title: The clinical and functional relevance of microparticles induced by activated protein C treatment in sepsis.
abstract: BACKGROUND
  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.
authors.affiliation: Roald Dahl Haemostasis and Thrombosis Centre, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK.
authors.forename: Margarita
authors.initials: M
authors.lastname: Pérez-Casal
authors.forename: Victoria
authors.initials: V
authors.lastname: Thompson
authors.forename: Colin
authors.initials: C
authors.lastname: Downey
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Welters
authors.forename: Duncan
authors.initials: D
authors.lastname: Wyncoll
authors.forename: Jecko
authors.initials: J
authors.lastname: Thachil
authors.forename: Cheng Hock
authors.initials: CH
authors.lastname: Toh
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001779:Blood Coagulation Factors / Q000494:pharmacology* / Q000627:therapeutic use; D055252:Cell-Derived Microparticles / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology; D012720:Severity of Illness Index; D016019:Survival Analysis
chemical_list: D000890:Anti-Infective Agents; D001779:Blood Coagulation Factors; D011486:Protein C; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C091963:activated protein C receptor; C421124:drotrecogin alfa activated