Application of a plasmin generation assay to define pharmacodynamic effects of tranexamic acid in women undergoing cesarean delivery.

Abstract

Essentials Tranexamic acid (TXA) is an antifibrinolytic drug used to reduce bleeding. Assaying plasmin generation (PG) in plasma detects clinically relevant TXA levels in vitro and ex vivo. 3.1-16.2 µg/mL TXA half-maximally inhibits PG in plasma from women undergoing cesarean delivery. PG velocity shows the strongest dose-relationship at low TXA concentrations (≤10 µg/mL). ABSTRACT: Background Tranexamic acid (TXA) is used to reduce bleeding. TXA inhibits plasmin(ogen) binding to fibrin and reduces fibrinolysis. TXA antifibrinolytic activity is typically measured by clot lysis assays; however, effects on plasmin generation (PG) are unclear due to a lack of tools to measure PG in plasma. Aims Develop an assay to measure PG kinetics in human plasma. Determine effects of TXA on PG and compare with fibrinolysis measured by rotational thromboelastometry (ROTEM). Methods We characterized effects of plasminogen, tissue plasminogen activator, fibrinogen, and α2 -antiplasmin on PG in vitro. We also studied effects of TXA on PG in plasma from 30 pregnant women administered intravenous TXA (5, 10, or 15 mg/kg) during cesarean delivery. PG was measured by calibrated fluorescence. PG parameters were compared with TXA measured by mass spectrometry and ROTEM of whole blood. Results The PG assay is specific for plasmin and sensitive to tissue plasminogen activator, fibrin(ogen), and α2 -antiplasmin. Addition of TXA to plasma in vitro dose dependently prolonged the clot lysis time and delayed and reduced PG. For all doses of TXA administered intravenously, the PG assay detected delayed time-to-peak (≤3 hours) and reduced the velocity, peak, and endogenous plasmin potential (≤24 hours) in plasma samples obtained after infusion. The PG time-to-peak, velocity, and peak correlated significantly with TXA concentration and showed less variability than the ROTEM lysis index at 30 minutes or maximum lysis. Conclusions The PG assay detects pharmacologically relevant concentrations of TXA administered in vitro and in vivo, and demonstrates TXA-mediated inhibition of PG in women undergoing cesarean delivery.

• Authors: Adam Miszta, Homa K Ahmadzia, Naomi L C Luban, Shuhui Li, Dong Guo, Lori A Holle, Jeffrey S Berger, Andra H James, Jogarao V S Gobburu, John van den Anker, Bas de Laat, Alisa S Wolberg
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 19 Issue 1 Pg. 221-232 (01 2021) ISSN: 1538-7836 [Electronic] England
• PMID: 33001565 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2020 International Society on Thrombosis and Haemostasis.

Chemical References

• Antifibrinolytic Agents
• Tranexamic Acid
• Tissue Plasminogen Activator
• Fibrinolysin

Topics

• Antifibrinolytic Agents (pharmacology)
• Cesarean Section
• Female
• Fibrinolysin (pharmacology)
• Fibrinolysis
• Humans
• Pregnancy
• Tissue Plasminogen Activator (pharmacology)
• Tranexamic Acid (pharmacology)