Tissue factor promotes activation of coagulation and inflammation in a mouse model of sickle cell disease.
Sickle cell disease (SCD) is associated with a complex vascular pathophysiology that includes activation of coagulation and inflammation. However, the crosstalk between these 2 systems in SCD has not been investigated. Here, we examined the role of tissue factor (TF) in the activation of coagulation and inflammation in 2 different mouse models of SCD (BERK and Townes). Leukocytes isolated from BERK mice expressed TF protein and had increased TF activity compared with control mice. We found that an inhibitory anti-TF antibody abrogated the activation of coagulation but had no effect on hemolysis or anemia. Importantly, inhibition of TF also attenuated inflammation and endothelial cell injury as demonstrated by reduced plasma levels of IL-6, serum amyloid P, and soluble vascular cell adhesion molecule-1. In addition, we found decreased levels of the chemokines MCP-1 and KC, as well as myeloperoxidase in the lungs of sickle cell mice treated with the anti-TF antibody. Finally, we found that endothelial cell-specific deletion of TF had no effect on coagulation but selectively attenuated plasma levels of IL-6. Our data indicate that different cellular sources of TF contribute to activation of coagulation, vascular inflammation, and endothelial cell injury. Furthermore, it appears that TF contributes to these processes without affecting intravascular hemolysis.
Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, NC 27599, USA.
Pichika
P
Chantrathammachart
Nigel
N
Mackman
Erica
E
Sparkenbaugh
Jian-Guo
JG
Wang
Leslie V
LV
Parise
Daniel
D
Kirchhofer
Nigel S
NS
Key
Rafal
R
Pawlinski
D000755:Anemia, Sickle Cell / Q000097:blood / Q000276:immunology*; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D018932:Chemokine CCL2 / Q000097:blood; D054360:Chemokine CXCL1 / Q000097:blood; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000502:physiology; D005260:Female; D006461:Hemolysis / Q000502:physiology; D007249:Inflammation / Q000097:blood / Q000276:immunology*; D015850:Interleukin-6 / Q000097:blood; D007962:Leukocytes / Q000276:immunology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology; D000683:Serum Amyloid P-Component / Q000378:metabolism; D013925:Thromboplastin / Q000276:immunology* / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D015850:Interleukin-6; D000683:Serum Amyloid P-Component; D019010:Vascular Cell Adhesion Molecule-1; D013925:Thromboplastin