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An accompanying genetic severe deficiency of tissue factor protects mice with a protein C deficiency from lethal endotoxemia.

Authors: Castellino, FJ  Donahue, DL  Navari, RM  Ploplis, VA  Walsh, M 
Citation: Castellino FJ, etal., Blood. 2011 Jan 6;117(1):283-9. doi: 10.1182/blood-2010-07-299057. Epub 2010 Sep 21.
Pubmed: (View Article at PubMed) PMID:20858853
DOI: Full-text: DOI:10.1182/blood-2010-07-299057

Mice with a severe genetic deficiency of protein C (PC), PC(-/-)PC(tg4), display enhanced susceptibility to lethal effects of gram-negative endotoxemia induced by lipopolysaccharide (LPS), whereas mice severely deficient in tissue factor (TF), TF(-/-)hTF(tg), are protected from LPS-mediated lethality. In this study, we show that a simultaneous severe deficiency of TF protected low-PC mice from LPS-induced death, resulting in a survival profile similar to that experienced by wild-type (WT) mice. Plasma and whole blood coagulation assays, the latter measured by thromboelastography, demonstrated development of coagulopathies in LPS-treated mice, which were more severe in the case of the doubly deficient TF(-/-)hTF(tg)/PC(-/-)PC(tg4) mice, mainly reflecting earlier signs of disseminated intravascular coagulation in this latter cohort. Markers of inflammation were also elevated in response to LPS in both groups of mice at times just preceding death. We conclude that whereas coagulopathies are more exacerbated in LPS-treated TF(-/-)hTF(tg)/PC(-/-)PC(tg4) mice, the lowering of TF levels in mice with an accompanying severe PC deficiency confers protection against death compared with mice with a single severe PC deficiency. This suggests that proteases generated as a result of factor VIIa/TF-mediated thrombin generation play a mechanistic role in the enhanced lethality seen under very low PC conditions in an endotoxemia model in mice.

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CRRD Object Information
CRRD ID: 11341685
Created: 2016-06-30
Species: All species
Last Modified: 2016-06-30
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.