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Pharmacological modulation of procoagulant microparticles improves haemodynamic dysfunction during septic shock in rats.

Abstract：

:Circulating microparticles play a pro-inflammatory and procoagulant detrimental role in the vascular dysfunction of septic shock. It was the objective of this study to investigate mechanisms by which a pharmacological modulation of microparticles could affect vascular dysfunction in a rat model of septic shock. Septic or sham rats were treated by activated protein C (aPC) and resuscitated during 4 hours. Their microparticles were harvested and inoculated to another set of healthy recipient rats. Haemodynamic parameters were monitored, circulating total procoagulant microparticles assessed by prothrombinase assay, and their cell origin characterised. Mesenteric resistance arteries, aorta and heart were harvested for western blotting analysis. We found that a) the amount and phenotype of circulating microparticles were altered in septic rats with an enhanced endothelial, leucocyte and platelet contribution; b) aPC treatment significantly reduced the generation of leucocyte microparticles and norepinephrine requirements to reach the mean arterial pressure target in septic rats; c) Microparticles from untreated septic rats, but not from aPC-treated ones, significantly reduced the healthy recipients' mean arterial pressure; d) Microparticle thromboxane content and aPC activity were significantly increased in aPC-treated septic rats. In inoculated naïve recipients, microparticles from aPC-treated septic rats prompted reduced NF-κB and cyclooxygenase-2 arterial activation, blunted the generation of pro-inflammatory iNOS and secondarily increased platelet and endothelial microparticles. In conclusion, in this septic shock model, increased circulating levels of procoagulant microparticles led to negative haemodynamic outcomes. Pharmacological treatment by aPC modified the cell origin and levels of circulating microparticles, thereby limiting vascular inflammation and favouring haemodynamic improvement.

journal_name

Thromb Haemost

journal_title

Thrombosis and haemostasis

authors

Boisramé-Helms J,Delabranche X,Degirmenci SE,Zobairi F,Berger A,Meyer G,Burban M,Mostefai HA,Levy B,Toti F,Meziani F

doi

10.1160/TH13-04-0313

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

154-64

issue

eissn

0340-6245

issn

2567-689X

pii

13-04-0313

journal_volume

111

pub_type

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Pharmacological modulation of procoagulant microparticles improves haemodynamic dysfunction during septic shock in rats.