Introduction: Factor IX (FIX) deficiency (FIXdef) is an X-linked disorder where affected males manifest various hemorrhagic tendencies based on the severity of deficiency. Women who carry the causal mutation exhibit a range of FIX activity levels (FIXact) and may experience bleeding when the FIXact is below the minimum hemostatic level. There is a paucity of reported data regarding the range of FIXact and bleeding events in FIX carriers. We report the FIXact and associated bleeding symptoms in the female carriers of a large kindred of moderate FIXdef caused by a common point mutation (31008 C>T [thr296met]).
Methods: Since 2000, our facility has compiled a database containing information on over 1300 patients with bleeding disorders, including 402 males with FIXdef representing 98 families, 469 confirmed FIX carriers, and 406 at-risk females not yet tested for carrier status. Overall there are 121 FIX carriers with FIX act; this kindred represents 108 documented carriers of which 83 have had FIXact. In this kindred, data on FIXact and bleeding symptoms were collected on carriers. A bleeding symptom questionnaire was developed specific to this population and administered to the target population; at this time questionnaires on 42 of the known carriers is available. Responses on the questionnaire were compared to the FIXact to determine if a correlation existed between reported symptoms/events to FIXact.
Data: For 83 female carriers included in this kindred’s analysis, the mean FIXact was 52% (range 14–114%, median 46%). Of the 42 women completing the bleeding questionnaire, the mean FIXact was 50.2% (range 21–114% median 41%). Typical bleeding events reported included epistaxis, postpartum bleeding, menorrhagia, and easy bruising. By comparing reported bleeding events to FIXact we found that women with FIXact <40% reported increased rate of easy bruising/hematoma formation (9.8% vs. 2.4%) and postoperative bleeding (14.6% vs. 2.4%) compared to women with FIXact >40%. While other bleeding events demonstrated no direct correlation with FIXact, our limited sample available at this time likely impacted this association.
Conclusions: This effort represents the largest report of data from a single kindred of FIX deficiency to date. Female carriers in this kindred have an identical mutation causing moderate FIXdef, yet exhibit a wide range of FIXact; the etiology for this variability is not known and requires further investigation. Ongoing data collection in our FIX carrier population will provide additional information to determine an association between the range of FIXact and bleeding symptoms. FIX carriers require documentation of levels (regardless of the level of deficiency for which the specific mutation codes) and monitoring of symptoms, particularly related to childbirth or surgery, as treatment with exogenous FIX may be required for prevention of hemorrhage and optimal care.
Disclosure:Consultancy: Dr. Shapiro has served as a consultant for: Baxter BioScience, Kedrion, Inspiration Biopharmaceuticals, Syntonix. Research Funding: Dr. Shapiro has reported research funding from: Baxter BioScience, Novo Nordisk, Bayer, Wyeth, Octagen, CSL Behring, Syntonix, Inspiration Biopharmaceuticals. Membership Information: Dr. Shapiro reports serving for the Scientific Advisory Board for these agencies: Bayer, Syntonix, Kedrion, Inspiration Biopharmaceuticals, Baxter BioScience.