PROTEIN Z DEPENDENT PROTEINASE INHIBITOR

Summary

Principal Investigator: George J Broze
Abstract: Protein Z (PZ) is a vitamin K-dependent plasma protein that serves as a cofactor for the inhibition of factor Xa by PZ-dependent Protease Inhibitor (ZPI). ZPI is a member of the serpin superfamily of protease inhibitors and not only inhibits factor Xa in a PZ, Ca2+, and phospholipid-dependent manner, but also directly inhibits coagulation factor XIa. Evidence from mouse models demonstrates that the PZ/ZPI system plays a physiologic important role in the regulation of coagulation. The goals of this proposal are to 1) carefully characterize the role of the phospholipid surface (including that of platelets) in the anticoagulant function of PZ/ZPI, 2) determine the molecular mechanisms underlying the inhibition of factors Xa and XIa by PZ and ZPI, 3) evaluate the processes affecting the expression and plasma clearance of PZ and ZPI and, in particular, characterize their recently discovered expression in the kidney and explore its physiologic significance, and 4) further define the relationship between PZ and ZPI deficiency and thrombotic disease with an emphasis on the antiphospholipid syndrome, atherosclerosis, and potential mechanisms for the development of acquired PZ/ZPI deficiency. The work will utilize biochemical techniques, the production of recombinant, altered forms of the proteins for structure/function analysis, and mouse models to define the pathophysiologic relevance of the PZ/ZPI system. The goals of this proposal will provide important and comprehensive information, currently lacking, that will enhance our understanding of this previously unidentified pathway for the regulation of coagulation and its role in human disease. PUBLIC HEALTH RELEVANCE: Protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) are plasma proteins that regulate coagulation by inhibiting the action of two coagulation enzymes, factor Xa and factor XIa. The goals of this proposal are to better characterize the expression and metabolism of PZ and ZPI, determine the molecular mechanisms underlying their anticoagulant action, and further define their role in thromboembolic disease. The work will provide important information that will enhance our understanding of the regulation of coagulation by PZ and ZPI and its role in human thrombotic disease.
Funding Period: ----------------1998 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. pmc Protein Z-dependent protease inhibitor deficiency produces a more severe murine phenotype than protein Z deficiency
    Jing Zhang
    Division of Hematology, Washington University, St Louis, MO, USA
    Blood 111:4973-8. 2008
  2. pmc Contribution of protein Z and protein Z-dependent protease inhibitor in generalized Shwartzman reaction
    Antje Butschkau
    1Institute for Experimental Surgery, University of Rostock, Rostock, Germany 2Division of Hematology, Washington University Medical Center, St Louis, MO
    Crit Care Med 41:e447-56. 2013
  3. pmc Protein Z-dependent protease inhibitor and protein Z in peripheral arterial disease patients
    F Sofi
    Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Florence, Italy
    J Thromb Haemost 7:731-5. 2009
  4. pmc A meta-analysis of potential risks of low levels of protein Z for diseases related to vascular thrombosis
    Francesco Sofi
    Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Florence, Italy
    Thromb Haemost 103:749-56. 2010

Scientific Experts

  • Francesco Sofi
  • Antje Butschkau
  • George J Broze
  • Jing Zhang
  • Dietmar Zechner
  • Brigitte Vollmar
  • Philipp Nagel
  • Eberhard Grambow
  • Lan Lu
  • Nina Lasky
  • Yizheng Tu

Detail Information

Publications6

  1. pmc Protein Z-dependent protease inhibitor deficiency produces a more severe murine phenotype than protein Z deficiency
    Jing Zhang
    Division of Hematology, Washington University, St Louis, MO, USA
    Blood 111:4973-8. 2008
    ..The studies in mice suggest that human PZ and ZPI deficiency would be associated with a modest thrombotic risk with ZPI deficiency producing a more severe phenotype...
  2. pmc Contribution of protein Z and protein Z-dependent protease inhibitor in generalized Shwartzman reaction
    Antje Butschkau
    1Institute for Experimental Surgery, University of Rostock, Rostock, Germany 2Division of Hematology, Washington University Medical Center, St Louis, MO
    Crit Care Med 41:e447-56. 2013
    ..The functions of protein Z and protein Z-dependent protease inhibitor in the inflammatory and coagulant responses to septic illness have not been evaluated...
  3. pmc Protein Z-dependent protease inhibitor and protein Z in peripheral arterial disease patients
    F Sofi
    Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Florence, Italy
    J Thromb Haemost 7:731-5. 2009
    ..The aim of this study was to more fully assess the protein Z-ZPI system in individuals with atherosclerosis selected by the presence of symptomatic PAD...
  4. pmc A meta-analysis of potential risks of low levels of protein Z for diseases related to vascular thrombosis
    Francesco Sofi
    Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Florence, Italy
    Thromb Haemost 103:749-56. 2010
    ..18, 95%CI 1.19-4.00; p=0.01). The results of this meta-analysis are consistent with a role for protein Z deficiency in thrombotic diseases, including arterial thrombosis, pregnancy complications and venous thromboembolism...