Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is characterized by deficient and/or defective von Willebrand factor (VWF) which results in spontaneous and traumatic mucosal bleeding. In women with VWD, pregnancy is associated with excess blood loss and poor quality of life. Recently, a prospective cohort study by James et al Haemophilia 2015, determined that even when treatment is given, women with VWD had lower VWF levels, greater blood loss at delivery, and lower hematocrit than controls without VWD. The reason for this finding remains unknown. Current VWF dosing is weight-based, but does not account for the ~1.4-1.5-fold increase in blood volume during pregnancy. To address this, we conducted a feasibility study for a prospective, randomized phase III trial comparing weight-based, 50 IU/kg, with volume-based, 80 IU/kg, VWF to prevent postpartum hemorrhage (PREVENT PPH Trial). Methods: To establish trial feasibility: 1) we compared pre-pregnancy and 8th-month VWF levels in women with VWD with and without PPH (≥500 cc blood loss in the 1st 24 hours) following vaginal delivery; 2) we evaluated VWF dosing in women with PPH in the James study; 3) we assessed thrombosis risk and VWF concentrate dose by literature review; 4) we surveyed current practice regarding VWF concentrate use at delivery by U.S. hemophilia treatment center (HTC) MDs; and 5) we conducted structured interviews of MDs and VWD patients to determine trial acceptability. Analysis was by Student9s t-test for continuous data, and Fisher9s exact test for discrete data. Results:In the Retrospective VWD-PPH Study of 16 women with VWD (14 type 1; 2 type 2) undergoing vaginal delivery, PPH was associated with higher pre-delivery weight, pre: 88.1 vs. 67.6 kg; 8thmonth: 99.9 vs. 75.0 kg; and delivery: 104.0 vs. 78.6 kg, all p Conclusions: The findings of this feasibility study indicate that pre-pregnancy VWF:RCo may be a better predictor of PPH than 8thmonth VWF:RCo. High pre-delivery weight which is associated with high blood volume may increase PPH, possibly through dilution of VWF levels. A VWF dose of ~50 IU/kg, which is the first line of therapy at delivery and the current standard of practice, may not prevent PPH. Thrombosis risk with VWF in published studies is low even at doses >80 IU/kg. Drug safety, local obstetric collaboration, and coverage of staff, travel, and childcare costs are critical issues to address in trial design. Disclosures Ragni:SPARK: Research Funding; Genentech: Research Funding; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding; Novo Nordisk: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Baxalta: Research Funding; Biogen: Consultancy, Research Funding; Biomarin: Consultancy; Shire: Consultancy; CSL Behring: Research Funding. James:Intramural University of Ghana Research Fund: Research Funding; Vanderbilt University Medical Center Gift Funds: Research Funding. Malec:Biogen: Consultancy; Vascular Medicine Institute: Research Funding; Biogen: Research Funding; Baxalta: Research Funding. Kessler:Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Genentech: Consultancy, Research Funding; Biogen: Consultancy; Bayer: Consultancy, Research Funding; Pfizer: Consultancy; Baxalta: Consultancy, Research Funding; LFB: Other: Member of DSMB. Kouides:CSL Behring: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Baxalta: Consultancy. Neff:Shire: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Other: DSMB Chair for research study; ABIM: Other: Hematology Exam committee; CSL Behring: Membership on an entity9s Board of Directors or advisory committees; HEMA Biologics: Membership on an entity9s Board of Directors or advisory committees. Philipp:Novo Nordisk: Membership on an entity9s Board of Directors or advisory committees; Baxalta: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Merck: Other: Data Safety Monitoring Board. Brooks:Gilead Sciences: Research Funding.