Impaired Bone Health and Wound Dehiscence in Carriers of Hemophilia a and B

Introduction: FVIII and FIX have a well-established pivotal role in the promotion and maintenance of hemostasis. There is emerging evidence, however, for a role of FVIII and FIX in regulating processes beyond thrombin generation, such as bone health and macrophage function affecting wound healing. Previous studies on bone mineral density (BMD) and fractures have primarily investigated persons with hemophilia A (PwHA) and hemophilia B (PwHB), but not hemophilia carriers. It has been estimated that 35% of hemophilia carriers have FVIII and FIX levels below 40IU/dL. However, it is not known if hemophilia carriers have a similar potential to develop decreased BMD and poor wound healing as PwHA or PwHB. This study aims to assess the prevalence of bone health issues and wound healing among women who are hemophilia carriers comparing them to control women in the general population.

Methods: A commercial database (Explorys Inc, Cleveland, OH, USA), an aggregate of electronic health record data from 26 major integrated US healthcare systems, was queried for data, using Systematized Nomenclature of Medicine (SNOMED) clinical terms or codes. Cases were defined as female patients of any age, with a diagnosis of Hemophilia carrier. Controls were defined as female patients of any age, with at least one medical encounter, and who did not have a diagnosis of Hemophilia Carrier. The prevalence rates of osteoporosis, osteoarthritis, fractures and wound dehiscence among cases and controls were estimated based on binomial distribution theory. The prevalence rates of the comorbidities were compared in the Hemophilia Carrier group and control group using chi-square or Fisher's exact test, and relative risk calculations for bone health issues were adjusted for age > 50, as the risk of osteoporosis and osteoporotic fractures is higher in post-menopausal women above the age of 50.

Results: Our database search identified 740 hemophilia carriers and 34,129,790 women in the control group (Table 1). Among the hemophilia carrier group, there was increased prevalence of osteoporosis (7% vs 3.6%, p<0.0001), osteoarthritis (26% vs 11%, p<0.0001), and fractures (12% vs 6%), p<0.0001) as compared to the control group. Wound dehiscence had a prevalence of 270 cases per 10,000 in the hemophilia carrier group, vs 120 per 10,000 in the control group. The age-adjusted relative risk of osteoporosis, osteoarthritis, and fractures due to hemophilia was 2.72 (95% CI 2.20 to 3.41), 2.85 (95% CI: 2.55 to 3.17), and 2.57 (95% CI: 2.16 to 3.05), respectively (Table 2).

Conclusions: Our study suggests an association between hemophilia carrier state and poor bone health and wound healing. Prospective studies are required to confirm these findings, including the role of factor levels in these patients in relation to bone turnover markers and macrophage function. This data may also have relevance for the importance of exposure to factor in the era of emerging non-factor therapies in hemophilia.

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