Characterization of Bleeding in Hemophilia Carriers and Comparison to Women with Type 1 Von Willebrand Disease, Type 3 Von Willebrand Disease Obligate Carriers and Controls

Abstract

Background: Hemophilia carriers report abnormal bleeding, even when factor VIII or IX levels are normal. Information comparing bleeding events between carriers and women with other inherited bleeding disorders is lacking. Purpose: The purpose of our study was to characterize bleeding in hemophilia carriers using the International Society on Thrombosis and Hemostasis Bleeding Assessment Tool (ISTH-BAT) and to compare it with bleeding in normal controls, women with Type 1 VWD and Type 3 VWD obligate carriers (OC). Method: This was a prospective, observational, cross-sectional study performed by members of GEHEP (Global Emerging HEmostasis Panel). Study participants were recruited from GEHEP members9 clinics in North America (Kingston, Canada, Detroit and Philadelphia, USA), Europe (Malaga, Spain; Milan, Italy; Munich, Germany; Oslo, Norway) and South Africa (Johannesburg). Potential participants were identified through local patient databases and approached during clinic visits. All participants signed informed consent. Hemophilia carriers were defined by a documented FVIII or FIX mutation and/or by an appropriate family history (daughter of a man with hemophilia or mother of two sons with hemophilia or mother of one son with hemophilia with at least one other affected male relative). Demographic information was collected using a CRF and the ISTH-BAT was completed for each participant by study personnel. Existing ISTH-BAT data for women with Type 1 VWD, Type 3 VWD OC and age-matched female controls were used for comparison. Results: A total of 329 participants were included in this study; 168 hemophilia carriers, 83 women with Type 1 VWD, 32 Type 3 VWD OC and 46 female normal controls. Hemophilia carriers and normal controls were similar in age (40.1 vs 41.6, p=0.445). The mean overall ISTH-BAT bleeding score (BS) was significantly higher in carriers than in controls (5.7 vs 2.48, p Conclusion: In summary, our study showed that hemophilia carriers report significantly more bleeding by overall ISTH-BAT BS than age-matched female controls. Carriers experience both mucocutaneous bleeding as well as musculoskeletal bleeding. They score higher for mucocutaneous bleeding when compared with controls and when compared with Type 3 VWD OC. Overall Type 1 VWD patients experience more severe mucocutaneous bleeding than hemophilia carriers. However, hemophilia carriers report more musculoskeletal bleeding in the form of hemarthrosis and hematomas than all other groups. A comparison of overall ISTH-BAT BS between groups shows that bleeding in women with Type 1 VWD > hemophilia carriers > Type 3 VWD OC > controls. Additional research into the underlying pathophysiology of this abnormal bleeding is a critical next step in understanding and determining how to appropriately manage these patients. Disclosures Bidlingmaier:Novo Nordisk: Honoraria; Sobi: Honoraria; Pfizer: Honoraria; Biotest: Honoraria; Baxalta: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria, Research Funding. Mingot-Castellano:Amgen: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy; Bayer: Consultancy, Research Funding. Chitlur:Novo Nordisk: Consultancy; Baxalta: Honoraria; Bayer: Honoraria; Biogen-Idec: Honoraria; Pfizer: Honoraria. Fogarty:Bayer Healthcare: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Baxter/Baxalta: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Biogen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity9s Board of Directors or advisory committees; CSL Behring: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Employment, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Spark Therapeutics: Research Funding. Cuker:T2 Biosystems: Research Funding; Genzyme: Consultancy; Biogen-Idec: Consultancy, Research Funding; Amgen: Consultancy; Stago: Consultancy. Mancuso:Bayer Healthcare: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Sobi/Biogen Idec: Consultancy, Speakers Bureau; Pfizer: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Kedrion: Consultancy. Holme:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Investigator Clinical Studies. Mathew:Bayer: Employment. James:CSL Behring: Research Funding; Octapharma: Research Funding; Biogen: Consultancy; Basalt: Consultancy; Bayer: Research Funding.