Computational model of tranexamic acid on urokinase mediated fibrinolysis

PLoS One. 2020 May 26;15(5):e0233640. doi: 10.1371/journal.pone.0233640. eCollection 2020.

Abstract

Understanding the coagulation process is critical to developing treatments for trauma and coagulopathies. Clinical studies on tranexamic acid (TXA) have resulted in mixed reports on its efficacy in improving outcomes in trauma patients. The largest study, CRASH-2, reported that TXA improved outcomes in patients who received treatment prior to 3 hours after the injury, but worsened outcomes in patients who received treatment after 3 hours. No consensus has been reached about the mechanism behind the duality of these results. In this paper we use a computational model for coagulation and fibrinolysis to propose that deficiencies or depletions of key anti-fibrinolytic proteins, specifically antiplasmin, a1-antitrypsin and a2-macroglobulin, can lead to worsened outcomes through urokinase-mediated hyperfibrinolysis.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antifibrinolytic Agents / therapeutic use
  • Blood Coagulation / genetics
  • Blood Coagulation Disorders / blood
  • Blood Coagulation Disorders / drug therapy*
  • Blood Coagulation Disorders / genetics
  • Blood Coagulation Disorders / pathology
  • Computer Simulation
  • Fibrin / genetics
  • Fibrin Clot Lysis Time
  • Fibrinolysin / genetics
  • Fibrinolysis / drug effects
  • Hemorrhage / blood
  • Hemorrhage / drug therapy
  • Hemorrhage / genetics
  • Humans
  • Membrane Proteins / genetics
  • Mortality
  • Pregnancy-Associated alpha 2-Macroglobulins / genetics
  • Thrombin / genetics
  • Thrombin / metabolism
  • Tranexamic Acid / therapeutic use*
  • Urokinase-Type Plasminogen Activator / genetics*
  • Wounds and Injuries / blood
  • Wounds and Injuries / drug therapy*
  • Wounds and Injuries / genetics
  • Wounds and Injuries / pathology
  • alpha 1-Antitrypsin / genetics

Substances

  • Antifibrinolytic Agents
  • Membrane Proteins
  • PLAU protein, human
  • Pregnancy-Associated alpha 2-Macroglobulins
  • alpha 1-Antitrypsin
  • Tranexamic Acid
  • Fibrin
  • Thrombin
  • Fibrinolysin
  • Urokinase-Type Plasminogen Activator

Grants and funding

This material is based upon work supported by the US Army Contracting Command, Aberdeen Proving Ground, Natick Contracting Division under Contract No. W911QY-15-C-0026. Funding was granted to Linda Petzold (LP). The funders had no role in study design, analysis, decision to publish, or preparation of the manuscript.