Functional Testing for Tranexamic Acid Duration of Action Using Modified Viscoelastometry

Abstract

Introduction: Tranexamic acid (TXA) is the standard medication to prevent or treat hyperfibrinolysis. However, prolonged inhibition of lysis (so-called "fibrinolytic shutdown") correlates with increased mortality. A new viscoelastometric test enables bedside quantification of the antifibrinolytic activity of TXA using tissue plasminogen activator (TPA).

Materials and methods: Twenty-five cardiac surgery patients were included in this prospective observational study. In vivo, the viscoelastometric TPA test was used to determine lysis time (LT) and maximum lysis (ML) over 96 h after TXA bolus. Additionally, plasma concentrations of TXA and plasminogen activator inhibitor 1 (PAI-1) were measured. Moreover, dose effect curves from the blood of healthy volunteers were performed in vitro. Data are presented as median (25-75th percentile).

Results: In vivo TXA plasma concentration correlated with LT (r = 0.55; p < 0.0001) and ML (r = 0.62; p < 0.0001) at all time points. Lysis was inhibited up to 96 h (LT_TPA-test: baseline: 398 s [229-421 s] vs. at 96 h: 886 s [626-2,175 s]; p = 0.0013). After 24 h, some patients (n = 8) had normalized lysis, but others (n = 17) had strong lysis inhibition (ML <30%; p < 0.001). The high- and low-lysis groups differed regarding kidney function (cystatin C: 1.64 [1.42-2.02] vs. 1.28 [1.01-1.52] mg/L; p = 0.002) in a post hoc analysis. Of note, TXA plasma concentration after 24 h was significantly higher in patients with impaired renal function (9.70 [2.89-13.45] vs.1.41 [1.30-2.34] µg/mL; p < 0.0001). In vitro, TXA concentrations of 10 µg/mL effectively inhibited fibrinolysis in all blood samples.

Conclusions: Determination of antifibrinolytic activity using the TPA test is feasible, and individual fibrinolytic capacity, e.g., in critically ill patients, can potentially be measured. This is of interest since TXA-induced lysis inhibition varies depending on kidney function.

Keywords: Cardiac surgery; Fibrinolysis shutdown; Hyperfibrinolysis; Thromboelastometry; Tranexamic acid; Viscoelastometry.

Fig. 1

In vivo thromboelastometric variables (median + IQR; n = 25) over time. A Tranexamic acid (TXA) plasma concentration. B Lysis time (LT_TPA-test) = time span between CT and 50% lysis. C Lysis onset time (LOT_TPA-test) = time span from clotting time to 15% lysis. D Maximum lysis (ML_TPA-test) = difference between MCF and lowest amplitude in % of MCF. * p < 0.05 vs. baseline (before TXA); ** p < 0.01 vs. baseline; *** p < 0.001 vs. baseline; **** p < 0.0001 vs. baseline.

Fig. 2

In vitro, dose-effect curves of thromboelastometric variables (median + IQR; n = 25) and increasing whole-blood concentrations of tranexamic acid (TXA). A Lysis time (LT_TPA-test) = time span between CT and 50% lysis. B Lysis onset time (LOT_TPA-test) = time span from clotting time to 15% lysis. C Maximum lysis (ML_TPA-test) = difference between MCF and lowest amplitude in % of MCF. * p < 0.05 vs. baseline (before TXA); ** p < 0.01 vs. baseline; *** p < 0.001 vs. baseline; **** p < 0.0001 vs. baseline.