Type 1 and 3 von Willebrand disease (VWD) represent the most frequent and rarest forms, respectively of the most common inherited bleeding disorder described in humans. Both conditions are quantitative traits with reductions of von Willebrand factor (VWF) being mild/moderate in type 1 VWD and severe in type 3 disease. In this research proposal, we will further pursue the pathogenesis of these conditions.
In Aim #1 of the project we will carry out studies to further examine the role of sequence variation in and around the VWF gene in the pathogenesis of type 1 and 3 VWD. These studies will determine the potential pathogenetic role of regulatory region variants, intronic variants and copy number variation.
Aim #2 of the project will involve a re-assessment of the association data presented in the recently published CHARGE genome-wide association study meta-analysis. These studies will be performed primarily to fine-map the original SNP associations described in the CHARGE meta-analysis.
Aims 3 and 4 will involve studies to address the finding of five novel pathogenetic candidates reported in the CHARGE GWAS report.
In Aim #3 we will perform studies to evaluate the role of two candidates identified in CHARGE that appear to have the potential to play a role in VWF biosynthesis, storage and/or secretion. These studies will involve a combination of cell biology and genetic approaches to determining the role of Syntaxin Binding Protein 5 (STXBP5) and Syntaxin 2 (STX2) in regulating VWF synthesis and release from cells. In parallel with the studies to evaluate normal STXBP5 and STX2 function, we will search for variants of these proteins in our type 1 and 3 VWD populations and will determine the influence of selected variants in the experimental systems that we have established. Finally, in Aim #4 we will use a similar combination of biology and genetics to investigate the influence of accelerated clearance of VWF by the receptors C-type lectin domain family 4 member M, Stabilin-2 and Scavenger receptor class A member 5. Again, after characterizing the role of the normal receptors in binding to and clearing VWF, we will evaluate the influence of variant forms of the receptors derived from a genetic search of our type 1 VWD patient cohorts.

Public Health Relevance

This research project addresses the genetic background of two inherited bleeding disorders, one, type 1 von Willebrand disease, that is the most common bleeding problem encountered in the general population, and the second, type 3 von Willebrand disease, a rare variant form of the condition. Both diseases result in chronic morbidities due to recurrent excessive mucocutaneous bleeding.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Bloodcenter of Wisconsin, Inc.
United States
Zip Code
Goodeve, A C; Pavlova, A; Oldenburg, J (2014) Genomics of bleeding disorders. Haemophilia 20 Suppl 4:50-3
Fahs, Scot A; Hille, Matthew T; Shi, Qizhen et al. (2014) A conditional knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Blood 123:3706-13
de Brasi, C; El-Maarri, O; Perry, D J et al. (2014) Genetic testing in bleeding disorders. Haemophilia 20 Suppl 4:54-8
Laffan, Mike A; Lester, Will; O'Donnell, James S et al. (2014) The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 167:453-65
Hampshire, Daniel J; Goodeve, Anne C (2014) p.P2063S: a neutral VWF variant masquerading as a mutation. Ann Hematol 93:505-6
Elbatarny, M; Mollah, S; Grabell, J et al. (2014) Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project. Haemophilia 20:831-5
Castaman, G; Hillarp, A; Goodeve, A (2014) Laboratory aspects of von Willebrand disease: test repertoire and options for activity assays and genetic analysis. Haemophilia 20 Suppl 4:65-70
Shida, Yasuaki; Rydz, Natalia; Stegner, David et al. (2014) Analysis of the role of von Willebrand factor, platelet glycoprotein VI-, and ?2?1-mediated collagen binding in thrombus formation. Blood 124:1799-807
Rusu, Luiza; Andreeva, Alexandra; Visintine, David J et al. (2014) G protein-dependent basal and evoked endothelial cell vWF secretion. Blood 123:442-50
Brott, David A; Katein, Anne; Thomas, Heath et al. (2014) Evaluation of von Willebrand factor and von Willebrand factor propeptide in models of vascular endothelial cell activation, perturbation, and/or injury. Toxicol Pathol 42:672-83

Showing the most recent 10 out of 49 publications