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

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
Blood (Impact Factor: 10.45). 10/2009; 114(23):4886-96. DOI: 10.1182/blood-2009-06-228940
Source: PubMed


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.

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    • "Recently, however, Campbell et al.117 reported that ECs stimulated by inflammatory cytokines to express TF, similarly to normal TF-expressing extravascular cells (fibroblasts, SMCs), caused the production of abnormally dense fibrin networks that resisted fibrinolysis. Moreover, activated platelets, commonly found in sepsis, not only alter the fibrin structure and reduce susceptibility to lysis via the direct interaction between fibrin and αIIbβ3 integrin117 but also release, together with the causative micro-organism, inorganic polyphosphates, which have been recently shown to modify the fibrin architecture and to reduce the binding of t-PA and plasminogen to fibrin, thereby increasing fibrin resistance to fibrinolysis.118 "
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