Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia

Abstract

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) wholeblood 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. (Blood. 2004;103:4545-4553)

Microparticles in endothelial cell and vascular homeostasis: are they really noxious?

“…Volunteers receiving an infusion of endotoxin exhibited an early increase in tissue factor + -microparticles and to a lesser extent of EMP. 28 Beneficial effects of microparticles in patients with septic shock were more recently suggested by Soriano et al 29 In their study, lower levels of endothelial, platelet and leukocytederived microparticles were associated with higher mortality rates and organ dysfunction. In septic shock, vascular hyporeactivity together with tissue hypoperfusion and hypoxia account for severe hypotension enabling amplification of the shock.…”

Tissue Factor and Cardiovascular Disease: Quo Vadis?

“…56,58 In addition, activated ECs release TF-containing MPs, which could potentially be transferred to platelets as well. 59,60 Recent studies confirmed the possibility for true de novo TF protein expression in platelets upon stimulation by using metabolic radiolabeling. 54 ADP, a potent inducer of platelet activation, enhanced platelet TF activity.…”

Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis

“…TF is expressed by subendothelial cells that are not normally exposed to the circulating blood, but disruption of vascular integrity exposes TF and initiates the coagulation cascade (35). Inflammatory mediators and LPS induce the expression of TF on endothelial and polymorphonuclear cells and platelets, thereby increasing blood thrombogenicity (36,37).…”