Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall

Abstract

Leukocytes and leukocyte-derived micro-particles contain low levels of tissue factor (TF) and incorporate into forming thrombi. Although this circulating pool of TF has been proposed to play a key role in thrombosis, its functional significance relative to that of vascular wall TF is poorly defined. We tested the hypothesis that leukocyte-derived TF contributes to thrombus formation in vivo. Compared to wild-type mice, mice with severe TF deficiency (ie, TF / , hTF-Tg , or "low-TF") demonstrated markedly impaired throm-bus formation after carotid artery injury or inferior vena cava ligation. A bone marrow transplantation strategy was used to modulate levels of leukocyte-derived TF. Transplantation of low-TF marrow into wild-type mice did not suppress arterial or venous thrombus formation. Similarly, transplantation of wild-type marrow into low-TF mice did not accelerate thrombosis. In vitro analyses revealed that TF activity in the blood was very low and was markedly exceeded by that present in the vessel wall. Therefore, our results suggest that thrombus formation in the arterial and venous macrovasculature is driven primarily by TF derived from the blood vessel wall as opposed to leuko-cytes. (Blood. 2005;105:192-198)

Histone Deacetylase Inhibitors Suppress TF-κB-dependent Agonist-driven Tissue Factor Expression in Endothelial Cells and Monocytes

“…The circulating pool of TF, derived almost exclusively from monocytes and monocyte-derived microparticles, plays an important role in thrombus propagation by sustaining thrombin production on the clot surface (65). Vessel wall-derived TF plays roles in thrombus initiation immediately after vessel wall damage, especially in the macrovascular system (66). Of note, previous studies found that the HDACi TSA (67) and butyrate (67-69) increase expression of tissue-type plasminogen activator, a key activator of fibrinolysis, in HUVEC (67,69) and human peritoneal mesothelial cells (68).…”

“…This, in turn, suggests the possibility that HDACi, particularly TSA, could decrease aberrant TF expression in thrombotic diseases as well as in inflammatory/thrombotic states such as sepsis. Both vessel wall-derived TF and the circulating leukocyte-associated pool of TF participate in thrombus formation (65,66). The circulating pool of TF, derived almost exclusively from monocytes and monocyte-derived microparticles, plays an important role in thrombus propagation by sustaining thrombin production on the clot surface (65).…”

Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

“…Besides its effects on TF and TFPI, guggulsterone downregulated PAI-1 expression both in quiescent and TNF-a stimulated cells; hence, guggulsterone may be particularly beneficial in patients with diabetes mellitus. Photochemical injury was selected for examining thrombus formation because it is an established protocol for TF-dependent arterial thrombosis in vivo [5,7,8]. Guggulsterone inhibited thrombotic occlusion, indicating that it may protect from thrombus formation.…”

A Mathematical Model of Venous Thrombosis Initiation

“…However, the source of TF in VT remains unclear. For some animal studies (28), TF from the vascular wall was shown to be essential, but these studies involved some EC denudation and exposure of subendothelium (as in arterial thrombosis). In studies with the new mouse model, the vessel wall is intact (13) and compelling evidence has been obtained that the essential TF came from leukocytes, primarily monocytes, and from monocyte-derived microparticles (MPs) and that vessel wall TF played an insignificant role in this setting (9).…”