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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4545-4553.
Prepublished online as a Blood First Edition Paper on February 26, 2004; DOI 10.1182/blood-2003-03-0713.
Submitted March 6, 2003
Accepted February 18, 2004
Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia
Omer Aras, Arun Shet, Ronald R Bach, Jessica L Hysjulien, Arne Slungaard, Robert P Hebbel, Gines Escolar, Bernd Jilma, and Nigel S Key*
Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA; Vascular Biology Center, University of Minnesota, Minneapolis, MN, USA
Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA; Research Center, VA Medical Center, Minneapolis, MN, USA
Servicio de Hemoterapia-Hemostasia, Hospital Clinic, University of Barcelona, Barcelona, Spain
Clinical Pharmacology, TARGET, Vienna University Hospital, Vienna, Austria
* Corresponding author; email: keyxx001{at}umn.edu.
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 which measures microparticle (MP)-associated TF PCA from a number of cellular sources (but not platelets) demonstrated an eight-fold increase in activity at 3-4 hours after endotoxin administration (p < 0.001), with a return to baseline by 8 hours. TF antigen positive MPs isolated from plasma were visualized by electron microscopy. Inter-individual MP-associated TF response to 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 < 0.00001) at 3-4 hours, and persistence for > 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.
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