In the last decades, tranexamic acid (TXA) has emerged as an essential tool in blood loss management in obstetrics. TXA prophylaxis for postpartum haemorrhage (PPH) has been studied in double-blind, ...placebo-controlled, randomized clinical trials (RCTs). Given the small observed preventive effect, the systematic use of TXA for vaginal and/or caesarean deliveries is still subject to debate. The result of a pharmacokinetic modelling suggests that relative to intravenous administration, intramuscular administration may be an equally effective alternative route for preventing PPH and may enable access to this drug in low-resource countries. Prophylaxis is currently studied in high-risk populations, such as women with prepartum anaemia or placenta previa.
TXA effectively reduces blood loss and PPH-related morbidity and mortality during active PPH, as demonstrated by high-grade evidence from large RCTs. The drug has a good safety profile: in most cases, only mild gastrointestinal or visual adverse events may be observed. TXA use does not increase the risk of serious adverse events, such as venous or arterial thromboembolism, seizures, or acute kidney injury. The TRACES in vivo analysis of biomarkers of TXA’s antifibrinolytic effect have suggested that a dose of at least 1 gram is required for the treatment of PPH. The TRACES pharmacokinetic model suggests that because TXA can be lost in the haemorrhaged blood, a second dose should be administered if the PPH continues or if severe coagulopathy occurs. Future pharmacodynamic analyses will focus on the appropriateness of TXA dosing regimens with regard to the intensity of fibrinolysis in catastrophic obstetric events.
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.
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.
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.
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.
NCT 02797119.
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.
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.
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.
ClinicalTrials.gov, NCT02797119. Registered on 13 June 2016.
Postpartum haemorrhage (PPH) is the leading cause of maternal death worldwide. Tranexamic acid (TA), an antifibrinolytic drug, reduces bleeding and transfusion need in major surgery and trauma. In ...ongoing PPH following vaginal delivery, a high dose of TA decreases PPH volume and duration, as well as maternal morbidity, while early fibrinolysis is inhibited. In a large international trial, a TA single dose reduced mortality due to bleeding but not the hysterectomy rate. TA therapeutic dosages vary from 2.5 to 100 mg/kg and seizures, visual disturbances and nausea are observed with the highest dosages. TA efficiency and optimal dosage in haemorrhagic caesarean section (CS) has not been yet determined. We hypothesise large variations in fibrinolytic activity during haemorrhagic caesarean section needing targeted TA doses for clinical and biological efficacy.
The current study proposal is a blinded, randomised controlled trial with the primary objective of determining superiority of either 1 g of TXA or 0.5 g of TXA, in comparison to placebo, in terms of 30% blood-loss reduction at 6 h after non-emergency haemorrhagic caesarean delivery (active PPH > 800 mL) and to correlate this clinical effect in a pharmacokinetics model with fibrinolysis inhibition measured by an innovative direct plasmin measurement regarding plasmatic TA concentration. A sample size of 342 subjects (114 per group) was calculated, based on the expected difference of 30% reduction of blood loss between the placebo group and the low-dose group, out of which 144 patients will be included blindly in the pharmaco-biological substudy. A non-haemorrhagic reference group will include 48 patients in order to give a reference for peak plasmin level.
TRACES trial is expected to give the first pharmacokinetics data to determinate the optimal dose of tranexamic acid to reduce blood loss and inhibit fibrinolysis in hemorrhagic cesarean section.
ClinicalTrials.gov, ID: NCT02797119 . Registered on 13 June 2016.
Our purpose in conducting this study was to determine whether administration of high-dose tranexamic acid (TA) at the time of diagnosis of postpartum haemorrhage (PPH) could reduce blood loss.
This ...was a randomised, controlled, multicentred, open-label trial. Women with PPH >800 mL following vaginal delivery were randomly assigned to receive TA (loading dose 4 g over 1 hour, then infusion of 1 g/hour over 6 hours) or not. In both groups, packed red blood cells (PRBCs) and colloids could be used according to French guidelines. The use of additional procoagulant treatments was permitted only in cases involving intractable bleeding. The primary objective was to assess the efficacy of TA in the reduction of blood loss in women with PPH, and the secondary objectives were the effect of TA on PPH duration, anaemia, transfusion and the need for invasive procedures.
A total of 144 women fully completed the protocol (72 in each group). Blood loss between enrolment and 6 hours later was significantly lower in the TA group than in the control group (median, 173 mL; first to third quartiles, 59 to 377) than in controls (221 mL; first to third quartiles 105 to 564) (P = 0.041). In the TA group, bleeding duration was shorter and progression to severe PPH and PRBC transfusion was less frequent than in controls (P < 0.03). Invasive procedures were performed in four women in the TA group and in seven controls (P = NS). PPH stopped after only uterotonics and PRBC transfusion in 93% of women in the TA group versus 79% of controls (P = 0.016). Mild, transient adverse manifestations occurred more often in the TA group than in the control group (P = 0.03).
This study is the first to demonstrate that high-dose TA can reduce blood loss and maternal morbidity in women with PPH. Although the study was not adequately powered to address safety issues, the observed side effects were mild and transient. A larger international study is needed to investigate whether TA can decrease the need for invasive procedures and reduce maternal morbidity in women with PPH.
Controlled Trials ISRCTN09968140.
The aim of this study was to evaluate the population pharmacokinetics of tranexamic acid (TXA) administered intravenously at a single dose of 0.5 or 1 g in parturients undergoing active hemorrhagic ...cesarean delivery and to evaluate the influence of patient variables on TXA pharmacokinetics. Subjects from three recruiting centers were included in this PK sub-study if randomized in the experimental group (i.v TXA 0.5 g or 1 g over one minute) of the TRACES study. Blood samples and two urinary samples were collected within 6 h after TXA injection. Parametric non-linear mixed-effect modeling (Monolix v2020R1) was computed. The final covariate model building used 315 blood and 117 urinary concentrations from seventy-nine patients. A two-compartment model with a double first-order elimination from the central compartment best described the data. The population estimates of clearance (CL), central volume of distribution (V1), and half-life for a typical 70 kg patient with an estimated renal clearance of 150 mL/min (Cockroft-Gault) were 0.14 L/h, 9.25 L, and 1.8 h. A correlation between estimated creatinine clearance and CL, body weight before pregnancy, and V1 was found and partly explained the PK variability. The final model was internally validated using a 500-run bootstrap. The first population pharmacokinetic model of TXA in active hemorrhagic caesarean section was successfully developed and internally validated.
To compare the validity of two previously published diagnostic scores of disseminated intravascular coagulation (DIC) in pregnant women admitted to ICU for an acute thrombotic or hemorrhagic ...complication of delivery and postpartum.
This was a population based retrospective study of 154 patients admitted to ICU for severe delivery and postpartum complications in a University Hospital. A recently published score (adapted to physiological changes of pregnancy and based on three components: platelet count, prothrombin time difference and fibrinogen) was compared to the International Society for Thrombosis and Hemostasis (ISTH) score (based on four components: platelet count, fibrinogen, prothrombin time, and fibrin related marker). Both scores were calculated at delivery, ICU admission (day 0), day 1 and day 2 during the postpartum ICU stay. The validity of both scores was assessed by comparison with the consensual and blinded analysis of two experts. The sensitivity, specificity, and area under the curve (AUC) of each score were calculated at each time and overall by generalized linear mixed model. The agreement between the two scores was evaluated by the Kappa coefficient.
The new score had a sensitivity of 0.78, a specificity of 0.97 (p <0.01) and a global AUC of 96% while the ISTH score had a sensitivity of 0.31, a specificity of 0.99 and an AUC of 94% (p <0.01). The Kappa coefficient of correlation between both scores was 0.35. The lower sensitivity of the ISTH score was mainly explained by the lack of fibrinogen and fibrin-related peptides thresholds adapted to the physiological changes of coagulation induced by pregnancy.
The new DIC score seem highly discriminant in the subset of patients admitted to the ICU after delivery for an acute specific complication. The ISTH score is not recommended in pregnant women because of its poor sensitivity.
Postpartum haemorrhage (PPH) remains the leading cause of pregnancy-related deaths worldwide. Typically, bleeding is controlled by timely obstetric measures in parallel with resuscitation and ...treatment of coagulopathy. Early recognition of abnormal coagulation is crucial and haemostatic support should be considered simultaneously with other strategies as coagulopathies contribute to the progression to massive haemorrhage. However, there is lack of agreement on important topics in the current guidelines for management of PPH. A clinical definition of PPH is paramount to understand the situation to which the treatment recommendations relate; however, reaching a consensus has previously proven difficult. Traditional definitions are based on volume of blood loss, which is difficult to monitor, can be misleading and leads to treatment delay. A multidisciplinary approach to define PPH considering vital signs, clinical symptoms, coagulation and haemodynamic changes is needed. Moreover, standardised algorithms or massive haemorrhage protocols should be developed to reduce the risk of morbidity and mortality and improve overall clinical outcomes in PPH. If available, point-of-care testing should be used to guide goal-directed haemostatic treatment. Tranexamic acid should be administered as soon as abnormal bleeding is recognised. Fibrinogen concentrate rather than fresh frozen plasma should be administered to restore haemostasis where there is elevated risk of fibrinogen deficiency (e.g., in catastrophic bleeding or in cases of abruption or amniotic fluid embolism) as it is a more concentrated source of fibrinogen. Lastly, organisational considerations are equally as important as clinical interventions in the management of PPH and have the potential to improve patient outcomes.
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