Receptor controlling tissue-factor-dependent thrombosis identified
MedWire News: Researchers have identified a receptor that is essential to regulation of tissue factor (TF) production in thrombosis.
Wolfram Ruf (Scripps Research Institute, La Jolla, California, USA) and colleagues explain that in the traditional model of thrombosis, damage to smooth muscle cells in vessel walls exposes TF to blood flow and initiates clotting.
The new findings suggests that "TF exists on the surfaces of these smooth muscle cells, as well as on circulating immune cells, but in an inactive state," comments Ruf and team.
Other research has suggested that the activation of TF is at least partly controlled by the oxidoreductase protein, disulfide isomerase.
For the current study, Ruf and co-workers looked for factors that regulate TF activity in cultured mouse myeloid cells and transgenic mouse models.
The research focused on the purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7 receptor), which has previously been implicated in thrombus formation via TF.
The investigators report that cellular signaling by ATP via the P2X7 receptor caused TF to change from an inactive to an active, procoagulant form as well as increasing the release of TF-positive microparticles from macrophages and smooth muscle cells. They also found that the release of procoagulant microparticles could be reduced by treatment with an antibody against disulfide isomerase.
Further research revealed that the production of prothrombotic microparticles was dependent on production of inflammatory reactive oxygen species via the P2X7 receptor. Indeed, mice lacking the gene for the P2X7 receptor were protected from TF-dependent carotid artery thrombosis. Of note, treatment with a second anti-disulfide isomerase antibody restored TF-dependent thrombosis in mice without the receptor.
"In the present study, we showed that the P2X7 receptor is crucial for TF activation and release on microparticles from myeloid cells as well as for the release of pro-coagulant microparticles from smooth muscle cells," conclude the investigators in the Journal of Clinical Investigation.
Commenting on the potential clinical applications of their work, the authors suggest that "targeting the P2X7 receptor may represent an unconventional approach to anti-coagulant therapy that disables prothrombotic TF activation, instead of neutralizing coagulation proteases, while disarming unregulated local inflammatory reactions."
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By Philip Ford