Impact of Tranexamic Acid Administration on Postpartum Hemorrhage in Women with Von Willebrand Disease Receiving Recombinant VWF at Delivery: The VWD Woman Trial

Von Willebrand disease (VWD) is the most common congenital bleeding disorder caused by deficient or defective von Willebrand factor (VWF). Women with VWD face a high rate of postpartum hemorrhage (PPH), with rates between 6.9-44%. The WOMAN trial demonstrated reduced PPH and mortality by tranexamic acid (TA), administered at 1 g IV within 3 hours of delivery and current guidelines recommend antifibrinolytic agents for managing PPH. No randomized trials have evaluated TA for PPH prevention in VWD. This randomized pilot trial compared the efficacy and safety of TA (1 g IV within 3 hours of delivery) with recombinant VWF (rVWF) before delivery and on days 1 and 2 postpartum vs. rVWF alone in reducing PPH in VWD.

Methods:

This pilot trial was an investigator-initiated industry-sponsored pilot phase III prospective, open-label, randomized trial comparing rVWF (Vonvendi®, supplied by Takeda) plus TA versus rVWF alone to reduce PPH (clinicaltrials.gov NCT04344860). Inclusion criteria were women ≥18 years of age with a historic diagnosis of VWD (RCoF <0.50 IU/dL and bleeding history). Exclusion criteria included D1472H mutation, history of thrombosis, cardiovascular diseases or platelet count <100,000/uL. Subjects were randomized 1:1 to receive rVWF 80 IU/kg IV (per pre-pregnancy weight) at delivery and on days 1 and 2 postpartum plus TA (1 g IV within 3 hours of delivery) or rVWF 80 IU/kg IV at delivery and days 1 and 2 postpartum alone. The primary endpoint was quantitative blood loss (QBL) at delivery determined by labor and delivery nurse. Secondary endpoints included patient-reported 21-day lochial blood loss by pictorial blood assessment charts (PBAC), and safety by hemoglobin (hgb), blood product usage, and hysterectomy. Between 6/4/21-5/17/24, 103 subjects were screened, of whom 42 were eligible and 20 were enrolled, randomized, and received study medication. QBL was compared between arms by a two-sample t-test. Stratified analyses of treatment and QBL were conducted by age group, BMI at delivery, VWF activity, and type of delivery. As this pilot study was not powered for statistical significance, descriptive statistics are provided.

Results:

All 20 subjects completed the trial, 10 randomized to receive rVWF+TA and 10 to rVWF alone. The mean age was 28.9 years (SD 5.34; range 18-37). All 20 subjects had type 1 VWD. The majority of subjects were white (90%). Pre-pregnancy BMI for the cohort was 30.9 (SD 8.38; range 19-48), and BMI at delivery was 36.0 (SD 8.12; range 24-56), with no significant differences between groups. Mean hgb at enrollment was 11.9 g/dL (SD 0.93; range 9.4-13.7), mean ferritin was 15 ng/mL (SD 9.1; range 6-39), and 19 of 20 (95%) subjects were treated with IV iron prior to delivery. At enrollment, vWAg was 1.65 IU/mL (SD 0.89; range 0.61-4.03), RCoF was 1.07 IU/mL (SD 0.59; range 0.26-2.9), and FVIII was 1.56 IU/dL (SD 0.47; range 0.76-2.48), with no significant differences between groups.

13 (65%) deliveries were vaginal and 7 (35%) were cesarean section, including 4 and 6, respectively, in the rVWF+TA group, and 9 and 1, respectively, in the rVWF-alone group. The mean QBL in the rVWF+TA group was 727 mL (SD 409.0; range 150-1345), compared to mean QBL of 539.7 mL (SD 569.8; range 140-2060) in the rVWF-alone group (p=0.41). PPH occurred in 4 (40%) participants in the rVWF+TA group and 2 (20%) in the rVWF-alone group (p=YY). The mean change in postpartum hemoglobin was -1.9 g/dL (SD 1.51; range -4.8-0.50) with rVWF+TA and -1.42 g/dL (SD 1.62; range -4.0-0.8) with rVWF-alone (p=0.49), and mean 21-day PBAC score was 416 (SD 282.1; range 100-935) vs. 315 (SD 183.7; range 97-604), respectively (p=0.36). Stratified analysis showed no significant impact of BMI at delivery, age, VWF activity, or type delivery on QBL. The study interventions were well tolerated, with no serious adverse events.

Conclusion:

This pilot study demonstrated the feasibility of enrollment, protocol implementation, and outcome collection. Adding TA to rVWF did not significantly prevent PPH, reduce QBL, or affect 21-day PBAC scores in women with VWD. The combination of rVWF+TA was safe, with no thrombosis. Given the 95% observed prevalence of iron deficiency, screening and treatment should be standard in pregnant women with VWD. Better approaches are needed to reduce or prevent the 30% rate of PPH despite treatment.

This investigator-initiated research study received support from Takeda Pharmaceuticals in the form of funding and Vonvendi.

Machin:Sanofi: Honoraria; Takeda: Research Funding. Ragni:Hema Biologics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPARK: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeBio: Membership on an entity's Board of Directors or advisory committees; BioMarin: Membership on an entity's Board of Directors or advisory committees, Research Funding.