Fibrinolysis after an Elective Caesarean Section without Postpartum Hemorrhage: Pilot Study for Reference Values from the Simultaneous Thrombin and Plasmin Generation Assay

Research Article

Austin Hematol. 2021; 6(1): 1035.

Fibrinolysis after an Elective Caesarean Section without Postpartum Hemorrhage: Pilot Study for Reference Values from the Simultaneous Thrombin and Plasmin Generation Assays

Ducloy-Bouthors A-S1,2*, Lassalle F3, Gilliot S2, Kyheng M4,5, Favier R6, Peynaud E7, Hémar C8, Hennart B9, Turbelin A1, Lebuffe G1,2, Duhamel A4,5, Susen S3, Jeanpierre E3 and Odou P2

1Obstetric Anesthesia and Intensive Care Unit, Jeanne de Flandre Women’s Hospital, Lille University Medical Center, Lille, France

2University of Lille, ULR 7365-GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France

3Hemostasis Unit, Biology and Pathology Center, Lille University Medical Center, Lille, France

4University of Lille, CHU Lille, ULR 2694 - METRICS: évaluation des technologies de santé et des pratiques médicales, Lille, France

5CHU Lille, Département de Biostatistiques, Lille, France

6Hemostasis Unit, Hematological Laboratory, Armand Trousseau Children’s Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

7Hemostasis Unit, Hematological Laboratory, Louis Mourrier Hospital, Assistance Publique-Hôpitaux de Paris, Colombes, France

8Hemostasis Unit, Hematological Laboratory, Valenciennes General Hospital, Valenciennes, France

9Toxicology Unit, Biology and Pathology Center, Lille University Medical Center, Lille, France

*Corresponding author: Anne-Sophie Ducloy-Bouthors, Obstetric Anesthesia and Intensive Care Unit, Jeanne de Flandre Women’s Hospital, Lille University Medical Center, avenue Oscar Lambret, F-59037 Lille, France

Received: April 01, 2021; Accepted: April 20, 2021; Published: April 27, 2021


Introduction: Postpartum Hemorrhage (PPH)-induced coagulopathy should be better explored. An innovative Simultaneous Generation of Thrombin and Plasmin Assay (SGTPA) was developed.

Objective: To establish postpartum SGTPA references.

Methods: Blood samples collected immediately after delivery (T0) and then 30, 60, 120 and 360 minutes later. Thrombin Generation (TG) and Plasmin Generation (PG) changes over time analyzed in 51 women after elective cesarean section without PPH and compared with Non-Pregnant (NP) women. The SGTPA variables’ correlations with fibrinogen levels, D-dimer levels and physiological blood loss were assessed in a mixed model.

Results: 37 women were included. TG and PG were higher in the postpartum group than in the NP group. TG increased early and then remained stable (baseline TG Area Under the Curve (AUC) [95% Confidence Interval (CI)] = 41037 [36850-43537] nM.min). The fibrinogen level varied over time, along with TG (p<0.001). Plasmin generation increased from 30 to 120 minutes (AUC [95% CI]: 2104 [1437; 2613] nM.min), along with a change in the D-dimer level (p=0.018). The time to the plasmin peak and the time interval between the TG and PG peaks showed the greatest inter-individual variability at T0 and were associated with physiological volumes of blood loss during cesarean delivery.

Conclusion: Reference SGTPA postpartum range was established. The SGTPA appears to be valuable for measuring TG and PG. TG and coagulation activation increased immediately after delivery, whereas PG and fibrinolysis increased later.

Keywords: Postpartum; Fibrinolysis; Plasmin; D-dimers; Fibrinogen; Thrombin

Key Points

• The simultaneous generation of thrombin and plasmin assay appeared to be reliable in a population of women without postpartum hemorrhage. Levels of thrombin and plasmin generation were higher than in non-pregnant women.

• Thrombin generation started immediately after delivery and then remained stable, whereas plasmin generation started 30 to 120 minutes after delivery. The time to the plasmin peak and the time interval between the thrombin and plasmin peaks were associated with the occurrence of physiological postpartum bleeding.


Fibrinolysis is a complex physiological system involved in massive bleeding disorders [1,2]. Tranexamic Acid (TA) (Exacyl®, Sanofi, France) is an antifibrinolytic drug that inhibits Plasmin Generation (PG) by competitively blocking the native fibrin lysine binding sites on the kringle 5 domain of activated plasminogen [1,2]. TA reduces bleeding and the transfusion requirement in major surgery and trauma [3,4]. Hyperfibrinolysis was previously identified as a part of Postpartum Hemorrhage (PPH)-induced coaguloapthy in an open labelled controlled study demonstrating a significant early increase in levels of D-dimer and Plasmin-Antiplasmin (PAP) complex, maximal at the second hour after delivery [5]. A high dose of TA inhibited this hyperfibrinolysis and reduced PPH volume and duration and maternal morbidity since the 30th minute until the second hour after administration [5,6]. An international doubleblind, placebo-controlled, randomized clinical trial (WOMAN) demonstrated a reduction of maternal mortality due to bleeding after a single 1g dose of TA dose [7]. In a one center-study of the WOMAN trial including 167 women experiencing PPH, hyperfibrinolysis was detected as ex-vivo thromboelastometric maximal lysis >15% in 35 (23%) [8]. The tranexamic acid impact was demonstrated on the D-dimers’s level decrease: The mean (SD) D-dimer concentration was 7.1 (7.0) mg/l in TA-group and 9.6 (8.6) mg/l in placebo-group (p=0.09). After adjusting for baseline, the D-dimer concentration was 2.16mg/l lower in TXA-treated women (-2.16, 95% CI -4.31 to 0.00, (p=0.05)). There was no significant difference in ML between TXA- and placebo-treated women (12.3% (18.4) and 10.7% (12.6), respectively; p=0.52) nor on any other parameters [9]. Although TA is clearly effective, the optimal dose for administration during Cesarean Section (CS) with a risk of PPH has yet to be determined. Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Caesarean Delivery (TRACES) dose-ranging placebo-controlled trial was designed to reach this objective [10,11]. An innovative assay has been developed to improve hyperfibrinolysis detection and appreciate its intensity, adapted from the Van Geffen et al. method [11]. This novel hemostasis assay (NHA, referred to here as the Simultaneous Generation of Thrombin and Plasmin Assay (SGTPA)) measured Thrombin Generation (TG), Plasmin Generation (PG) and the interaction between the two in the general population and in patients with rare bleeding disorders [11,12]. Thrombin generation has been previously measured in normal pregnancy and preeclamptic patients [13,14], in order to predict thrombotic risk [15] or to detect PPHassociated coagulopathy [16]. Plasmin generation cannot be assayed directly, given plasmin’s short half-life in plasma. In the TRACES trial, SGTPA is being used to provide additional data on acute obstetric coagulopathy and on TA’s dose-dependent antifibrinolytic impact during hemorrhagic vs. non-hemorrhagic Cesarean Section (CS) [9,10]. The objective of the present sub-study of the TRACES dataset was to use the SGTPA to establish reference ranges for TG, PG and other biomarkers of coagulation and fibrinolysis in the group of women without PPH [9,10].

Materials and Methods

The TRACES multicenter DBPC RCT was approved by an investigational review board (CPP Nord Ouest IV, Lille France; reference: 15/50_020216) [9].

Study design

An ancillary study of the TRACES dataset explored the pharmacokinetics and pharmacodynamics of TA during PPH after CS and was funded by the French National Agency for Medicines and Healthcare Products (Agence nationale de sécurité du médicament et des produits de santé, ANSM) [10]. In the TRACES study, the SGTPA and conventional laboratory tests are used to investigate TA’s antifibrinolytic effect vs. placebo during PPH after CS [11]. Hence, the present “TRACES non-PPH” unblinded ancillary study was designed to provide SGTPA reference values after an elective, nonhemorrhagic CS (Appendix 1) [9]. Four centers participated in this ancillary study, which was promoted by Lille University Medical Center (Lille, France).


We included patients undergoing elective CS with normal bleeding (blood loss <500mL) (Appendix 1). All patients received comprehensive information on the study’s objectives and procedures and gave their written consent to participation. The main exclusion criteria were age under 18, a lack of social security coverage, difficult venous access, and unexpected perioperative bleeding.

We recorded clinical data, obstetric data and the volume of blood loss, together with laboratory test results for blood samples collected upon delivery (T0) and then 30 (T30), 60 (T60), 120 (T120) and 360 (T360) minutes and 2 (±1) and 42 (±14) days thereafter (Appendix 1).

The present pilot study included 51 patients undergoing an elective, non-hemorrhagic CS after a normal pregnancy in 4 centers from March 2016 to June 2019. Thirteen of the 51 patients were then excluded due to PPH (blood loss >500mL: n=3), a disease condition affecting the mother or the fetus (uterine fibroids, and small for gestational age: n=3), or failure to freeze the patients’ samples (n=7, in one center). A total of 37 patients (Non-PPH group) met the inclusion criteria, provided all samples and attended follow-up visits (Figure 2). The study population’s anthropometric and obstetric characteristics are summarized in Table 1.