title: Temporally and regionally disparate differences in plasmin activity by tranexamic acid.
abstract: BACKGROUND
  A major complication associated with cardiac surgery is excessive and prolonged bleeding in the perioperative period. Improving coagulation by inhibiting fibrinolysis, primarily through inhibition of plasmin activity (PLact) with antifibrinolytics such as tranexamic acid (TXA), has been a pharmacological mainstay in cardiac surgical patients. Despite its almost ubiquitous use, the temporal and regional modulation of PLact profiles by TXA remains unexplored. Accordingly, we developed a fluorogenic-microdialysis system to measure in vivo dynamic changes in PLact after TXA administration in a large animal model.
  
  
  METHODS
  Pigs (25-35 kg) were randomly assigned to receive TXA (30 mg/kg, diluted into 50 mL normal saline; n = 9) or vehicle (50 mL normal saline; n = 7). Microdialysis probes were placed in the liver, myocardium, kidney, and quadriceps muscle compartments. The microdialysate infusion contained a validated plasmin-specific fluorogenic peptide. The fluorescence emission (standard fluorogenic units [SFU]) of the interstitial fluid collected from the microdialysis probes, which directly reflects PLact, was determined at steady-state baseline and 30, 60, 90, and 120 min after TXA/vehicle infusion. Plasma PLact was determined at the same time points using the same fluorogenic substrate approach.
  
  
  RESULTS
  TXA reduced plasma PLact at 30 min after infusion by >110 SFU compared with vehicle values (P < 0.05). Specifically, there was a decrease in liver PLact at 90 and 120 min after TXA infusion of >150 SFU (P < 0.05) and 175 SFU (P < 0.05), respectively. The decrease in liver PLact occurred 60 min after the maximal decrease in plasma PLact. In contrast, kidney, heart, and quadriceps PLact transiently increased followed by an overall decrease at 120 min.
  
  
  CONCLUSIONS
  Using a large animal model and in vivo microdialysis measurements of PLact, the unique findings from this study were 2-fold. First, TXA induced temporally distinct PLact profiles within the plasma and selected interstitial compartments. Second, TXA caused region-specific changes in PLact profiles. These temporal and regional differences in the effects of TXA may have important therapeutic considerations when managing fibrinolysis in the perioperative period.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Medical University of South Carolina, Charleston, SC 29403, USA.
authors.forename: Daryl L
authors.initials: DL
authors.lastname: Reust
authors.forename: Scott T
authors.initials: ST
authors.lastname: Reeves
authors.forename: James H
authors.initials: JH
authors.lastname: Abernathy
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Dixon
authors.forename: William F
authors.initials: WF
authors.lastname: Gaillard
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Christine N
authors.initials: CN
authors.lastname: Koval
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stroud
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005341:Fibrinolysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D052097:Quadriceps Muscle / Q000187:drug effects / Q000378:metabolism; D015203:Reproducibility of Results; D013050:Spectrometry, Fluorescence; D013552:Swine; D013997:Time Factors; D014148:Tranexamic Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000933:Antifibrinolytic Agents; D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D; D014148:Tranexamic Acid; D005341:Fibrinolysin