Effects of early factor XIII replacement in postpartum hae morrhage: study protocol for a multicentre, open-label, randomised, controlled, investigator-initiated trial

Abstract

Introduction: The primary objective of this trial is to evaluate the effect of replenishing coagulation factor XIII (FXIII) in women with postpartum haemorrhage (PPH) on measured blood loss (MBL). Based on earlier research, we hypothesise that the administration of FXIII leads to a significant reduction in postpartum blood loss.

Methods and analysis: This is a randomised, controlled trial that will allocate eligible patients in the event of a PPH and after receiving tranexamic acid either to the treatment group, receiving FXIII, or to the control group (standard of care). The primary endpoint is the MBL within 24 hours using a standardised method. For the primary analysis, estimation of the OR under a proportional odds assumption is conducted simultaneously for all possible cut-off points. A corresponding estimate, along with a two-sided 95% CI and two-sided p value against the null hypothesis OR=1, is obtained from the Continuous Outcome Logistic Regression model. More than 7000 patients will be screened in order to include a total of 988 eligible patients into the trial. Secondary outcomes include the rate of adverse maternal outcomes related to PPH, the rate of women breastfeeding after PPH and the safety of the administration of FXIII in women with PPH. Dynamics of blood coagulation factors in women with PPH and their association with MBL will be assessed in specific centres. A preliminary overview on costs and potential savings through early treatment of PPH with FXIII is included in the analysis as well as a patient and public involvement report, asking for patients' personal experience during PPH in the main study centre.

Ethics and dissemination: Ethics approval was granted by the central ethics committee (Kantonale Ethikkommission Zürich/Switzerland) on 16 June 2024, reference number: BASEC 2024-00374. Results will be disseminated via open-access publication in a relevant medical journal.

Trial registration number: ClinicalTrials.gov ID NCT06481995.

Keywords: Bleeding disorders & coagulopathies; Postpartum Period; Pregnant Women; Randomized Controlled Trial.

Figure 1. Eligibility criteria, before and after delivery. Hb, haemoglobin; MBL, measured blood loss; PPH, postpartum haemorrhage; TXA, tranexamic acid.

Figure 2. Trial flow. Women who signed the informed consent are monitored for blood loss right after delivery. After blood loss of 300 mL and ongoing bleeding: blood collection bag for quantitative measurement of blood loss is installed. After blood loss of 500 mL and ongoing bleeding: 1 g of tranexamic acid (TXA) is administered. After blood loss of 700 mL and ongoing bleeding: randomisation with allocation to study or control group. Volume and coagulation management follows a standardised procedure until measured blood loss (MBL) of 1500 mL (or 1100 mL for women<60 kg); after that threshold, coagulation management is released to local practice. Blood withdrawals (BWs) before, during and 48 hours after postpartum haemorrhage (PPH) treatment are applicable to a subgroup of patients only. FXIII, factor XIII; IU, International Units; iv, intravenous

Figure 3. Blood collection bag with a quantitative scale for blood loss measurement in vaginal deliveries.