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Tranexamic Acid Administered During Cesarean Delivery in High-Risk Patients: Maternal Pharmacokinetics, Pharmacodynamics, and Coagulation Status

  • Sara M. SEIFERT
    Correspondence
    CORRESPONDING AUTHOR: Sara M Seifert, MD, Brigham & Women’s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United [email protected], Tel: (617) 759-1609
    Affiliations
    Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
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  • Mario I. LUMBRERAS-MARQUEZ
    Affiliations
    Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
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  • Susan M. GOOBIE
    Affiliations
    Department of Anesthesiology, Critical Care & Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts, United States
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  • Daniela A. CARUSI
    Affiliations
    Department of Obstetrics and Gynecology, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
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  • Kara G. FIELDS
    Affiliations
    Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
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  • Author Footnotes
    4 Current position post study, Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford Hospital, Stanford University School of Medicine, Stanford, California, United States
    Brian T. BATEMAN
    Footnotes
    4 Current position post study, Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford Hospital, Stanford University School of Medicine, Stanford, California, United States
    Affiliations
    Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
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  • Michaela K. FARBER
    Affiliations
    Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
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  • Author Footnotes
    4 Current position post study, Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford Hospital, Stanford University School of Medicine, Stanford, California, United States
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      ABSTRACT

      Background

      Tranexamic acid is frequently administered for postpartum hemorrhage. The World Health Organization recommends 1g intravenous dosing repeated once at 30 minutes for ongoing bleeding. Understanding the pharmacokinetics and pharmacodynamics of tranexamic acid in patients at high risk for PPH may enable dosage tailoring for optimal antifibrinolysis with minimal adverse events such as thrombosis or renal cortical necrosis.

      Objectives

      We report tranexamic acid pharmacokinetics and pharmacodynamics after 1g IV dosing during cesarean delivery in patients at risk for hemorrhage. The primary endpoint was tranexamic acid plasma concentration >10μg/mL, known to inhibit 80% of fibrinolysis. Correlation with patient demographics and rotational thromboelastometry coagulation changes were also analyzed.

      Study Design

      In this prospective study we recruited 20 women aged 18-50 years, ≥23 weeks’ gestation undergoing cesarean delivery with at least (1) major (placenta previa, suspected placenta accreta spectrum, active bleeding) or (2) minor (>2 prior cesarean deliveries, prior postpartum hemorrhage, chorioamnionitis, polyhydramnios, macrosomia, obesity, or suspected placental abruption) risk factors for PPH. Exclusion criteria were allergy to tranexamic acid, inherited thrombophilia, prior or current thrombosis, seizure history, renal or liver dysfunction, anticoagulation, or category III fetal heart tracing. Tranexamic acid 1g was administered after umbilical cord clamping. Blood samples were drawn at 3, 7, 15, and 30 minutes, then at 30-minute intervals up to 5 hours. Plasma concentrations were evaluated as mean (standard error). Serial rotational thromboelastometry was performed and correlated with tranexamic acid plasma concentrations.

      Results

      Median age of participants was 37.5 years (interquartile range [IQR] 35-39.5) and median body mass index (BMI) was 28.6 kg/m2 (IQR 24.9-35). Median blood loss (estimated or quantitative) was 1,500 mL (IQR 898.5-2,076). Nine of 20 (45%) received a transfusion of packed red blood cells (PRBCs). The mean peak tranexamic acid plasma concentration at 3 minutes was 59.8 +/- 4.7 μg/mL. All patients had a plasma concentration above 10μg/mL for one hour following infusion. Plasma concentration was >10μg/mL in more than half of patients at 3 hours and fell below 10μg/mL in all patients at 5 hours. There was a moderate negative correlation between body mass index and the plasma concentration area under the curve (AUC; r = -0.49, 95% confidence interval [CI] -0.77, -0.07, P=0.026). Rotational thromboelastometry EXTEM-maximum clot firmness had a weak positive correlation with longitudinal plasma concentration (r = 0.32, 95% CI 0.21, 0.46, P<0.001). EXTEM-maximum clot lysis was 0% post-infusion in 18 (90%) of patients and no patients in the study demonstrated a maximum lysis >15% at any interval from 3 minutes to 5 hours. There was no significant correlation between EXTEM-LY30 and longitudinal TXA plasma concentrations (r = 0.10, 95% CI -0.20, 0.19, P=0.252).

      Conclusions

      After standard 1g IV dosing of tranexamic acid during cesarean delivery in patients at high-risk for hemorrhage, a plasma concentration of >10μg/mL was sustained for at least 60 minutes. Plasma tranexamic acid levels correlated inversely with body mass index. Concurrent use of rotational thromboelastometry may demonstrate tranexamic acid impact on clot firmness but not a hyperfibrinolysis-derived trigger for therapy.

      KEYWORDS

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