Abstract

Tissue factor pathway inhibitor (TFPI) is the in vivo inhibitor of factor VIIa/tissue factor-induced coagulation and, as such, plays a critical physiologic role in regulating the coagulant and inflammatory effects of factor VIIa/tissue factor action. We have recently shown that two forms of the TFPI protein, produced by alternative mRNA splicing, are expressed in human cells. Both forms associate with the surface of cells in a glycosylphosphatidylinositol (GPI)-anchored fashion, but through different mechanisms. TFPI-alpha, a soluble protein, appears to bind to another GPI-anchored protein(s), whereas TFPI-beta contains an intrinsic GPI-anchor. The thrust of this proposal is to characterize and contrast the location, functional activity, and potential physiologic roles of TFPI-alpha and TFPI-beta. In our specific aims we propose to: 1) Compare the expression of TFP-alpha and TFPI-beta; 2) Determine the structural components of TFPR-alpha that mediate its cell surface binding; 3) Identify and characterize the TFPI-alpha surface binding protein(s); 4) Compare the activities of cell-surface TFPI-alpha and TFPI-beta, and soluble TFPI-alpha; and 5) Investigate the in vivo relevance of TFPI GPI-anchorage.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077193-02
Application #
6921383
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Link, Rebecca P
Project Start
2004-07-15
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$344,250
Indirect Cost

  Institution

Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Girard, T J; Grunz, K; Lasky, N M et al. (2018) Re-evaluation of mouse tissue factor pathway inhibitor and comparison of mouse and human tissue factor pathway inhibitor physiology. J Thromb Haemost 16:2246-2257
Feng, D; Stafford, K A; Broze, G J et al. (2013) Evidence of clinically significant extravascular stores of factor IX. J Thromb Haemost 11:2176-8
Girard, Thomas J; Tuley, Elodee; Broze Jr, George J (2012) TFPI? is the GPI-anchored TFPI isoform on human endothelial cells and placental microsomes. Blood 119:1256-62
Ndonwi, M; Girard, T J; Broze Jr, G J (2012) The C-terminus of tissue factor pathway inhibitor ? is required for its interaction with factors V and Va. J Thromb Haemost 10:1944-6
Ndonwi, Matthew; Tuley, Elodee A; Broze Jr, George J (2010) The Kunitz-3 domain of TFPI-alpha is required for protein S-dependent enhancement of factor Xa inhibition. Blood 116:1344-51