Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice.
Tissue factor (TF) is the primary activator of the coagulation cascade. During endotoxemia, TF expression leads to disseminated intravascular coagulation. However, the relative contribution of TF expression by different cell types to the activation of coagulation has not been defined. In this study, we investigated the effect of either a selective inhibition of TF expression or cell type-specific deletion of the TF gene (F3) on activation of coagulation in a mouse model of endotoxemia. We found that inhibition of TF on either hematopoietic or nonhematopoietic cells reduced plasma thrombin-antithrombin (TAT) levels 8 hours after administration of bacterial lipopolysaccharide (LPS). In addition, plasma TAT levels were significantly reduced in endotoxemic mice lacking the TF gene in either myeloid cells (TF(flox/flox),LysM(Cre) mice) or in both endothelial cells (ECs) and hematopoietic cells (TF(flox/flox),Tie-2(Cre) mice). However, deletion of the TF gene in ECs alone had no effect on LPS-induced plasma TAT levels. Similar results were observed in mice lacking TF in vascular smooth muscle cells. Finally, we found that mouse platelets do not express TF pre-mRNA or mRNA. Our data demonstrate that in a mouse model of endotoxemia activation of the coagulation cascade is initiated by TF expressed by myeloid cells and an unidentified nonhematopoietic cell type(s).
Pawlinski
Rafal
R
Hematology and Oncology Division, Department of Medicine, University of North Carolina at Chapel Hill, NC, USA.
Wang
Jian-Guo
JG
Owens
A Phillip
AP
Williams
Julie
J
Antoniak
Silvio
S
Tencati
Michael
M
Luther
Thomas
T
Rowley
Jesse W
JW
Low
Elizabeth N
EN
Weyrich
Andrew S
AS
Mackman
Nigel
N
D000818:Animals; D000990:Antithrombin III / Q000032:analysis; D001777:Blood Coagulation / Q000502:physiology*; D001792:Blood Platelets / Q000378:metabolism; D002478:Cells, Cultured; D004211:Disseminated Intravascular Coagulation / Q000209:etiology / Q000503:physiopathology; D042783:Endothelial Cells / Q000378:metabolism; D019446:Endotoxemia / Q000097:blood / Q000503:physiopathology*; D017353:Gene Deletion; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000032:analysis; D012322:RNA Precursors / Q000096:biosynthesis / Q000097:blood; D012333:RNA, Messenger / Q000096:biosynthesis / Q000097:blood; D011828:Radiation Chimera; D013045:Species Specificity; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D008070:Lipopolysaccharides; D012322:RNA Precursors; D012333:RNA, Messenger; C046193:antithrombin III-protease complex; C440499:lipopolysaccharide, Escherichia coli O111 B4; D000990:Antithrombin III; D013925:Thromboplastin; D010447:Peptide Hydrolases
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