Abstract
Tissue factor (TF) plays a central role in haemostasis and thrombosis. Following vascular damage, vessel wall TF initiates the extrinsic coagulation cascade. TF can also be exposed by monocytes. Inflammatory or infectious stimuli trigger synthesis of new TF protein by monocytes over the course of hours. It has also been suggested that monocytes can expose TF within minutes when stimulated by activated platelets. Here, we have confirmed that monocytes rapidly expose TF in whole blood and further demonstrate that platelet P-selectin exposure is necessary and sufficient. Monocyte TF exposure increased within five minutes in response to platelet activation by PAR1-AP, PAR4-AP or CRP-XL. PAR1-AP did not trigger TF exposure on isolated monocytes unless platelets were also present. In whole blood, PAR1-AP-triggered TF exposure required P-selectin and PGSL-1. In isolated monocytes, although soluble recombinant P-selectin had no effect, P-selectin coupled to 2 µm beads triggered TF exposure. Cycloheximide did not affect rapid TF exposure, indicating that de novo protein synthesis was not required. These data show that P-selectin on activated platelets rapidly triggers TF exposure on monocytes. This may represent a mechanism by which platelets and monocytes rapidly contribute to intravascular coagulation.
Highlights
Tissue factor (TF; CD142) plays a central role in haemostasis and thrombosis[1,2]
This increase in TF gene expression occurs over hours[12], so on-going TF gene expression in monocytes may contribute to increased thrombosis risk in inflammatory or infectious disease states, it may be less likely to contribute to rapid arterial thrombosis if it has not previously been triggered
We demonstrate that activated platelets can rapidly trigger surface exposure of TF in monocytes through P-selectin interaction with monocyte PSGL1 (Fig. 5e)
Summary
Tissue factor (TF; CD142) plays a central role in haemostasis and thrombosis[1,2]. TF is a transmembrane glycoprotein constitutively expressed in the adventitia of normal blood vessels[2]. Bacterial lipopolysaccharide (LPS), for example, induces increased expression of TF in monocytes[12] This is dependent on synthesis of new TF protein[13]. TF on the monocyte surface is often shed in extracellular vesicles known as microparticles[14] These circulating, TF-positive microparticles are likely to be the major source of blood-borne TF. There have been isolated reports that monocytes can expose TF on their surface much more rapidly, for example, within ten minutes (e.g.15). This has been observed in whole blood, where cells other than monocytes are present. Monocyte TF and platelet P-selectin are shown on the same axes for comparison of concentration-dependency of their effects
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