TRAnexamic acid in hemorrhagic CESarean section (TRACES) randomized placebo controlled dose-ranging pharmacobiological ancillary trial: study protocol for a randomized controlled trial

Abstract

Background: Evidence increases that a high or a standard dose of tranexamic acid (TA) reduces postpartum bleeding. The TRACES pharmacobiological substudy aims to establish a therapeutic strategy in hemorrhagic (H) Cesarean section (CS) with respect to the intensity of fibrinolysis by using innovative assays.

Method/design: The TRACES trial is a multicenter, randomized, double-blind, placebo-controlled, TA dose-ranging study that measures simultaneously plasmatic and uterine and urine TA concentrations and the plasmin peak inhibition tested by a simultaneous thrombin plasmin generation assay described by Van Geffen (novel hemostasis assay [NHA]). Patients undergoing H CS (>800 mL) will receive blindly TA 0.5 g or 1 g or placebo. A non-hemorrhagic (NH) group will be recruited to establish plasmin generation profile. Venous blood will be sampled before, at the end, and then at 30, 60, 120, and 360 min after injection. Uterine bleeding will be sampled after injection. Urine will be sampled 2 h and 6 h after injection. The number of patients entered into the study will be 114 H + 48 NH out of the 390 patients of the TRACES clinical trial.

Discussion: To explore the two innovative assays, a preliminary pilot study was conducted. Blood samples were performed repeatedly in patients undergoing either a H (>800 mL) or NH (<800 mL) CS and in non-pregnant women (NP). H patients received TA (0-2 g). Dose-dependent TA plasmatic concentrations were determined by LC-MS/MS quantification. Plasmin generation and its inhibition were tested in vitro and in vivo using the simultaneous thrombin-plasmin generation assay (STPGA). The pilot study included 15 patients in the H group, ten patients in the NH group, and seven patients in the NP group. TA plasmatic concentration showed a dose-dependent variation. STPGA inter-assay variation coefficients were < 20% for all plasmin parameters. Inter-individual dispersion of plasmin generation capacity was higher in H and NH groups than in NP group. Profile evolution over time was different between groups. This preliminary technical validation study allows TRACES pharmacobiological trial to be conducted.

Trial registration: ClinicalTrials.gov, NCT02797119. Registered on 13 June 2016.

Keywords: Cesarean section; D-dimers; Fibrinolysis; Pharmacokinetics; Plasmin; Postpartum hemorrhage; Tranexamic acid.

Conflict of interest statement

Ethics approval and consent to participate

The TRACES trial obtained approval from the competent national authorities (ANSM 201500249926) and the Ethics Committee (CPP 15/50 020216) before beginning the study, in accordance with article L1121-4 of the Public Healthcare Code. According to the ethical approval, informed consent to participate will be obtained from all participants in the study. Informed consent to participate to the pilot study has been obtained from all participants. This trial has been declared on the clinical trials registration on 13 June 2016 under the number CT 02797119. Registration will be performed in accordance with decree dated 14 November 2006 about gathering data in the national register of individuals participating in biomedical research.

Consent for publication

Authors and sponsors have given their consent and defined the publication rules.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Inhibition of the natural hyperfibrinolysis by a high dose of TA administered at the early stage of PPH. D-Dimers and PAP complex evolution at the onset of PPH and 30, 120, and 360 min later in the untreated H group compared to the TA-treated group

Fig. 2

TA plasma concentration measurement method: determination of the optimal timing. A timed urinary sample is collected in a graduated urinary bag between inclusion (T0) and T120, then T120 and T360, and end of the observation period of 6 h to measure the cumulative dose of TA excreted in urine

Fig. 3

Parameters studied in the simultaneous thrombin–plasmin generation assay. Thrombin parameters: (1) lag time (min); (2) thrombin peak time (min); (3) thrombin peak (nM); and (4) area under the curve (AUC) (nM.min). Plasmin parameters: (5) plasmin peak (nM); (6) fibrin lysis time (FLT) (min); and (7) AUC during FLT (plasmin potential) (nM.min)

Fig. 4

a In vitro STPGA with different TA concentrations: thrombin generation. In vitro dose effect relationship between TA and thrombin generation. Thrombin generation in the STPGA performed with a pooled plasma sample and different TA concentrations in the range of 0–20 mg/L. b In vitro STPGA with different TA concentrations: plasmin generation. In vitro dose effect relationship between TA and plasmin generation. Plasmin generation in the STPGA performed with a pooled plasma sample and different TA concentrations in the range of 0–20 mg/L

Fig. 5

a In vivo study: TA dose impact on thrombin generation profiles at T30. In vivo thrombin generation variations at T30 depending on TA dose administered: four patients who received 0, 0.5, 1, and 2 g (IV bolus), respectively. b In vivo study: TA dose impact on plasmin generation profiles at T30. In vivo plasmin generation variations at T30 depending on TA dose administered: four patients who received 0, 0.5, 1, and 2 g (IV bolus), respectively.

Fig. 6

Time repeated profiles: evolution of thrombin (a) and plasmin (b) profiles over time points: T0, T30, T60, T120, and T360, in patients in the NH group, the H group, and TA group with increasing doses of TA: TA1/2: 0.5 g, TA1: 1 g, and TA2: 2 g. A-NH evolution of thrombin generation profile over time for a NH patient, B-NH evolution of plasmin generation profile over time for a NH patient, A-0 evolution of thrombin generation profile over time for a H patient receiving 0 g TA, B-0 evolution of plasmin generation profile over time for a H patient receiving 0 g TA, A-TA1/2 evolution of thrombin generation profile over time for a H patient receiving 0.5 g TA, B-TA1/2 evolution of plasmin generation profile over time for a H patient receiving 0.5 g TA, A-1 evolution of thrombin generation profile over time for a H patient receiving 1 g TA, B-1 evolution of plasmin generation profile over time for a H patient receiving 1 g TA, A-2 evolution of thrombin generation profile over time for a H patient receiving 2 g TA, B-2 evolution of plasmin generation profile over time for a H patient receiving 2 g TA

Fig. 7

Thrombin (a) and plasmin (b) AUCs measured in STPGA at T0 in NH and H + TA groups compared to the NP group. AUC area under the curve, NP non-pregnant group, NH non-hemorrhagic group, H hemorrhagic untreated group, TA hemorrhagic treated group. *Thrombin AUC in NP vs NH group: p = 0.02; **Plasmin AUC in NP vs NH group: p = 0.002

Fig. 8

Plasmin generation profile at T0 (baseline) and corresponding TA peak plasma concentration at T1 (following injection) in TA-treated patients. Plasmin generation profiles at T0 (baseline, before injection) and corresponding TA peak plasma concentrations at T1 (just after injection, values in mg/L bracketed in little sidebars) of six patients treated by TA: two patients by dose (0.5, 1, and 2 g)

Fig. 9

Kinetics of both TA plasma concentration and plasmin AUC in TA-treated patients: evolution of TA plasma concentration and plasmin AUC over time points: T0, T15, T30, T60, T120, T180, and T360, in six patients treated by TA (0.5, 1, or 2 g). a Kinetics of TA plasma concentration and plasmin AUC: group TA0.5 - patient 20. b Kinetics of TA plasma concentration and plasmin AUC: group TA0.5 - patient 19. c Kinetics of TA plasma concentration and plasmin AUC: group TA1 - patient 24. d Kinetics of TA plasma concentration and plasmin AUC: group TA1 - patient 25. e Kinetics of TA plasma concentration and plasmin AUC: group TA2 - patient 12. f Kinetics of TA plasma concentration and plasmin AUC: group TA2 - patient 17