This study will compare bone mineral density in patients with severe hemophilia A receiving prophylaxis with emicizumab or efanesoctocog alfa. Participants will undergo assessments of bone mineral density, bone remodeling biomarkers, thrombin generation, plasmin generation, and joint health over a five-year period. The study aims to evaluate whether differences in prophylactic therapy are associated with differences in bone health outcomes.

Reduced bone mineral density, osteoporosis, and fractures are increasingly recognized in persons with severe hemophilia A. The mechanisms underlying impaired bone health in hemophilia are multifactorial and may include reduced physical activity, chronic joint disease, inflammation, and abnormalities in coagulation-related pathways involved in bone remodeling.

Thrombin has been shown to play an important role in bone metabolism through activation of protease-activated receptor-1 (PAR-1) signaling pathways that influence osteoblast and osteoclast activity. Reduced thrombin generation in severe hemophilia A may contribute to decreased bone formation and increased bone resorption.

Efanesoctocog alfa is an extended half-life factor VIII replacement therapy that maintains higher circulating factor VIII levels and supports thrombin generation. Emicizumab is a non-factor prophylactic therapy that effectively prevents bleeding but does not replace factor VIII. The comparative effects of these therapies on long term bone health have not been well established.

This prospective observational study will compare longitudinal changes in bone mineral density among patients with severe hemophilia A receiving prophylaxis with emicizumab or efanesoctocog alfa over 5 years. Participants will undergo serial dual-energy X-ray absorptiometry (DXA) assessments and evaluation of bone remodeling biomarkers, inflammatory cytokines, thrombin generation, plasmin generation, and joint health over a five-year period.

Inclusion Criteria:

1. The participant or legally authorized representative is willing and able to provide written informed consent.
2. Diagnosis of severe hemophilia A (factor VIII activity < 1%).
3. Male sex.
4. Age between 30 and 50 years (inclusive).
5. BMI between 18.5 and 40 kg/m2
6. The participant must have been on prophylaxis with Efanesoctocog alfa or Emicizumab for at least 3 months prior to enrollment and intend to remain on the current regimen for the next 5 years.
7. Willingness to undergo all research procedures, including DEXA scans and the collection of blood samples.
8. Willingness to complete all standard-of-care bleeding and treatment logs.

Exclusion Criteria:

1. Unwillingness of the participant, parent, or legally authorized representative to provide informed consent.
2. Diagnosis of a bleeding disorder other than or in addition to severe hemophilia A.
3. Active Factor VIII inhibitors at the time of enrollment
4. History of a disease known to influence bone metabolism unrelated to a bleeding disorder. (Examples: Paget's disease, osteogenesis imperfecta, Ehlers Danlos syndrome, Hyperparathyroidism)
5. Past or present treatment with any anti-osteoporotic medication, excluding oral vitamin D or oral calcium supplements.
6. Documented HIV infection or HCV infection (whether in progress or cured) at the cirrhotic stage.
7. Presence of a non-removable metal device that would interfere with research procedures.
8. Inability to tolerate a DEXA scan due to limited range of motion or body habitus.
9. History of bone fractures or surgical repair within 8 weeks prior to enrollment.
10. Participants with weight >300 pounds, due to limitations of DEXA scanner

Males

Patients that are seen at dedicated Hemophilia treatment Centers

Individual participant data will not be shared with with other researchers , and each participating site has access to only their centers data; however , aggregated data will be included in future publications and will be made available toparticipating centers following study completion