Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis

Thomas A. White, Tucker Johnson, Natalia Zarzhevsky, Cindy Tom, Sinny Delacroix, Eric W. Holroyd, Susan A. Maroney, Ripudamanjit Singh, Shuchong Pan, William P. Fay, Jan Van Deursen, Alan E. Mast, Gurpreet S. Sandhu, Robert D. Simari

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice. Here we define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis using TFPI conditional knockout mice. We used a Cre-lox strategy and generated mice with a floxed exon 4 (TFPIFlox) which encodes for the TFPI-K1 domain. Mice bred into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPI Tie2) and myelomonocytic (TFPILysM) cells resulted in viable and fertile offspring. Plasma TFPI activity was reduced in the TFPI Tie2 (71% ± 0.9%, P < .001) and TFPILysM (19% ± 0.6%, P < .001) compared with TFPIFlox littermate controls. Tail and cuticle bleeding were unaffected. However, TFPI Tie2 mice but not TFPILysM mice had increased ferric chloride-induced arterial thrombosis. Taken together, the data reveal distinct roles for endothelial- and myelomonocytic-derived TFPI.

Original languageEnglish (US)
Pages (from-to)1787-1794
Number of pages8
JournalBlood
Volume116
Issue number10
DOIs
StatePublished - Sep 9 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    White, T. A., Johnson, T., Zarzhevsky, N., Tom, C., Delacroix, S., Holroyd, E. W., Maroney, S. A., Singh, R., Pan, S., Fay, W. P., Van Deursen, J., Mast, A. E., Sandhu, G. S., & Simari, R. D. (2010). Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis. Blood, 116(10), 1787-1794. https://doi.org/10.1182/blood-2009-10-250910