Hemophilia A, an inherited bleeding disorder caused by deficiency in clotting factor VIII (FVIII), continues to present significant clinical challenges despite advances in treatment options. Recent research emphasizes that maintaining higher FVIII levels—rather than just meeting minimum thresholds—may be key to improving long-term outcomes for patients.
Clinical Impact of Hemophilia A
People with hemophilia A experience recurring joint bleeds, primarily affecting knees, ankles, and elbows. These bleeds lead to hemophilic arthropathy, joint impairment, chronic pain, and diminished quality of life. Even a single bleed can trigger vascular changes that facilitate further bleeding, chronic inflammation, and permanent damage to cartilage and bone.
According to the World Federation of Hemophilia (WFH), patients with mild hemophilia A (FVIII levels 5-40 IU/dL) remain vulnerable to traumatic and surgical bleeds. A retrospective study found that approximately half of patients with FVIII levels of 5 IU/dL were predicted to experience some form of bleeding over a one-year period.
Pain management represents a primary concern, with meta-analysis data showing that 47% of people with hemophilia experience chronic pain. Notably, prophylaxis does not appear to significantly change this rate, with 46% of men receiving primary prophylaxis still reporting ongoing pain in one study.
The condition also impacts bone health, with hemophilia patients showing reduced bone mineral density (BMD) and increased risk of osteoporosis compared to the general population. Evidence suggests FVIII may play a role in bone remodeling beyond its function in coagulation.
Evolving Treatment Goals
The WFH has established a clinical goal of zero bleeds for people with hemophilia A. While historically the primary goal of prophylaxis was maintaining factor levels above 1 IU/dL (1%), growing evidence demonstrates that factor trough levels of 1-3 IU/dL are insufficient to prevent disease progression in all patients.
"In general, the higher the factor levels at all times, the less the bleeding," note WFH guideline authors, who now advocate for maximizing FVIII trough levels. Expert opinions recommend minimum FVIII activity levels of 4% for low-risk activities and 38% for high-risk activities in individuals without joint morbidity, with even higher levels (7% and 47%, respectively) for those with known joint disease.
Treatment goals are shifting from what is minimally feasible to focusing on achieving optimal health equity. Higher FVIII levels are associated with lower bleeding risk during activities and may enable patients to lead more active lifestyles. FVIII activity levels above 50% of normal may allow individuals to participate in high-impact activities, including sports, without disease-related pain.
Treatment Options and FVIII Levels
Several treatment approaches are available for hemophilia A, each with different capabilities for sustaining elevated FVIII trough levels:
Standard and Extended Half-Life Replacement Therapies
Standard half-life (SHL) FVIII replacement therapies typically require infusions 3-4 times weekly. Extended half-life (EHL) products can be administered less frequently or, if given at the same frequency, offer greater bleed protection. The PROPEL study demonstrated that targeting higher trough levels with an EHL more effectively reduced bleed rates than targeting lower trough levels, though 72% of participants targeting higher trough levels (≥10%) required dosing at least every other day.
Non-Factor Replacement Therapies
Emicizumab-kxwh (Hemlibra) is a bispecific antibody that binds to both activated factor IX and factor X, compensating for missing activated FVIII. Administered subcutaneously, it can be dosed weekly, every 2 weeks, or every 4 weeks after an initial loading period. The HAVEN studies showed that prophylaxis with emicizumab results in low bleed rates and enhanced quality of life compared to previous treatments.
Marstacimab-hncq (Hympavzi), approved in October 2024, is the only FDA-approved tissue factor pathway inhibitor antagonist for hemophilia A. This monoclonal antibody neutralizes TFPI, enhancing coagulation, and is administered subcutaneously at 150 mg once weekly after a loading dose.
Gene Therapy
Valoctocogene roxaparvovec-rvox (Roctavian) is the only FDA-approved gene therapy for hemophilia A. It introduces a functional copy of a transgene encoding a deleted form of FVIII in the liver. While phase 3 trials demonstrated increased FVIII activity and reduced bleeding sustained over 2 years, FVIII expression is expected to decrease over time, with variability in FVIII activity levels observed by year 2 following therapy.
High-Sustained FVIII Replacement Therapy
Efanesoctocog alfa (Altuviiio), approved by the FDA in 2023, is a first-in-class FVIII replacement therapy. This rFVIII analogue fusion protein is independent of endogenous von Willebrand factor, which typically imposes a half-life ceiling on other agents. In the XTEND-1 study, once-weekly efanesoctocog alfa offered superior bleed protection compared to previous standard-of-care FVIII prophylaxis, with mean annualized bleed rate decreasing by 77%.
Managed Care Considerations
Despite advances in treatment options, significant barriers to optimal care remain. The WFH recommends that patients receive care from a comprehensive, multidisciplinary team of healthcare professionals specialized in hemophilia, preferably at a designated hemophilia treatment center.
Treatment adherence is a major concern, especially during the transition to self-infusion during adolescence. Lower adherence is linked to decreased treatment effectiveness, resulting in bleeding and complications. A meta-analysis of 73 studies identified the primary barrier to adherence as the perceived high burden of treatment, which often involves frequent, time-consuming administration.
Limited access to comprehensive hemophilia care centers and insurance restrictions can adversely affect patient outcomes. An analysis of commercial coverage policies for hemophilia A treatments found that 57% covered a more limited patient population than specified by FDA labeling, with 30% including step-therapy mandates requiring patients to fail other treatments before reimbursement for specific FVIII products.
Persistent Unmet Needs
Despite advancements in treatment options, unmet needs persist in hemophilia management. A recent real-world study (explorer6) across 33 countries assessed the unmet needs of patients with hemophilia A and B, both with and without inhibitors.
The study found that annualized bleeding rates were generally lower for patients receiving prophylaxis compared to on-demand treatment. However, significant challenges remain, particularly for patients with inhibitors—antibodies that neutralize infused factor VIII or IX—who often have limited treatment options, leading to higher disease burden and reduced health-related quality of life.
Conclusion
While significant progress has been made in hemophilia A treatment, standard-of-care prophylaxis does not prevent or reverse joint damage or change the rate of chronic pain reported by patients. The WFH advocates for maximizing FVIII trough levels, but FDA-approved treatments vary in their ability to sustain high FVIII levels.
A holistic approach combining early intervention, personalized prophylaxis, and strategies to address treatment barriers is essential to achieving better outcomes and the WFH goal of zero bleeds. Comprehensive care, individualized treatment, and overcoming barriers to treatment access remain fundamental goals in the managed care of patients with this rare disease.
