Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms

Platelets. 2009 Feb;20(1):50-7. doi: 10.1080/09537100802503368.

Abstract

Platelet activation contributes to microvascular thrombosis and organ failure in systemic inflammation. We tested the hypothesis whether anti-platelet drugs might favourably affect outcome in patients at risk for organ failure as well as in a mouse model of endotoxin shock. Two hundred twenty-four consecutive patients who were admitted for community acquired pneumonia over a time period of 5 years to a University Hospital were enrolled; about 20% of whom received anti-platelet drugs (acetylsalicylic acid, thienopyridines) for secondary prevention of cardiovascular disease. Patients with anti-platelet drugs were about 12 years old but did not differ in SOFA score and routine laboratory parameters at admission. Logistic regression and 2 x 2 table analysis in age-matched subgroups indicated that anti-platelet drugs may reduce the need of intensive care treatment (odds ratio (OR) 0.32 [95% confidential interval: 0.10-1.00] and 0.19 [0.04-0.87], respectively). In age-matched subgroups, the use of anti-platelet drugs was also associated with a shorter stay in hospital (13.9 +/- 6.2 vs. 18.2 +/- 10.2 days; p < 0.02). In the animal model Balb/c mice were pre-treated with clopidogrel (added to drinking water) for 4 days prior to intraperitoneal (i.p.) administration of endotoxin (lipopolsaccharide (LPS) from Escherichia coli 0111:B4). Within the first 48 hours after LPS there were no differences between clopidogrel and control animals (n = 26 each) in macro-haemodynamics. However, clopidogrel abolished the LPS-induced drop in platelet count and reduced fibrin deposition in lung tissue. Using DNA microarray technology, we could show that clopidogrel suppressed endotoxin-induced up-regulation of inflammation-relevant genes, including arachidonate-5-lipoxygenase activating protein and leukotriene B4 receptor 1. According to our data a possible benefit of anti-platelet drugs in patients on risk for systemic inflammation and organ failure should be tested in a prospective trial.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cell Line
  • Clopidogrel
  • Female
  • Fibrin / metabolism
  • Gene Expression Profiling
  • Hemodynamics / drug effects
  • Humans
  • Infections / drug therapy*
  • Infections / pathology
  • Intensive Care Units / statistics & numerical data
  • Length of Stay / statistics & numerical data
  • Leukocytes / cytology
  • Leukocytes / drug effects
  • Leukocytes / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Platelet Activation / drug effects
  • Platelet Aggregation Inhibitors / pharmacology
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Pneumonia / diagnosis
  • Pneumonia / drug therapy
  • Retrospective Studies
  • Shock, Septic / metabolism
  • Shock, Septic / prevention & control*
  • Ticlopidine / analogs & derivatives
  • Ticlopidine / pharmacology
  • Ticlopidine / therapeutic use

Substances

  • Platelet Aggregation Inhibitors
  • Fibrin
  • Clopidogrel
  • Ticlopidine