Von Willebrand Factor for Menorrhagia: A Survey and Literature Review
Authors: Machin Nicoletta , Ragni Margaret V. , Malec Lynn M. , Brambilla Donald , Coyle Thomas , Davis Joanna A. , Drygalski Annette , James Andra H , Jobe Shawn M , Konkle Barbara A. , Kouides Peter , Kuriakose Philip , Ma Alice D. , Majerus Elaine M. , Nance Danielle , Neff Anne T. , Philipp Claire S. , Wang Tzu-Fei , Yaish Hassan M. 
Published: October 2019

Abstract
Background: von Willebrand disease (VWD) is the most common congenital bleeding disorder. In affected women, menorrhagia is the most common bleeding symptom. Combined oral contraceptives (COCs), the first choice therapy recommended by NHLBI 2007 guidelines, reduce menstrual loss by increasing coagulation factor levels, but at least 30% are unresponsive or intolerant. Non-hormonal options include the antifibrinolytic tranexamic acid (TA), reduces menstrual bleeding by 30-50%, but requires dosing three times a day. Intranasal desmopressin (Stimate) is simpler to use, but ineffective in ~20%. Effective treatment for menorrhagia, thus, remains the greatest unmet health need in women with VWD. Von Willebrand factor (VWF) is used typically when first-line and second-line treatments fail, but few data exist regarding its effectiveness in reducing menorrhagia.
Methods: We therefore conducted a survey of U.S. hemophilia treatment centers (HTCs) of current therapy for menorrhagia in VWD, utilizing Centers for Disease Control (CDC) website https://www2a.cdc.gov/ncbddd/htcweb/Main.asp, and the Hemostasis and Research Society (HTRS) site http://htrs.org. To specifically assess the use of VWF concentrate for menorrhagia, we also performed a literature review using medical subject heading (MeSH) search terms "von Willebrand factor," "menorrhagia," and "von Willebrand disease." Statistical analysis was by descriptive statistics.
Results: Of 83 surveys distributed to hemophilia treatment centers (HTCs) caring for adult patients, 35 HTC MDs responded (42.2%) but only 20 HTC MDs (24.1%) provided sufficient data for analysis. These 20 HTC MDs reported a total of 1,321 women with VWD age 18-45 years seen during the 3-year period 2011-2014, of whom 816 (61.8%) had menorrhagia. Among these women, the most common first-line therapy was COCs, reported by 50.0% of the 20 HTC MDs, TA in 30.0% and desmopressin (DDAVP) in 20.0%. Overall, including all therapies (first-, second-, third-line), DDAVP was prescribed by 90.0% of the 20 HTC MDs, TA in 80.0%, COCs in 70.0%, aminocaproic acid (amicar) in 25.0%, and the levonorgestrel-releasing intrauterine system (Mirena IUD) in 15.0%. Only 4 HTC MDs (20.0%) prescribed VWF concentrate (VWF) for menorrhagia: all used VWF as third-line therapy after first-line and second-line treatments had failed. In the 13 women with type 1, 2, or 3 VWD and menorrhagia treated with intravenous VWF by these 4 HTC MDs, there was reduction in menorrhagia in all 13 (100%), with no adverse effects. These patients learned intravenous technique and infused VWF at 40-50 IU/kg at home for up to 5 days of menstrual bleeding each cycle, with good acceptability. In the literature search, we identified six published studies, including two prospective clinical trials, two retrospective observational trials, and two observational network studies. A total of 455 subjects with VWD reported in these six studies were treated with either plasma-derived (pdVWF) or recombinant (rVWF) VWF for bleeds. Of these, nearly one-third or 138 (30.3%) were women with type 1, 2, or 3 VWD and menorrhagia who were treated with pdVWF or rVWF at a dose of 36-50 IU/kg for 1-6 days of menstrual cycle bleeding. In these studies, 95-100% of these women reported reduction in menorrhagia, with no reported adverse events.
Discussion: This survey and literature review of 151 women with VWD and menorrhagia represent the largest treatment experience to date. DDAVP, TA, and COCs are the most common first-line therapies. VWF is a third-line therapy but safely and effectively reduces menorrhagia in at least 95% of women with VWD. Prospective clinical trials of VWF are needed to establish the minimal dose required for menorrhagia, to determine patient acceptability of this intravenous therapy, and to compare safety and efficacy with standard therapy.

Disclosures
Off Label Use: recombinant VWF and plasma-derived VWF for treatment of menorrhagia in VWD. Ragni:Bristol Myers Squibb: Research Funding; Biogen: Research Funding; Bayer: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Dimension Therapeutics: Research Funding; CSL Behring: Research Funding; Foundation Women Girls Blood Disorders: Membership on an entity's Board of Directors or advisory committees; Genentech Roche: Research Funding; Medscape, Web MD: Honoraria; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; SPARK: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Ferring Pharmceuticals: Research Funding; Biomarin: Research Funding; Vascular Medicine Institute: Research Funding. Malec:Baxalta: Research Funding; Biogen: Research Funding. Coyle:Bayer: Membership on an entity's Board of Directors or advisory committees. Drygalski:Biogen: Consultancy; Baxalta: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Hematherix Inc: Equity Ownership; Biogen: Research Funding; Baxalta: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; CSL Behring: Speakers Bureau; Hematherix Inc: Membership on an entity's Board of Directors or advisory committees. James:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees. Jobe:Biogen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Membership on an entity's Board of Directors or advisory committees. Konkle:Octapharma: Research Funding; Baxalta: Consultancy; CSL Behring: Consultancy; Baxalta: Research Funding. Kouides:CSL Behring: Membership on an entity's Board of Directors or advisory committees. Kuriakose:Kedrion: Speakers Bureau. Ma:Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Nance:Patient Services, Inc.: Membership on an entity's Board of Directors or advisory committees. Neff:Alexion: Membership on an entity's Board of Directors or advisory committees; Novonordisk: Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novonordisk: Membership on an entity's Board of Directors or advisory committees. Philipp:Baxter: Research Funding. Yaish:Agios: Membership on an entity's Board of Directors or advisory committees.