Contributions of extravascular and intravascular cells to fibrin network formation, structure, and stability

Blood. 2009 Nov 26;114(23):4886-96. doi: 10.1182/blood-2009-06-228940. Epub 2009 Oct 1.

Abstract

Fibrin is essential for hemostasis; however, abnormal fibrin formation is hypothesized to increase thrombotic risk. We previously showed that in situ thrombin generation on a cell's surface modulates the 3-dimensional structure and stability of the fibrin network. Currently, we compared the abilities of extravascular and intravascular cells to support fibrin formation, structure, and stability. Extravascular cells (fibroblasts, smooth muscle) supported formation of dense fibrin networks that resisted fibrinolysis, whereas unstimulated intravascular (endothelial) cells produced coarse networks that were susceptible to fibrinolysis. All 3 cell types produced a fibrin structural gradient, with a denser network near, versus distal to, the cell surface. Although fibrin structure depended on cellular procoagulant activity, it did not reflect interactions between integrins and fibrin. These findings contrasted with those on platelets, which influenced fibrin structure via interactions between beta3 integrins and fibrin. Inflammatory cytokines that induced prothrombotic activity on endothelial cells caused the production of abnormally dense fibrin networks that resisted fibrinolysis. Blocking tissue factor activity significantly reduced the density and stability of fibrin networks produced by cytokine-stimulated endothelial cells. Together, these findings indicate fibrin structure and stability reflect the procoagulant phenotype of the endogenous cells, and suggest abnormal fibrin structure is a novel link between inflammation and thrombosis.

Publication types

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

MeSH terms

  • Adult
  • Blood Coagulation / physiology*
  • Cell Line, Transformed / physiology
  • Cells, Cultured / physiology
  • Endothelial Cells / drug effects
  • Endothelial Cells / physiology*
  • Endothelium, Vascular / cytology
  • Factor V / physiology
  • Factor Xa / physiology
  • Female
  • Fibrin / chemistry
  • Fibrin / ultrastructure*
  • Fibrinolysis
  • Fibroblasts / physiology*
  • Humans
  • Male
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Multiprotein Complexes
  • Muscle Cells / physiology*
  • Muscle, Smooth, Vascular / cytology
  • Protein C / physiology
  • Thrombin / biosynthesis
  • Thromboplastin / physiology
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Multiprotein Complexes
  • Protein C
  • Tumor Necrosis Factor-alpha
  • prothrombinase complex
  • Factor V
  • Fibrin
  • Thromboplastin
  • Thrombin
  • Factor Xa