What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies

Roberto Picetti, Haleema Shakur-Still, Robert L Medcalf, Joseph F Standing, Ian Roberts, Roberto Picetti, Haleema Shakur-Still, Robert L Medcalf, Joseph F Standing, Ian Roberts

Abstract

: Intravenous tranexamic acid (TXA) reduces death because of bleeding in patients with trauma and postpartum haemorrhage. However, in some settings intravenous injection is not feasible. To find different routes of administration, we first need to determine the minimal concentration of TXA in the blood that is required to inhibit fibrinolysis.We conducted a systematic review of in-vitro and in-vivo pharmacodynamics studies. We searched MEDLINE, EMBASE, OviSP, and ISI Web of Science from database inception to November 2017 for all in-vitro (including simulated clotting models) or in-vivo studies reporting the relationship between the TXA concentration in blood or plasma and any reliable measure of fibrinolysis.We found 21 studies of which 20 were in vitro and one was in vivo. Most in-vitro studies stimulated fibrinolysis with tissue plasminogen activator and measured fibrinolysis using viscoelastic, optical density, or immunological assays. TXA concentrations between 10 and 15 mg/l resulted in substantial inhibition of fibrinolysis, although concentrations between 5 and 10 mg/l were partly inhibitory.TXA concentrations of 10-15 mg/l may be suitable targets for pharmacokinetic studies, although TXA concentrations above 5 mg/l may also be effective.

Figures

Fig. 1
Fig. 1
Flow diagram of search. Modified with permission [8].
Fig. 2
Fig. 2
Plot showing the tPA concentrations used in in-vitro studies and the corresponding minimal TXA concentration needed to inhibit at least 80% of fibrinolysis. The regression line with 95% CI is also shown. Five studies were excluded: three studies that used only one very high concentration of TXA to inhibit fibrinolysis [28,29,39], one study that used a concentration of tPA so high [30] that it falls in the range of tPA levels used in thrombolytic treatment (960–1830 ng/ml [52]), and one study that did not report the concentration needed for 80% inhibition of fibrinolysis were excluded [38]. tPA, tissue plasminogen activator; TXA, tranexamic acid.

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