Abstract

There are two proteins that are deficient in von Willebrand's disease: von Willebrand factor and von Willebrand Antigen II. Each is present in platelet alpha granules (released by platelet activation) and colocalized in specific granules in cultured endothelial cells. Although no immunologic relationship between these two proteins can be demonstrated in plasma, serum, or platelets, recent studies demonstrate the synthesis of a complex for vWf and vW AgII within the endothelial cell that is cleaved upon secretion into the culture media. Studies will be performed to determine the structure and function of both vWf and vW AgII in plasma, platelets, and endothelial cells. Since vWf is cleaved by platelet calpain, studies will be performed to determine the significance of this fragmentation on the physiologic function of vWf and to determine ways in which vWF proteolysis can be avoided. Platelet vWf and vW AgII will be purified and their binding to platelet membrane receptors will studied in comparison to their plasma-derived counterparts. The synthesis of the vWf/vW AgII complex in endothelial cells will be studied to determine whether the complex is a precursor or a synthetic intermediate. Genetic studies will be performed with mRNA and cDNA probes. Endothelial cell proteins released by activation will be characterized and their use as specific indicators of endothelial cell activation will be determined.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL033721-05
Application #
3345861
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1984-07-01
Project End
1991-01-31
Budget Start
1988-02-01
Budget End
1989-01-31
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Bloodcenter of Wisconsin, Inc.
Department
Type
DUNS #
City
Milwaukee
State
WI
Country
United States
Zip Code
53233

  Publications

Shi, Q; Schroeder, J A; Kuether, E L et al. (2015) The important role of von Willebrand factor in platelet-derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies. J Thromb Haemost 13:1301-9
Flood, Veronica H; Schlauderaff, Abraham C; Haberichter, Sandra L et al. (2015) Crucial role for the VWF A1 domain in binding to type IV collagen. Blood 125:2297-304
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
Kanaji, S; Fahs, S A; Ware, J et al. (2014) Non-myeloablative conditioning with busulfan before hematopoietic stem cell transplantation leads to phenotypic correction of murine Bernard-Soulier syndrome. J Thromb Haemost 12:1726-32
Flood, Veronica H; Gill, Joan Cox; Friedman, Kenneth D et al. (2013) Collagen binding provides a sensitive screen for variant von Willebrand disease. Clin Chem 59:684-91
Jacobi, Paula M; Gill, Joan Cox; Flood, Veronica H et al. (2012) Intersection of mechanisms of type 2A VWD through defects in VWF multimerization, secretion, ADAMTS-13 susceptibility, and regulated storage. Blood 119:4543-53
Flood, V H; Gill, J C; Christopherson, P A et al. (2012) Comparison of type I, type III and type VI collagen binding assays in diagnosis of von Willebrand disease. J Thromb Haemost 10:1425-32
Kanaji, S; Fahs, S A; Shi, Q et al. (2012) Contribution of platelet vs. endothelial VWF to platelet adhesion and hemostasis. J Thromb Haemost 10:1646-52
Kanaji, Sachiko; Kuether, Erin L; Fahs, Scot A et al. (2012) Correction of murine Bernard-Soulier syndrome by lentivirus-mediated gene therapy. Mol Ther 20:625-32
Madabhushi, Sri R; Shang, Chengwei; Dayananda, Kannayakanahalli M et al. (2012) von Willebrand factor (VWF) propeptide binding to VWF D'D3 domain attenuates platelet activation and adhesion. Blood 119:4769-78

Showing the most recent 10 out of 59 publications