Medical Director Boston Bleeding Disorders Center Boston, United States
Elimination of spontaneous bleeding is paramount for hemophilia patients of all ages. As such, prophylaxis is the standard of care for hemophilia patients with a severe bleeding phenotype. Innovation in hemostatic therapies (engineered clotting factor concentrates, FVIIIa mimetics, gene therapies, rebalancing agents) has facilitated emergence of products with the capability of sustaining individuals in at least the mild hemophilia disease range thus bolstering hemostatic protection above mere prevention of spontaneous bleeding, to the prevention of situationally abnormal bleeding with participation in more rigorous physical activities including work requirements and athletic pursuits. Assessment of bleed prevention remains a fundamental efficacy outcome for hemophilia products intended for prophylaxis; however, given the efficacy of many of these novel therapies, achieving bleed prevention is no longer an adequate outcome measure for differentiating among hemophilia products.
The annualized bleed rate (ABR) remains the most common metric to report bleed events but has inherent logistical challenges and analytic limitations. Although bleed events can be objectively documented as with overt peri-procedural bleeding or abnormal musculoskeletal imaging, in most cases bleeding is based on subjective patient-reported/clinician-assessed symptoms, perhaps informed by a formal definition such as that published by the ISTH SSC FVIII/IX & RBD subcommittee or one defined by the trial protocol. Many factors such as the presence of hemophilic arthropathy or mechanism of acute injury, may impact whether the symptoms indicate a "true" bleed as a sign of prophylaxis failure versus an alternative etiology. Implementation of new technologies including use of point-of-care ultrasound provide valuable tools for increasing assessment objectivity, however, are still hampered by several logistical challenges.
Direct comparison between and among prophylaxis therapeutics for hemophilia is needed across all age ranges and prior factor concentrate exposure groups to better differentiate the efficacy, therapeutic burden, treatment-related risk profile, and impacts on quality of life and the concept of a “disease-free” mindset. In our youngest hemophilia cohort now initiating primary prophylaxis, bleed prevention, potential alteration of the risk of clotting factor alloantibody development “inhibitors” due to the infrequent cadence of factor exposures, and natural history of musculoskeletal changes will be critical outcomes to follow longitudinally.
Learning Objectives:
Licensed, innovative prophylaxis options now include numerous therapeutic categories: engineered clotting factor concentrates, FVIIIa mimetics, gene therapies, and biologics to bolster thrombin generation (rebalancing agents). Many of these therapeutic categories are still not approved in young children (< 12 years old), let alone PUPs, and are still not readily available in many parts of the world. Comparative clinical trial design and execution of registry studies with thoughtful hemophilia outcome measures will be critical in capturing the short-term and longitudinal utility of these therapies on bleed prevention, incremental improvements in musculoskeletal health, and impact on life quality and functionality.
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