This is a completive renewal application for years 6-10 of Program Project Grant HL081588 entitled the Zimmerman Program for the Molecular and Clinical Biology of VWD. This project began as a means of characterizing patients diagnosed with VWD in the USA and correlating them at a molecular, laboratory phenotype, and clinical phenotype within our country as well as with cohorts studied in Canada and the European Union. This PPG has identified problems with the fidelity of the historical VWD diagnosis and problems with using certain tests that perform poorly with newly define common polymorphisms in African American. Project 1 (Montgomery) proposes studies to improve the fidelity of the diagnosis of VWD and studies approaches to better contrast the clinical, clinical lab, and research correlation of the VWD diagnosis. Some newer pilot studies will also study the impact of VWD on clinical menorrhagia and Quality of Life studies in VWD patients. Project 2 (Haberichter) studies the in vivo and in vitro correlates of VWF mutations. In the mouse, clearance mechanisms will be defined and whether an individual, with accelerated clearance as the reason for type 1C VWD, has increased clearance through normal pathways or increased clearance through pathologic pathways. Project 3 (Lillicrap/Goodeve explores broader mechanisms for reduced plasma, and/or cellular, VWF. Within this PPG and in both the Canadian and European Union Cohorts, subjects have been identified with quite low VWF but in whom no coding region mutation of VWF are identified. Individually, these studies have insufficient numbers to systematically study this phenomenon, but collectively this group is expected to be enabling. The Administrative Core not only oversees the day-to-day management of this Program but also maintains a supporting clinical network of Primary and Secondary Clinical Centers. The Clinical Laboratory Core performs the clinical laboratory testing (needed by all three projects), the coding sequence of VWF, and will coordinate the next-generation sequencing the full VWF gene (Project 1 and 3) and GWAS-associated sequencing. Taken together this PPG will set the stage for the appropriate diagnosis and phenotypic understanding of VWD - both in the US and throughout the world.

Public Health Relevance

This PPG is tightly focused on von Willebrand Disease that is a very common clinical bleeding disorder. In some studies its prevalence may be as high as 1-2% of the general population. Based on the NHLBI Guidelines (2006), the importance of under-diagnosis and over-diagnosis are major Public Health issues. This PPG and its three tightly interactive projects is focused on addressing these issues at a clinical, diagnostic and a molecular level. (End of Abstract)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Kindzelski, Andrei L
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Bloodcenter of Wisconsin, Inc.
United States
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Flood, Veronica H; Abshire, Thomas C; Christopherson, Pamela A et al. (2018) Von Willebrand disease in the United States: perspective from the Zimmerman program. Ann Blood 3:
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Baumgartner, C K; Mattson, J G; Weiler, H et al. (2017) Targeting factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice. J Thromb Haemost 15:98-109
Selvam, Soundarya; James, Paula (2017) Angiodysplasia in von Willebrand Disease: Understanding the Clinical and Basic Science. Semin Thromb Hemost 43:572-580
Lorenz, Viola; Ramsey, Haley; Liu, Zhi-Jian et al. (2017) Developmental Stage-Specific Manifestations of Absent TPO/c-MPL Signalling in Newborn Mice. Thromb Haemost 117:2322-2333

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