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Background: Hemophilia is a bleeding disorder associated with frequent hemarthroses and ensuing debilitating arthropathies. Patients with hemophilia (PWH) are encouraged to participate in low impact physical activities to improve joint health, mobility, and quality of life (QoL). However, activities such as walking, swimming or physical therapy are often perceived as "boring", which results in participation in high risk activities that may cause injury or bleeding. Indoor therapeutic rock climbing is practiced successfully to improve physical and psychological well-being in patients with neuromuscular disorders, and may be a "fun" alternative for PWH. The aim of this study was to investigate the safety of therapeutic rock climbing and its effects on joint health for PWH with arthropathies. Methods: Twelve adult male patients (median age 31 years, IQR=24,41) with moderate to severe hemophilia A and arthropathies (defined by decreased normative range of motion (ROM)) were recruited from the Hemophilia Treatment Centers at University of California, San Diego, USA (UCSD) and Ludwig Maximilians University, Munich, Germany (LMU)). All participants completed 12 sessions of individually tailored indoor top rope rock climbing, instructed by a climbing coach and physical therapist. Functional and clinical joint status including ROM, Hemophilia Joint Health Score (HJHS) for elbows, knees, and ankles (n=12), climbing skills (UCSD: Yosemite Decimal Scale; LMU: Union Internationale des Associations d'Alpinisme scale), QoL measures (UCSD: Haem-A-Qol, Hep-Test-Q; LMU: Hemo-Qol-A), annual bleed rate (ABR), and clotting factor consumption were assessed in both cohorts (UCSD n=6; LMU n=6) pre and post climbing. Additionally, effects on cartilage health, joint inflammation and soft tissue hypertrophy were assessed by musculoskeletal ultrasound and power doppler (MSKUS/PD) in the UCSD cohort. Descriptive statistics and Wilcoxon matched-pairs signed-rank tests were used for data analysis. Data are expressed as median and inter-quartile range; p-values ≤ 0.05 were considered significant. Results: Compared to baseline, HJHS improved significantly after completion of the program (16.5 [IQR=6.0, 28.5] post vs 17.5 [6.0, 35.0] pre; n=12; p = 0.03). A significant increase in dorsiflexion was evident in arthropathic ankles (0 degrees [IQR= -4, 4] post vs -4 [IQR-10, -3] pre; n = 9; p Conclusions:Therapeutic rock climbing is not only safe but improves joint health and well-being in PWH with advanced arthropathies without triggering excessive clotting factor consumption. "Hemophilia Vertical" is an innovative athletic concept without the "boring" stigma of other low impact sports, and should be promoted to advance athletic hemophilia care concepts. Disclosures von Drygalski: Pfizer: Consultancy, Honoraria, Speakers Bureau; Biogen: Consultancy, Honoraria, Speakers Bureau; CSL-Behring: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Baxalta/Shire: Consultancy, Honoraria, Speakers Bureau; Hematherix LLC: Membership on an entity's Board of Directors or advisory committees.

Neoangiogenesis and vascular remodeling in the hypertrophic synovium of arthropathic hemophilic joints may disturb vascular integrity and contribute to repeated bleeding (A von Drygalski, et al. Vascular Remodeling Underlies Re-Bleeding in Hemophilic Arthropathy; ASH 2015; Abstract ID 78677). However, it is difficult to distinguish the importance of the contribution of abnormal vascular structures to hemophilic joint bleeding from the contribution of low clotting factor levels. This is because most prophylactic clotting factor replacement strategies are designed to avoid trough levels below 1-5%, but not to fully correct the factor deficiency. This report reveals the importance of aberrant angiogenesis for joint bleeding in two hemophilia patients whose clotting factor activity levels were constantly normal or near normal. The first patient had severe Hemophilia A with normalized Factor (f)VIII activity levels after liver transplantation 6 years previously. Abnormal vascularization of elbows, knees and ankles (absent bleeding) was detected by musculoskeletal ultrasound and Power Doppler (PD). Three months after the baseline exam the patient experienced severe elbow bleeding associated with new vascular changes on PD. These changes were characterized by pronounced confluent, patchy vascular signals and numerous enlarged and thickened vessels by angiography consistent with acute and chronic vascular remodeling. Bleeding could not be controlled by increasing fVIII activity to supra-normal levels, and ultimately required synovial embolization. The second patient has severe Hemophilia B and presented shortly after left knee joint replacement with fluctuating knee bleeding for many months associated with pronounced dynamic vascular changes on PD. Neither bleeding nor vascular changes were prevented by daily fIX treatment which maintained near normal plasma fIX activity levels. Within one year, additional chronic bleeding with vascular changes developed in the left elbow and left ankle and remained unresponsive to intense factor replacement. These cases provide several insights. First, vascular changes in hemophilic arthropathy persist and evolve in dynamic fashion even in the presence of normal clotting factor activities. Second, vascular disturbance and leakiness contributed to bleeding independent of clotting factor activity levels as exemplified by the first patient and as suggested by the second patient. Third, the sequence of bleeding events in the second patient suggests that at least some of the observed vascular abnormalities are mediated systemically. These observations provide clinical evidence in support of the hypothesis that neoangiogenesis and vascular remodeling contribute to hemophilic joint bleeding and should lead to new studies of the pathophysiology of vascular remodeling in such joints. Targeting angiogenesis may emerge as a new treatment strategy to enhance the effectiveness of clotting factor replacement hemophilic arthropathy. Disclosures Chang: Biogen: Research Funding. Rose:Sirtex Medical: Equity Ownership, Honoraria; XLSciTech: Consultancy; Surefire Medical: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Embolx: Consultancy. von Drygalski:Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Research Funding; Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.