Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia.
The precise role of intravascular tissue factor (TF) remains poorly defined, due to the limited availability of assays capable of measuring circulating TF procoagulant activity (PCA). As a model of inflammation-associated intravascular thrombin generation, we studied 18 volunteers receiving an infusion of endotoxin. A novel assay that measures microparticle (MP)-associated TF PCA from a number of cellular sources (but not platelets) demonstrated an 8-fold increase in activity at 3 to 4 hours after endotoxin administration (P <.001), with a return to baseline by 8 hours. TF antigen-positive MPs isolated from plasma were visualized by electron microscopy. Interindividual MP-associated TF response to lipopolysaccharide (LPS) was highly variable. In contrast, a previously described assay that measures total (cell and MP-borne) whole-blood TF PCA demonstrated a more modest increase, with a peak in activity (1.3-fold over baseline; P <.000 01) at 3 to 4 hours, and persistence for more than 24 hours. This surprisingly modest increase in whole-blood TF activity is likely explained by a profound although transient LPS-induced monocytopenia. MP-associated TF PCA was highly correlated with whole-blood TF PCA and total number of circulating MPs, and whole-blood TF PCA was highly correlated with TF mRNA levels.
Departments of Medicine (Hematology, Oncology and Transplantation) and Vascular Biology Center, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Omer
O
Aras
Arun
A
Shet
Ronald R
RR
Bach
Jessica L
JL
Hysjulien
Arne
A
Slungaard
Robert P
RP
Hebbel
Gines
G
Escolar
Bernd
B
Jilma
Nigel S
NS
Key
D000328:Adult; D001779:Blood Coagulation Factors / Q000187:drug effects / Q000378:metabolism; D015992:Body Mass Index; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D019446:Endotoxemia / Q000097:blood*; D004731:Endotoxins / Q000633:toxicity; D004926:Escherichia coli; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008833:Microcirculation; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D013925:Thromboplastin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014471:Umbilical Veins
D001779:Blood Coagulation Factors; D004731:Endotoxins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C045071:leukocyte procoagulant activity; D013925:Thromboplastin