Von Willebrand disease is a common diagnosis in the USA. In some cases the disorder is under-diagnosed, particularly in adult females with menorrhagia. In other situations, VWD may be over-diagnosed based on less precise laboratory testing at the time of diagnosis, incorrect interpretation of the lab results at diagnosis, the lab testing was abnormal but the patient had no clinical bleeding correlate, or the """"""""field"""""""" has changed concerning the stringency of diagnostic criteria (NHLBI Guidelines).
Aim 1 of this project will continue the ongoing study of type 1 (and other VWD types) to clarify the stringency of VWD diagnosis and provide a suggested approach to substantiating, questioning, or removing the diagnosis of VWD.
Aim 2 will develop improved alternative assays for VWF function. Currently the only widely utilized test of VWF function is the ristocetin co-factor assay (VWF:RCo). There are widely recognized problems with sensitivity, specificity, and clinical correlation of that assay - in part do to the interaction between ristocetin and the test VWF.
Aim 3 will continue to determine the genotype - phenotype correlation of VWF alteration by determining VWF sequence variations based on race or ethnicity within the US population.
Aim 4 will carry out clinical projects that are currently being piloted at single centers (menorrhagia at Milwaukee and QOL Studies at Indiana). Not only is this study population important to the studies proposed in Aim 1, but this cohort is also critical to the studies proposed in Project 2 and Project 3. This careful clinical and laboratory phenotyping in this project will not only improve the fidelity of VWD diagnosis, but it will begin the pathway of how to approach individuals with a prior diagnosis of VWD that might have neither abnormal laboratory testing nor a current abnormal clinical bleeding risk.

Public Health Relevance

This project addresses critical issues around the fidelity of the diagnosis of von Willebrand Disease in the United States. The diagnosis of this genetically acquired disorder may not be confirmed by subsequent retesting. Diagnostic category requires a careful evaluation and correlation of clinical laboratory testing, clinical phenotyping, and molecular genotyping on a world-wide basis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL081588-06
Application #
8246607
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-02-15
Budget End
2013-01-31
Support Year
6
Fiscal Year
2012
Total Cost
$277,008
Indirect Cost
$23,440
Name
Medical College of Wisconsin
Department
Type
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Obser, T; Ledford-Kraemer, M; Oyen, F et al. (2016) Identification and characterization of the elusive mutation causing the historical von Willebrand Disease type IIC Miami. J Thromb Haemost 14:1725-35
Hawke, Lindsey; Bowman, Mackenzie L; Poon, Man-Chiu et al. (2016) Characterization of aberrant splicing of von Willebrand factor in von Willebrand disease: an underrecognized mechanism. Blood 128:584-93
Ozel, A B; McGee, B; Siemieniak, D et al. (2016) Genome-wide studies of von Willebrand factor propeptide identify loci contributing to variation in propeptide levels and von Willebrand factor clearance. J Thromb Haemost 14:1888-98
Flood, Veronica H; Christopherson, Pamela A; Gill, Joan Cox et al. (2016) Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States. Blood 127:2481-8
Baumgartner, C K; Mattson, J G; Weiler, H et al. (2016) Targeting Factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice. J Thromb Haemost :
Haberichter, Sandra L (2015) von Willebrand factor propeptide: biology and clinical utility. Blood 126:1753-61
Chen, Junmei; Hinckley, Jesse D; Haberichter, Sandra et al. (2015) Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease. Blood 126:262-9
Goodeve, A C (2015) Hemophilia B: molecular pathogenesis and mutation analysis. J Thromb Haemost 13:1184-95
Avila, M L; Lee, K-J; Bouskill, V et al. (2015) Acquired von Willebrand syndrome in paediatric patients with congenital heart disease: challenges in the diagnosis and management of this rare condition. Haemophilia 21:e89-92
Deforest, M; Grabell, J; Albert, S et al. (2015) Generation and optimization of the self-administered bleeding assessment tool and its validation as a screening test for von Willebrand disease. Haemophilia 21:e384-8

Showing the most recent 10 out of 97 publications