BST).  
1. Dr. Francisco Vidal, UDTM coordinator. 
2. Dr. Irene Corrales. 
3. Dr. Nina Borràs. 
4. Mrs. Lorena Ramírez, lab technician 
5. Ms. Natalia Comes (Lab technician, UDTM department) 
Hemophilia Unit of the Vall d'Hebron University Hospital 
1. Dr. Rafael Parra (Head of Unit of Hematology, Hematology department). 
2. Dr. Carme Altisent (Doctor of Unit of Hematology, Hematology department). 
 
Experience 
The research team involved in the project comprised a balance of basic, applied and clinical researchers, 
as well as attending physicians. The research team members conducted basic and applied studies of high 
quality, all having complementary expertise optimally covers the different objectives of the proposed 
project.  

 
P a g e  16 | 24 
 
They have a broad expertise in clinical diagnosis and therapy of patients with VWD since the unit is the 
Congenital Coagulopathies Comprehensive Care Centre in Catalonia and is one of the largest in Spain, 
taking care of more that and none thousand patients and relatives. The Hemophilia Unit has an 
experienced multidisciplinary team comprised for a total of 12 professionals who perform their work 
exclusively on this service, developing comprehensive care of the patients and relatives. The continuous 
monitoring of the quality of care through clinical sessions, has converted the unit into a worldwide 
reference center for the congenital coagulation disorders. Equally significant, is the participation of the 
Unit in multicenter international clinical trials, as well as in phase III & IV trials for new drugs. Hemophilia 
Unit has the human and material resources necessary for diagnosis, patient selection and sample 
extraction. Specific coagulation studies are performed routinely in the Coagulation Laboratory of the 
Hospital Universitari Vall d'Hebron.  
This Unit has a dual character since their foundation in 1998: diagnostic support in congenital coagulation 
disorders as well as other hereditary diseases; research and development of new approaches in the field 
of medical diagnostics and therapeutics. In-depth studies of molecular events present in some affected 
individuals and the relation genotype-phenotype constitute the most basic area of the team objectives. 
The UDTM is comprised of a talented staff of scientists with a broad range of expertise to support clinical 
needs. Among the primary tasks of the lab there is the applied research in the molecular diagnosis of 
congenital blood coagulation disorders, genetic counseling and prenatal diagnosis. Also, an important part 
of the current research objectives is the innovation in technological tools and their transfer to the routine 
laboratory. The protocols designed and optimized in our laboratory for the molecular diagnosis of HA 
(Vidal et al. 2001. Thromb Haemost 85: 580-3) and HB (Vidal et al. 2000. Br J Haematol 111: 549-51) that 
are currently used to provide routine care service (certified according to the ISO 9001 standard), includes 
identification of the molecular defect in patients and offered genetic counseling and prenatal diagnosis. 
Also, the developed technology has been transferred to other national centers involved in diagnosis of 
hemophilia. These protocols were recognized as an outstanding technological contribution among 
international experts in the field. The UDTM counts with a molecular biology laboratory with three full-
equipped independent work areas: pre-PCR, post-PCR and cell culture.  
Dr. Irene Corrales, part of the UDTM staff since July 2006 and contracted by a grant awarded by the 
Catalan Private Foundation of Hemophilia and intramural funding from the BST, reached the PhD degree 
with the highest qualification. Her doctoral project has been focused on the development of optimized 
procedures for amplification and sequencing of the VWF by traditional and NGS sequencing, validation of 
this technique in patients with VWD with very satisfactory results. With above 10 years of experience in 
molecular biology she also has a broad experience in the in silico and in vivo analysis of the identified 
mutations. Since her incorporation to the UDTM, she performed the routinely molecular and prenatal 
diagnosis of congenital coagulopathies. Moreover, she also participates very effectively in research 
projects contributing with large technical and creative skills. 
Dr. Francisco Vidal, IP of this project and UDTM coordinator, has extensive experience in molecular 
biology, cell biology and molecular diagnosis of genetic diseases. Specifically, due to both the 
development of his current job as the projects in which he has been involved in his career, is closely 
familiar with theoretical and practical level with the genetic basis of hereditary diseases as well as with 
the methodology used to detect them. Also, an important part of his duties include the research and 
process innovation in the field of human genetics for their translation to the routine laboratory. The work 
on the characterization of genes involved in these coagulopathies allows epidemiological studies of the 
relationship between the type of mutation and clinical aspects of the disease and also offers the possibility 
of further study of specific mutations that provide information about some of the basic mechanisms 

 
P a g e  17 | 24 
 
associated to disease. Besides research activity also plays a care activity through molecular diagnosis of 
hereditary diseases, genetic counseling and prenatal diagnosis. 
Recent publications related to the field of the present proposal 
1. Corrales I, Catarino S, Ayats J, Arteta D, Altisent C, Parra R, Vidal F.High-throughput molecular 
diagnosis of von Willebrand disease by next generation sequencing methods. Haematologica. 
2012 Jul;97(7):1003-7. 
2. 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. 
3. 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. 2010 Nov;95(11):1982-4. 
4. Fidalgo T, Silva Pinto C, Corrales I, Borràs N, Oliveira A, Almeida H, Marques D, Oliveira C, Tavares 
A, Diniz MJ, Antunes M, Caetano  G, Kjöllerström P, Maia  R, Martinho  P, Gonçalves E, Sevivas T, 
Vidal F, Ribeiro  L. Genotype–phenotype correlation in a cohort of Portuguese patients comprising 
the entire spectrum of VWD types: meaningful contribution of NGS Thromb Haemost 2016;  (In 
press). 
5. 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. 
6. 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-Yuste V, Alonso N, Vilariño D, Arija O, 
Campos R, Paloma MJ, Bermejo N, Toll T, Mateo J, Arribalzaga K, Marco P, Palomo Á, Sarmiento 
L, Iñigo  B, Nieto Mdel M, Vidal R, Martínez MP, Aguinaco R, César JM, Ferreiro M, García-Frade J, 
Rodríguez-Huerta AM, Cuesta J, Rodríguez-González R, García-Candel F, Cornudella R, Aguilar C, 
Borràs N, Vidal F. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): 
Proposal for a new diagnostic paradigm. Thromb Haemost. 2015 Dec 22;115(1):40-50. 
9.3. Medical Team 3. Hospital Universitario Politécnico La Fe. Valencia.  
1. Dr. Ana Rosa Cid Haro. 
Experience 
Dr. Cid has participated in applied studies of high quality, all having complementary expertise optimally 
covers the different objectives of the proposed project. She has a broad expertise in clinical diagnosis and 
therapy of patients with VWD since the unit is the Congenital Coagulopathies Comprehensive of Valencia 
and is also one of the largest in Spain, taking care of patients and relatives. This Unit has participated in 
multicenter international clinical trials and has the human and material resources necessary for diagnosis, 
patient selection and sample extraction, as well as for specific coagulation studies.  
Recent publications related to the field of the present proposal 
1. 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-Yuste V, Alonso N, Vilariño D, Arija O, 
Campos R, Paloma MJ, Bermejo N, Toll T, Mateo J, Arribalzaga K, Marco P, Palomo Á, Sarmiento 

 
P a g e  18 | 24 
 
L, Iñigo  B, Nieto Mdel M, Vidal R, Martínez MP, Aguinaco R, César JM, Ferreiro M, García-Frade J, 
Rodríguez-Huerta AM, Cuesta J, Rodríguez-González R, García-Candel F, Cornudella R, Aguilar C, 
Borràs N, Vidal F. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): 
Proposal for a new diagnostic paradigm. Thromb Haemost. 2015 Dec 22;115(1):40-50. 
9.4. Engineer Informatics Team  
LapiSoft Projects S.L A Coruña. NIF: B70442140 contact@lapisoft.es 
In order to cope with the main objectives of the project it will be necessary to rely on a researchers group 
with technical expertise and experience on the field of Information Technologies. An important aspect of 
relying on professionals with the mentioned expertise, obeys not only to the need of engineering and 
developing both patient register and diagnosis platforms but also to the fact of the necessary cooperation 
with the medical team, creating a space of mutual collaboration and interaction, needed to develop the 
main platform through the specified iterative process. Lapisoft Projects S.L. has been chosen for this 
project because their experience in all of the required informatics and technological aspects.   
The technical team will contribute with the technological knowledge and thus helping to find solutions to 
the possible problems and guide the medical team in their main objectives. One of the main concept will 
consist on translate the diagnosis algorithms into software (by using BPM and flow-design) which will 
support the digital representation of the medical algorithmic. Some other aspects of the projects can be 
enhanced positively by informing and teaching the medical team about options that new technologies 
offer. 
The members of the technical team count with professional expertise on different fields of IT including 
experience on research and implementation of computer science applications in the field of biomedicine, 
including the data collection and analysis of biomedical datasets. In these projects, multi-modal data was 
collected (from different sources) and machine learning techniques were applied to find patterns to 
characterize the data. These projects were mainly developed in the Human Sensing Lab (Robotics 
Institute, Carnegie Mellon University). The adviser for these projects was the Prof. Fernando de la Torre. 
The experience acquired on the mentioned previous work in the university helped to lead several projects 
in PHRQL Inc., and innovative startup company dedicated to the field of biomedicine. As a briefly 
description of the technologies used, we can mention data encryption, secure data accessing, compliance 
of data protecting laws and a user-friendly design. 
Other team members on the tech team are specialists on business intelligence, data mining, big data 
processing and BMP modelling with huge experience across several IT projects. The team also counts with 
a former designer (Advertisement and Multimedia Communication) who has experience as leader of a 
designing team which cover all the phases of the design process, for instance, ideation, contents 
architecture, graphical interface design and usability tests. The objective was to create multi-devices 
applications (tv, portable devices, pc browsers) prioritizing the friendly user experience on the graphical 
interfaces as a key design concept. 
The already proved capabilities of the Tech Team to adapt the technological concepts to specific fields of 
work, particularly the biomedical one, will be crucial to bind both worlds, technological and medical to 
create a necessary synergy to cope with the objectives of the project. At the same time with the potential 
that the new technologies offer it is very important to apply the user friendly designs, which result into a 
better experience to the final user of the platform. 
As an external adviser, the Professor Fernando de la Torre, from the Robotics Institute in the Carnegie 
Mellon University will provide his expertise to engineer and run machine learning techniques over the 

 
P a g e  19 | 24 
 
datasets and the diagnosis algorithms to try to find behavioral and trend patterns which can lead to a 
better general comprehension of the VWD in general and diagnosis in particular. The collaboration with 
the mentioned CMU department (world leading institution) would eventually provide international 
visibility to the main project and specifically to the techniques applied on the data. Expenses for this 
collaboration are considered on the final budget. A letter of Prof. de la Torre accepting to collaborate in 
the project is included at the end of this proposal.  
Publications and awards of the team members. 
1. Fernando Batlle, Alberto Gil, Fernando de la Torre, Jessica Hodgins. Grand Challenge Data 
Collection: System Engineering & Technical Challenges. Quality of life workshop at Robotics 
Institute (Carnegie Mellon University) 2011. 
2. Fernando Batlle. Caremedia: creating a system to improve the knowledge of the elderly people 
behavior.  Cum laude in Master thesis (Carnegie Mellon University – University of Vigo) 2011. 
3. Breogán Amoedo, Manuel López, Francisco Vicente, Fernando de la Torre, Alexander Hauptmann, 
Dona Curti. Monitoring elderly in independent living and in nursing homes. Quality of life 
workshop at Robotics Institute (Carnegie Mellon University) 2012. 
4. Samarjit 
Das, Breogan 
Amoedo, 
Fernando 
De 
la 
Torre, 
Jessica 
Hodgins.  
Detecting Parkinsons' Symptoms in Uncontrolled Home Environments: A Multiple Instance 
Learning Approach. Engineering in Medicine and Biology Conference Management 
System (EMBC) 2012. 
5. Sanofi US Innovation Challenge Award 2013. Won by the startup PHRQL Inc. counting with two 
members of the tech team as tech lead designers.  
 
 
 

 
P a g e  20 | 24 
 
10. Study duration, timelines and milestones  
The estimated duration of the whole proposed project is three years.  
 
11. Relevance of the project in terms of clinical care and/or technological 
development 
All the advances generated during this project will have beneficial repercussions for the patients. 
1. Improvement of therapeutic strategies. 
2. Greater preventive capacity in patients to face up to risk situations of thrombosis or bleeding.  
3. To increase the cost-effectiveness of diagnostic methods and select the most appropriate 
therapeutic strategies. 
4. Adequate characterization of patients. 
5. Better knowledge of the actual state of the disease in Spain. 
6. Provide a platform of Spanish patients the best characterized possible and homogeneously which 
allows us to develop our own projects and participate in international projects such as the 
European project "3WINTERS-IPS" ("Type 3 VWD and international registries inhibitors 
prospective study") in which we are currently participating, or American project GWAS (Genome 
Wide Association Study). 
7. Create a registry into the Spanish Society of Thrombosis and Haemostasis (SETH). 
8. Develop consensus guidelines for diagnosis and treatment of the VWD  (Methodology GRADE). 
9. This project will contribute to the clinical diagnosis of VWD at international level, especially in 
patients with particularly complex symptoms and diagnostic. This project is otherwise essential 
to establish international partnerships, participate in international studies and to access to 
additional funding resources.  
10. An aim of this project is the accomplishment of doctoral theses. 
 
12. Relevance of the project in terms of scientific impact and 
technological development 
1. Dissemination of results: Target conferences to present the results of the project will be the 2017-
19 meetings and congresses of ISTH, World Federation of Haemophilia, ASH, EAHAD, SETH, aside 
from partial results will be presented in other minor workshops or meetings. It is expected to 
publish some articles with the results of this project in international journals (e.g., Journal 
Thrombosis and Haemostasis, Blood, Haemostasis and Thrombosis, Haematologica, American 

 
P a g e  21 | 24 
 
Journal of Haematology). The initial expected publications from the present Project are shown in 
Annex VIII 
2. Ellaboration of a website similar to that carried out in the European project MCMDM-1VWD. 
3. The partnership between LapiSoft and PCM workgroup has, among their aims, to participate and 
leading innovation and research projects with a markedly translational nature and with a direct 
impact on the quality of clinical care (applicability). To our knowledge there is no similar project 
in this field.  
4. Potential patents may derive from this project.  
5. Development of e-learning and new information technologies (forum discussion, ads, google 
search engine).  
6. Eventually, there will be a study of all the data gathered, and will consult to experts on pattern 
recognition and machine learning in order to achieve more knowledge of the disease. New 
computer science algorithms will be defined, and the results of applying them, will be submitted 
for their publication in either medical or technical international journals.  
7. We believe that this project will contribute to the clinical diagnosis of VWD at international level, 
especially in patients with particularly complex symptoms and diagnostic. This project is otherwise 
essential to establish international partnerships, participate in international studies and to access 
to additional funding resources. 

 
P a g e  22 | 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
P a g e  23 | 24 
 
13. Summary of the whole budget 
CONCEPT 
DESCRIPTION 
Consumables 
  
Central phenotipic study 
Central genotipic assay  
Staff 
Postdoctoral Investigator Fellowship 
  
Services 
  
  
Local patients sampling collection and transfer to central 
Laboratories 
Engineer Technical Teem budget contacted as a technical 
external service 
Whole requested 
budget 
  
US$ 374,473.00  
 
 
 
13.1. Postdoctoral Investigator Fellowship Research Medical Team. 
For the accomplishment of this project it is needed to contract a post-doctoral investigator (at half time) 
with a deep knowledge in VWF and VWD. His/her activity will include: 
1. Central phenotipic analysis of the 500 samples.  
2. Update of the database (monthly). Exhaustive bibliographical search will be realized as well as 
also there will be checked different database that already exist in order to incorporate all those 
mutations and polymorphisms that have been described recently, providing the most detailed 
information possible about them. 
3. Analysis of controversy. To help to adopt a position in those cases in which exist controversy.  
4. In collaboration with LapiSoft, will conduct some basic testing on each new feature developed 
and report any discrepancy with the initial specification.  
5. Elaboration of reports and modifications according new requirements and features of the 
algorithm. 
6. Validation of the platform.  
 
13.2. Sampling collection and transfer to central laboratories   
This budget has been calculated estimating a recruitment of 400 patients from approximately 35 
different centres from Spain with recollection of the samples from de local centres and transfer to 
Central Laboratory of La Coruña, Spain assuring to keep them permanently and adequately frozen.  
In order to make efficient this transfer, it will be carefully planned together with the enterprise 
chosen grouping as much as possible different centres form close geographical areas.  Once 
received the samples, aliquot fractions will be sent to Central Laboratory of Barcelona for molecular 
analysis.     

 
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13.3. Engineer Technical Team (Lapisoft Projects S.L) contacted as a technical external 
service. 
Based on Software engineer paradigms, Lapisoft will break down the implementation of the 
technical part of the project. These activities include the detailed design of the system by a System 
Analyst and a UX designer, the implementation by a software developer and the validation by a 
betatester. These will be considered for the full duration of the project: 
x 
Legal LOPD advising: To assure the compliance of the Spanish data privacy law. Professional 
expert consulting will be required. 
x 
Cloud resources and support:  this includes the cost of the infrastructure plus the support plan 
for both systems.  
x 
Machine learning consulting: As it was mentioned, since machine learning techniques will be 
applied to the dataset, external advising will provide guides to follow. 
 
We wish to emphasized that the present project will be funded by the grant requested to Baxalta and it 
will not suppose additional costs to the FETH.