The clinical and functional relevance of microparticles induced by activated protein C treatment in sepsis
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Published on: August 4, 2023
Margarita Pérez-Casal1, Victoria Thompson, Colin Downey
1Roald Dahl Haemostasis and Thrombosis Centre, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK.
Introduction:
Activated protein C (APC) induces release of microparticles (MP) from primary physiological cells, which are found in patients undergoing treatment with recombinant human APC (rhAPC) for severe sepsis. We hypothesised that APC on these circulating MPs activate endothelial protease-activated receptor 1 (PAR1) to induce anti-apoptotic and anti-inflammatory properties that can improve patient outcome.
Methods:
This was an experimental study on clinical samples in an intensive care setting, and included patients with severe sepsis who fulfilled criteria for treatment with rhAPC. The number of CD13+ MPs from the patients were analysed to determine their origin. They were also quantified for endothelial protein C receptor (EPCR) and APC expression. Clinical relevance of these MPs were ascertained by comparing survival between the group receiving rhAPC (n = 25) and a control group of untreated patients (n = 25). MPs were also incubated with endothelial cells to analyse apoptotic gene expression, cytoprotection and anti-inflammatory effects.
Results:
rhAPC treatment induced a significant increase in circulating MP-associated EPCR by flow cytometry (P < 0.05) and by quantitative ELISA (P < 0.005). APC expression also showed significant increases (P < 0.05). Numerically, CD13+ MPs were higher in rhAPC-treated survivors versus non-survivors. However, the number of non-survivors was low and this was not significantly different. APC on MPs was demonstrated to induce anti-apoptotic and endothelial barrier effects through the activation of endothelial PAR1.
Conclusions:
rhAPC treatment in patients with sepsis significantly increases circulating EPCR + MPs. These MPs were noted to express APC, which has specific anti-apoptotic and anti-inflammatory effects, with a non-significant correlative trend towards survival. This suggests that MPs could disseminate APC function and activate endothelial PAR1 at distal vascular sites.
Insights
Recombinant human activated protein C (rhAPC) treatment increases microparticles (MPs) expressing EPCR and APC in sepsis patients. These MPs activate endothelial PAR1, offering anti-apoptotic and anti-inflammatory benefits, potentially improving outcomes.
Area of Science:
- Biochemistry and Molecular Biology
- Critical Care Medicine
- Hematology
Background:
- Activated protein C (APC) is administered as recombinant human APC (rhAPC) for severe sepsis.
- APC induces microparticle (MP) release from physiological cells.
- Circulating MPs may carry APC to activate endothelial protease-activated receptor 1 (PAR1), conferring protective effects.
Purpose of the Study:
- To investigate if APC on circulating MPs activates endothelial PAR1.
- To determine if this activation confers anti-apoptotic and anti-inflammatory properties.
- To assess the clinical relevance of these MPs in severe sepsis patients.
Main Methods:
- Analysis of CD13+ MPs from severe sepsis patients treated with rhAPC versus controls.
- Quantification of endothelial protein C receptor (EPCR) and APC expression on MPs.
- Incubation of MPs with endothelial cells to assess gene expression, cytoprotection, and anti-inflammatory effects.
Main Results:
- rhAPC treatment significantly increased circulating MP-associated EPCR and APC expression.
- APC on MPs demonstrated anti-apoptotic and endothelial barrier effects via PAR1 activation.
- A trend towards improved survival was observed in rhAPC-treated survivors, though not statistically significant due to small sample size.
Conclusions:
- rhAPC treatment in sepsis patients significantly increases circulating EPCR+ MPs expressing APC.
- These MPs exert anti-apoptotic and anti-inflammatory effects by activating endothelial PAR1.
- MPs may serve as a mechanism to disseminate APC function to distal vascular sites.
