Polymicrobial sepsis and endotoxemia promote microvascular thrombosis via distinct mechanisms

J Thromb Haemost. 2010 Jun;8(6):1403-9. doi: 10.1111/j.1538-7836.2010.03853.x. Epub 2010 Mar 12.


Background: We reported recently that endotoxemia promotes microvascular thrombosis in cremaster venules of wild-type mice, but not in mice deficient in toll-like receptor 4 (TLR4) or von Willebrand factor (VWF).

Objective: To determine whether the clinically relevant model of polymicrobial sepsis induced by cecal ligation/perforation (CLP) induces similar responses via the same mechanisms as endotoxemia.

Methods: We used a light/dye-injury model of thrombosis in the cremaster microcirculation of wild-type mice and mice deficient in toll-like receptor-4 (C57BL/10ScNJ), toll-like receptor 2 (TLR2), or VWF. Mice underwent CLP or sham surgery, or an intraperitoneal injection of endotoxin (LPS) or saline. In the CLP model, we assessed the influence of fluid replacement on thrombotic responses.

Results: Both CLP and LPS enhanced thrombotic occlusion in wild-type mice. In contrast to LPS, CLP enhanced thrombosis in TLR4- and VWF-deficient strains. While TLR2-deficient mice did not demonstrate enhanced thrombosis following CLP, LPS enhanced thrombosis in these mice. LPS, but not CLP, increased plasma VWF antigen relative to controls. Septic mice, particularly those undergoing CLP, developed significant hemoconcentration. Intravenous fluid replacement with isotonic saline prevented the hemoconcentration and prothrombotic responses to CLP, though fluids did not prevent the prothrombotic response to LPS.

Conclusions: Polymicrobial sepsis induced by CLP and endotoxemia promote microvascular thrombosis via distinct mechanisms; enhanced thrombosis induced by CLP requires TLR2 but not TLR4 or VWF. The salutary effects of intravenous fluid replacement on microvascular thrombosis in polymicrobial sepsis remain to be characterized.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Endotoxemia / complications*
  • Endotoxemia / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Sepsis / complications
  • Sepsis / immunology
  • Sepsis / microbiology*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / physiology
  • von Willebrand Factor / genetics
  • von Willebrand Factor / immunology
  • von Willebrand Factor / physiology


  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • von Willebrand Factor