Inhibition of plasmin activity by tranexamic acid does not influence inflammatory pathways during human endotoxemia.
OBJECTIVE
Plasmin activates several proinflammatory pathways at the cellular level in vitro. Lipopolysaccharide (LPS) administration to healthy humans results in a rapid generation of plasmin activity, accompanied by activation of a number of inflammatory systems.


RESULTS
To determine the role of early plasmin activity in LPS-induced inflammation in vivo, 16 healthy males received an intravenous bolus injection with LPS (from Escherichia coli, 4 ng/kg) directly preceded by a 30-minute intravenous infusion of tranexamic acid (2 g, n=8), a plasmin activation inhibitor, or placebo (n=8). LPS injection induced marked increases in the plasma levels of D-dimer and plasmin-alpha2-antiplasmin complexes, indicative of plasmin activation and generation, respectively, which were strongly attenuated by tranexamic acid (both P<0.01 versus placebo). However, tranexamic acid did not influence LPS-induced coagulation activation, granulocytosis, neutrophil activation (expression of CD11b, CD66b, and L-selectin) or degranulation (plasma concentrations of elastase-alpha1-antitrypsin and bactericidal permeability-increasing protein), endothelial cell activation (plasma levels of von Willebrand factor and soluble E-selectin), or cytokine release.


CONCLUSIONS
These data argue against a role of early plasmin generation in the subsequent activation of other inflammatory pathways during human endotoxemia.
Renckens
Rosemarijn
R
Laboratory of Experimental Internal Medicine, Tropical Medicine & AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. r.renckens@amc.uva.nl
Weijer
Sebastiaan
S
de Vos
Alex F
AF
Pater
Jennie M
JM
Meijers
Joost C
JC
Hack
C Erik
CE
Levi
Marcel
M
van der Poll
Tom
T
D000328:Adult; D000990:Antithrombin III / Q000032:analysis; D001667:Binding, Competitive; D015415:Biomarkers; D016207:Cytokines / Q000097:blood; D019446:Endotoxemia / Q000097:blood*; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005341:Fibrinolysin / Q000096:biosynthesis*; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D010446:Peptide Fragments / Q000032:analysis; D010447:Peptide Hydrolases / Q000032:analysis; D010958:Plasminogen / Q000378:metabolism*; D011516:Prothrombin / Q000032:analysis; D014148:Tranexamic Acid / Q000494:pharmacology*
D015415:Biomarkers; D016207:Cytokines; D005338:Fibrin Fibrinogen Degradation Products; D008070:Lipopolysaccharides; D010446:Peptide Fragments; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; C045879:prothrombin fragment 1.2; D014148:Tranexamic Acid; D000990:Antithrombin III; D011516:Prothrombin; D010958:Plasminogen; D010447:Peptide Hydrolases; D005341:Fibrinolysin