Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms.
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.
Winning
Johannes
J
Anaesthesiology and Intensive Care Medicine, University Hospital Jena, Jena, Germany.
Reichel
Julia
J
Eisenhut
Yvonne
Y
Hamacher
Jürg
J
Kohl
Matthias
M
Deigner
Hans Peter
HP
Claus
Ralf A
RA
Bauer
Michael
M
Lösche
Wolfgang
W
D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D000077144:Clopidogrel; D005260:Female; D005337:Fibrin / Q000378:metabolism; D020869:Gene Expression Profiling; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007239:Infections / Q000188:drug therapy* / Q000473:pathology; D007362:Intensive Care Units / Q000706:statistics & numerical data; D007902:Length of Stay / Q000706:statistics & numerical data; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011014:Pneumonia / Q000175:diagnosis / Q000188:drug therapy; D012189:Retrospective Studies; D012772:Shock, Septic / Q000378:metabolism / Q000517:prevention & control*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D010975:Platelet Aggregation Inhibitors; D005337:Fibrin; D000077144:Clopidogrel; D013988:Ticlopidine