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

Anne-Sophie Ducloy-Bouthors (1, 2) , Sixtine Gilliot (1) , Maeva Kyheng (3, 4) , David Faraoni (5) , Alexandre Turbelin (2) , Hawa Keita-Meyer (6) , Agnès Rigouzzo (7) , Gabriela Moyanotidou , Benjamin Constant , Françoise Broisin , Agnès L. Gouez , Rémi Favier , Edith Peynaud , Louise Ghesquiere (8) , Gilles Lebuffe (1) , Alain Duhamel (4, 3) , Delphine Allorge (9) , Sophie Susen (10, 11) , Benjamin Hennart (10, 9, 12) , Emmanuelle Jeanpierre (10) , Pascal Odou (1) , Cyril Huissoud , Charles Garabedian , Frédéric J. Mercier , Catherine Barre-Drouard , Max Gonzalez Estevez , Julien Corouge , Anne-Sophie Baptiste , Anne-Frédérique Dalmas , Pierre Richart (10)

1 GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365
2 Hôpital Jeanne de Flandre [Lille]
3 Service de Biostatistiques [CHRU Lille]
4 METRICS - Evaluation des technologies de santé et des pratiques médicales - ULR 2694
5 BCM - Baylor College of Medicine
6 Hôpital Louis Mourier - AP-HP [Colombes]
7 CHU Trousseau [APHP]
8 Hôpital Jeanne de Flandres
9 Toxicologie et Génopathies [CHRU Lille]
10 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
11 RNMCD - Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011
12 IMPECS - Impact de l'environnement chimique sur la santé humaine - ULR 4483

Background The optimal dose of tranexamic acid to inhibit hyperfibrinolysis in postpartum haemorrhage is unclear. Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Cesarean Delivery (TRACES) was a double-blind, placebo-controlled, randomised, multicentre dose-ranging study to determine the dose–effect relationship for two regimens of intravenous tranexamic acid vs placebo. Methods Women experiencing postpartum haemorrhage during Caesarean delivery were randomised to receive placebo (n=60), tranexamic acid 0.5 g (n=57), or tranexamic acid 1 g i.v. (n=58). Biomarkers of fibrinolytic activation were assayed at five time points, with inhibition of hyperfibrinolysis defined as reductions in the increase over baseline in D-dimer and plasmin–antiplasmin levels and in the plasmin peak time. Results In the placebo group, hyperfibrinolysis was evidenced by a mean increase over baseline [95% confidence interval] of 93% [68–118] for D-dimer level at 120 min and 56% [25–87] for the plasmin–antiplasmin level at 30 min. A dose of tranexamic acid 1 g was associated with smaller increases over baseline (D-dimers: 38% [13–63] [P=0.003 vs placebo]; plasmin–antiplasmin: –2% [–32 to 28] [P=0.009 vs placebo]). A dose of tranexamic acid 0.5 g was less potent, with non-significant reductions (D-dimers: 58% [32–84] [P=0.06 vs placebo]; plasmin–antiplasmin: 13% [18–43] [P=0.051]). Although both tranexamic acid doses reduced the plasmin peak, reduction in plasmin peak time was significant only for the 1 g dose of tranexamic acid. Conclusions Fibrinolytic activation was significantly inhibited by a dose of intravenous tranexamic acid 1 g but not 0.5 g. Pharmacokinetic–pharmacodynamic modelling of these data might identify the best pharmacodynamic monitoring criteria and the optimal tranexamic acid dosing regimen for treatment of postpartum haemorrhage.

Mots clés: antifibrinolytic drug; D-dimer; fibrinogen; fibrinolysis; plasmin; plasmin–antiplasmin complex; postpartum haemorrhage; thrombin; tranexamic acid

Domaines: Sciences du Vivant [q-bio]

Anne-Sophie Ducloy-Bouthors, Sixtine Gilliot, Maeva Kyheng, David Faraoni, Alexandre Turbelin, et al.. Tranexamic acid dose-response relationship for antifibrinolysis in postpartum haemorrhage during Caesarean delivery: TRACES, a double-blind, placebo-controlled, multicentre, dose-ranging biomarker study.. Br J Anaesth, 2022, Br J Anaesth, 129 (6), pp.937-945. ⟨10.1016/j.bja.2022.08.033⟩. ⟨hal-04144301⟩