Optimal use of intravenous tranexamic acid for hemorrhage prevention in pregnant women.

Background Every 2 minutes there is a pregnancy related death worldwide, with one third due to severe postpartum hemorrhage (PPH). While international trials demonstrated efficacy of 1,000 mg TXA in treating PPH, to our knowledge there are no dose finding studies of TXA in pregnant women for PPH prevention. Objective To determine the optimal TXA dose needed to prevent PPH. Methods We enrolled 30 pregnant women undergoing scheduled cesarean delivery in an open-label, dose ranging study. Subjects were divided into 3 cohorts receiving 5, 10 or 15 mg/kg (max 1000 mg) of intravenous TXA at umbilical cord clamping. Inclusion criteria were ≥34 week's gestation and normal renal function. Primary endpoints were pharmacokinetic and pharmacodynamic profiles. TXA plasma concentration greater than 10 μg/mL and maximum lysis less than 17% were defined as therapeutic targets independent to the current study. Rotational thromboelastometry (ROTEM) of tissue plasminogen activator (tPA)-spiked samples was used to evaluate pharmacodynamic profiles at time points up to 24 hours after TXA administration. Safety was assessed by plasma thrombin generation, D-dimer, and TXA concentrations in breast milk. Results There were no serious adverse events including hemorrhage or venous thromboembolism. Plasma concentrations of TXA increased in a dose-proportional manner. The lowest dose cohort received an average of 448 ± 87 mg TXA. Plasma TXA exceeded 10 μg/mL and maximum lysis was less than 17% more than 1 hour after administration for all TXA doses tested. Median estimated blood loss for cohorts receiving 5, 10, or 15 mg/kg TXA was 750, 750 and 700 mL, respectively. Plasma thrombin generation did not increase with higher TXA concentrations. D-dimer changes from baseline were not different among the cohorts. Breast milk TXA concentrations were 1% or less than maternal plasma concentrations. Conclusions While large randomized trials are necessary to support clinical efficacy of TXA for prophylaxis, we propose an optimal dose of 600 mg in future TXA efficacy studies to prevent PPH.