Abstract
Platelet-driven reduction in blood clot volume (clot contraction or retraction) has been implicated to play a role in hemostasis and thrombosis. Although these processes are often linked with inflammation, the role of inflammatory cells in contraction of blood clots and thrombi has not been investigated. The aim of this work was to study the influence of activated monocytes on clot contraction. The effects of monocytes were evaluated using a quantitative optical tracking methodology to follow volume changes in a blood clot formed in vitro. When a physiologically relevant number of isolated human monocytes pre-activated with phorbol-12-myristate-13-acetate (PMA) were added back into whole blood, the extent and rate of clot contraction were increased compared to addition of non-activated cells. Inhibition of tissue factor expression or its inactivation on the surface of PMA-treated monocytes reduced the extent and rate of clot contraction back to control levels with non-activated monocytes. On the contrary, addition of tissue factor enhanced clot contraction, mimicking the effects of tissue factor expressed on the activated monocytes. These data suggest that the inflammatory cells through their expression of tissue factor can directly affect hemostasis and thrombosis by modulating the size and density of intra- and extravascular clots and thrombi.
Highlights
Blood cells and vascular endothelial cells that come in direct contact with the circulating blood do not express TF under normal physiological conditions
Since monocytes are incorporated into clots and thrombi, we hypothesized that monocytes have the potential to influence the rate and extent of clot contraction by direct or indirect cooperation with platelets[32]
PMA-activated monocytes added to whole blood were found to enhance the extent and velocity of clot contraction (Fig. 1A–C) when compared to monocytes that had not been activated with PMA
Summary
Blood cells and vascular endothelial cells that come in direct contact with the circulating blood do not express TF under normal physiological conditions. As is observed in angioplasty, exposure of cellular and extracellular TF to the circulating blood plays a pivotal role in mediating fibrin-rich thrombus formation leading to acute coronary syndromes[30]. Despite ample evidence for the critical importance of monocyte-expressed TF in thrombosis, the role of inflammatory cells bearing TF in the remodeling of blood clots has never been studied. The novelty of our work is the effects of activated monocytes mediated by TF on clot contraction These data motivate a need to test the role of activated monocytes as modulators of clot contraction, which may be a pathogenic factor that regulates local blood flow and potentially affects the course and outcomes of ischemic tissue damage. We hypothesize that activated monocytes enhance the process of clot contraction, which may suggest an additional pathophysiologic mechanism of shrinkage of a hemostatic clot or obstructive thrombus in inflammatory conditions with important pathogenic consequences
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