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

Abstract

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 BackgroundTranexamic 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. AimsDevelop an assay to measure PG kinetics in human plasma. Determine effects of TXA on PG and compare with fibrinolysis measured by rotational thromboelastometry (ROTEM). MethodsWe 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. ResultsThe 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. ConclusionsThe 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.

Population pharmacokinetics and pharmacodynamics of Tranexamic acid in women undergoing caesarean delivery

“…5 TXA inhibits both plasminogen activation and plasmin activity, preventing the process that dissolves fibrin clots. 6 Renal clearance is the major elimination pathway, with 95% of the dose found unchanged in urine. 4 Despite its important role in blood conservation, the pharmacokinetics (PK) and pharmacodynamics (PD) of TXA are poorly characterized, especially in pregnant women.…”

“…Currently, TXA is widely used in various settings to reduce blood loss, including acute trauma, and in select cardiac, orthopaedic and obstetrical surgeries 5 . TXA inhibits both plasminogen activation and plasmin activity, preventing the process that dissolves fibrin clots 6 . Renal clearance is the major elimination pathway, with 95% of the dose found unchanged in urine 4…”

A Lipid Atlas of the Human Kidney

“…As such, these lipids may be a renal response to an obese phenotype and serve as putative therapeutic or diagnostic markers. As an example, obesity represents a chronically inflamed state and under these conditions, coagulation factors are aberrantly expressed or regulated, promoting increased prothrombotic risk 54,55 . The oxidized phospholipid, PAz-PC, could be an important molecule in the feedback loop that exists between obesity and risk factors for cardiovascular disease as PAz-PC inhibits the tissue factor pathway inhibitor (TFPI) 56,57 .…”

Tranexamic acid dose–response relationship for antifibrinolysis in postpartum haemorrhage during Caesarean delivery: TRACES, a double-blind, placebo-controlled, multicentre, dose-ranging biomarker study

“…Primary outcome was the difference in the increase over baseline in plasma D-dimer level 120 min after the start of the infusion between treatment and placebo. Secondary outcomes were the treatment vs placebo differences in plasma D-dimer (Immunoturbidimetric, STA-LIAtest®, Diagnostica STAGO, Asnières-sur-Seine, France) and plasmin–antiplasmin (PAP) complex level increase over baseline ( TECHNOZYM® PAP Complex ELISA Kit ; Technoclone, Vienna, Austria) at four time points, plasmin generation (PG), thrombin generation (TG), 13 , 14 , 15 , 16 haemostatic variables (fibrinogen, fibrin monomers, factor II, factor V, antithrombin, and thrombin–antithrombin complexes), and the clinical outcomes at each time point. 10 , 17 …”