Hemophilia Prophylaxis in the Era of Non-Factor Therapies

---

---

Check out our extensive video library (see channel for our latest videos)

---

---

Introduction

Hemophilia affects approximately 400,000 people worldwide, with most cases being hemophilia A (factor VIII deficiency) or hemophilia B (factor IX deficiency). For decades, the standard approach to prevent bleeding episodes has been regular infusions of clotting factor concentrates. While effective, this approach comes with significant challenges including frequent intravenous administration, development of inhibiting antibodies, and high treatment costs.

The landscape of hemophilia care has shifted with the development of non-factor therapies. These treatments work through different mechanisms than traditional factor replacement, offering new possibilities for prophylactic care. Emicizumab, approved for hemophilia A, mimics factor VIII function and can be given subcutaneously. Other therapies in development target different parts of the clotting process, potentially expanding options for both hemophilia A and B patients.

Understanding these new therapies is crucial for healthcare providers. The decisions around when to use non-factor therapies, how to combine them with traditional treatments, and how to monitor patients require careful consideration. This paper provides a comprehensive examination of current non-factor options and their role in modern hemophilia prophylaxis.

---

Current Landscape of Hemophilia Prophylaxis

Traditional Factor Replacement Therapy

Factor replacement therapy has been the backbone of hemophilia treatment since the 1960s. Patients receive regular infusions of factor VIII or IX concentrates to maintain adequate clotting factor levels. This approach significantly reduces spontaneous bleeding episodes and joint damage compared to on-demand treatment.

Standard prophylaxis protocols typically involve infusions every other day for hemophilia A and twice weekly for hemophilia B. The goal is to maintain factor levels above 1% of normal, though many experts now recommend target trough levels of 3-5% or higher for optimal joint protection.

Despite its effectiveness, factor replacement therapy has limitations. Intravenous access can be challenging, especially in young children. The frequency of infusions affects quality of life and treatment adherence. Most significantly, 25-30% of people with severe hemophilia A develop neutralizing antibodies (inhibitors) that make factor VIII ineffective.

The Need for Alternative Approaches

Several factors have driven the search for alternative prophylactic strategies. Inhibitor development remains a major clinical challenge, requiring expensive and complex treatment with bypassing agents or immune tolerance induction. Even without inhibitors, some patients experience breakthrough bleeding despite regular prophylaxis.

Quality of life considerations also play a role. Many patients, particularly adolescents and young adults, struggle with the burden of frequent intravenous infusions. This can lead to reduced adherence and increased bleeding risk. Additionally, the high cost of factor concentrates creates access challenges in many healthcare systems.

The development of non-factor therapies addresses these limitations by offering different mechanisms of action, alternative routes of administration, and potentially improved convenience and effectiveness.

---

Non-Factor Therapy Options

Emicizumab (Hemlibra)

Emicizumab represents the first approved non-factor therapy for hemophilia A prophylaxis. This humanized bispecific antibody mimics the function of factor VIII by bridging factor IXa and factor X, allowing the coagulation cascade to proceed normally.

The drug offers several advantages over traditional factor VIII. It can be administered subcutaneously, eliminating the need for intravenous access. The half-life of approximately 4-5 weeks allows for weekly, every two weeks, or even monthly dosing after an initial loading period. Emicizumab is effective regardless of inhibitor status, making it valuable for patients who cannot use factor VIII.

Clinical trials have demonstrated impressive efficacy. The HAVEN studies showed that emicizumab prophylaxis reduced bleeding rates by 87% compared to no prophylaxis and by 68% compared to factor VIII prophylaxis in patients without inhibitors. In patients with inhibitors, bleeding reductions of 79-87% were observed compared to bypassing agent prophylaxis.

Safety data from clinical trials and real-world experience show emicizumab is generally well-tolerated. The most common side effects include injection site reactions and headache. More serious concerns include thrombotic microangiopathy and thromboembolism, particularly when used with activated prothrombin complex concentrates for breakthrough bleeding treatment.

RNA Interference Therapies

Fitusiran represents a different approach to hemophilia prophylaxis through RNA interference (RNAi) technology. This small interfering RNA targets antithrombin, a natural anticoagulant that inhibits several clotting factors. By reducing antithrombin levels, fitusiran restores hemostatic balance in people with hemophilia.

The advantage of targeting antithrombin is that it works for both hemophilia A and B, regardless of inhibitor status. Clinical trials have shown promising results, with monthly subcutaneous injections reducing bleeding rates significantly in both patient populations.

Safety monitoring for fitusiran focuses on thrombotic risk due to the reduction in natural anticoagulant activity. Careful patient selection and monitoring protocols are essential, particularly for patients with additional thrombotic risk factors.

Other RNAi therapies in development target different components of the coagulation system, potentially expanding treatment options for various patient populations.

Tissue Factor Pathway Inhibitor Antagonists

Another class of non-factor therapies works by blocking tissue factor pathway inhibitor (TFPI), which normally regulates the initiation of coagulation. By reducing TFPI activity, these therapies enhance thrombin generation and improve hemostasis in people with hemophilia.

Concizumab, an anti-TFPI antibody, has shown efficacy in clinical trials for both hemophilia A and B patients. The therapy can be administered subcutaneously and works regardless of inhibitor status. However, development has faced challenges, including cases of non-fatal thromboembolism that led to temporary holds in clinical trials.

Protein S Mimetics

Protein S mimetics represent an emerging approach that targets the protein S/tissue factor pathway inhibitor interaction. These therapies aim to improve hemostatic balance by modulating natural anticoagulant pathways.

While still in early development stages, protein S mimetics show promise as potential treatments for both hemophilia A and B, offering another mechanism of action for patients who may not be suitable candidates for other non-factor therapies.

---

Clinical Applications and Patient Selection

Choosing Appropriate Candidates

Patient selection for non-factor therapies requires careful consideration of multiple factors. Current treatment response, bleeding patterns, lifestyle factors, and patient preferences all play important roles in decision-making.

Patients with inhibitors represent an obvious target population for non-factor therapies. These individuals often have suboptimal bleeding control with bypassing agents and may benefit significantly from alternatives like emicizumab. The subcutaneous route of administration can be particularly valuable for patients with difficult venous access.

Young children and their families may prefer non-factor therapies to avoid the challenges of regular intravenous infusions. The improved convenience can lead to better treatment adherence and potentially better long-term outcomes.

Adults with demanding schedules or frequent travel may find the reduced dosing frequency of non-factor therapies appealing. Healthcare providers should consider quality of life factors when discussing treatment options with patients.

Integration with Existing Treatment Protocols

Incorporating non-factor therapies into existing treatment protocols requires careful planning. Transition strategies vary depending on the patient’s current treatment and the chosen non-factor therapy.

For patients switching from factor prophylaxis to emicizumab, the transition period requires attention to timing and monitoring. The loading dose schedule for emicizumab should be coordinated with the last factor infusion to maintain adequate hemostatic coverage.

When treating breakthrough bleeding in patients on non-factor therapies, healthcare providers must be aware of potential interactions. Emicizumab patients experiencing bleeding typically require factor VIII or IX for treatment, while bypassing agents should be used cautiously due to thrombotic risk.

Patient education becomes particularly important when introducing non-factor therapies. Patients need to understand the different mechanism of action, the importance of adherence to the new dosing schedule, and when to seek medical attention for bleeding episodes.

Monitoring and Laboratory Considerations

Monitoring patients on non-factor therapies presents unique challenges. Traditional coagulation tests like activated partial thromboplastin time (aPTT) may not accurately reflect hemostatic function in patients receiving these treatments.

For emicizumab patients, standard factor VIII activity assays become unreliable. Alternative monitoring strategies focus on clinical bleeding assessment rather than laboratory parameters. When laboratory monitoring is needed, chromogenic factor X-based assays may provide more accurate results.

Global coagulation assays like thrombin generation tests and viscoelastic testing methods show promise for monitoring non-factor therapies, but their clinical utility is still being established. Healthcare providers must rely more heavily on clinical assessment of bleeding patterns and treatment response.

Regular safety monitoring remains important, particularly for therapies that affect natural anticoagulant pathways. This includes monitoring for signs of thrombotic complications and assessing liver function when appropriate.

---

Comparative Analysis: Non-Factor vs Traditional Therapies

Efficacy Comparison

Direct comparisons between non-factor and traditional therapies show varying results depending on the specific treatments and patient populations studied. Emicizumab has demonstrated superior bleeding protection compared to no prophylaxis and comparable or superior protection compared to factor VIII prophylaxis in clinical trials.

The HAVEN-3 study directly compared emicizumab to factor VIII prophylaxis in patients without inhibitors, showing a 68% reduction in treated bleeds with emicizumab. However, this comparison involved patients who had previously experienced bleeding on factor prophylaxis, which may have influenced the results.

For patients with inhibitors, non-factor therapies generally show superior efficacy compared to bypassing agent prophylaxis. This represents a significant advancement for this challenging patient population.

Long-term joint health outcomes with non-factor therapies are still being studied, but early data suggest comparable joint protection to traditional factor prophylaxis when adequate bleeding control is achieved.

Safety Profiles

The safety profiles of non-factor and traditional therapies differ significantly. Factor concentrates have decades of safety data, with low rates of serious adverse events. The main safety concern with plasma-derived products is pathogen transmission, though modern viral inactivation methods have made this extremely rare.

Non-factor therapies introduce different safety considerations. Emicizumab’s association with thrombotic microangiopathy and thromboembolism, while rare, requires careful monitoring and patient education. These events are most commonly associated with concurrent use of activated prothrombin complex concentrates.

The immunogenicity profiles also differ. While factor concentrates can induce inhibitor development, non-factor therapies may cause different immune responses. Anti-drug antibodies to emicizumab have been reported but appear to have minimal clinical impact in most cases.

Long-term safety data for non-factor therapies is still accumulating. Healthcare providers must weigh the known risks of traditional therapies against the evolving safety profile of newer options.

Quality of Life Impact

Quality of life improvements represent one of the most significant advantages of non-factor therapies. The reduced dosing frequency and subcutaneous administration route can dramatically improve patient satisfaction and treatment adherence.

Studies consistently show that patients prefer less frequent dosing when given the choice. The ability to self-administer subcutaneous injections, often learned more easily than intravenous techniques, can increase patient independence and reduce healthcare utilization.

For families with young children, non-factor therapies can reduce the stress and difficulty associated with regular intravenous access. This can improve family dynamics and reduce treatment-related anxiety.

However, some patients may prefer the familiar routine of factor prophylaxis or feel more confident with treatments that have longer safety records. Patient preferences should always be considered in treatment decisions.

Cost Considerations

The economic impact of non-factor therapies compared to traditional factor replacement is complex and varies by healthcare system. While non-factor therapies often have high upfront costs, they may offer savings through reduced healthcare utilization and improved productivity.

Emicizumab’s reduced dosing frequency can lower administration costs and reduce the burden on healthcare systems. Patients may require fewer clinic visits and experience fewer missed work or school days due to treatment or bleeding episodes.

For patients with inhibitors, non-factor therapies may provide cost savings compared to expensive bypassing agents or immune tolerance induction protocols. The improved bleeding control may also reduce costs associated with joint damage and orthopedic interventions.

Cost-effectiveness analyses are ongoing, but early data suggests that non-factor therapies may be economically favorable in certain patient populations, particularly those with inhibitors or high bleeding rates on traditional prophylaxis.

---

Challenges and Limitations

Clinical Challenges

Several clinical challenges complicate the use of non-factor therapies in routine practice. The lack of established laboratory monitoring methods makes it difficult to assess treatment adequacy objectively. Healthcare providers must rely primarily on clinical bleeding assessment, which can be subjective and may miss subclinical changes in hemostatic function.

Managing breakthrough bleeding in patients on non-factor therapies requires different approaches than traditional factor replacement. The potential for drug interactions, particularly with bypassing agents in emicizumab patients, necessitates careful treatment planning and patient education.

The development of treatment protocols for surgery and invasive procedures in patients receiving non-factor therapies remains an area of active investigation. Limited data exists on optimal perioperative management, creating uncertainty for healthcare providers and patients.

Patient Selection Limitations

Not all patients are suitable candidates for non-factor therapies. Age restrictions, comorbidities, and concurrent medications may limit treatment options. For example, fitusiran may not be appropriate for patients with increased thrombotic risk factors.

Some patients may not respond adequately to non-factor therapies, experiencing continued bleeding despite treatment. The mechanisms underlying variable treatment response are not fully understood, making it difficult to predict which patients will benefit most.

Patient and family preferences also play a role in treatment selection. Some individuals may prefer traditional therapies due to familiarity, perceived safety, or specific lifestyle factors that make non-factor therapies less convenient.

Healthcare System Challenges

Implementation of non-factor therapies requires significant changes in healthcare delivery systems. Staff training, new monitoring protocols, and updated treatment guidelines all require time and resources to implement effectively.

Access to non-factor therapies varies significantly between healthcare systems and geographic regions. Cost considerations, regulatory approval timelines, and reimbursement policies all affect patient access to these treatments.

The need for specialized expertise in managing non-factor therapies may create disparities in care quality. Centers with limited hemophilia experience may struggle to implement these treatments safely and effectively.

 

---

Future Directions and Research

Emerging Therapies

The pipeline of non-factor therapies for hemophilia continues to expand. Gene therapy approaches show promise for providing long-term treatment with single or infrequent dosing. Early results from gene therapy trials demonstrate sustained factor expression and reduced bleeding rates, though long-term safety and durability data are still being collected.

New targets for non-factor therapies are being explored, including other components of the coagulation and fibrinolytic systems. These approaches may offer additional options for patients who do not respond adequately to current therapies.

Combination approaches using multiple non-factor therapies simultaneously are being investigated. The potential for enhanced efficacy must be balanced against increased complexity and safety concerns.

Personalized Medicine Approaches

The future of hemophilia treatment likely lies in personalized medicine approaches that match specific therapies to individual patient characteristics. Genetic markers, bleeding phenotypes, and lifestyle factors may all play roles in determining optimal treatment strategies.

Biomarkers that predict treatment response to non-factor therapies are being investigated. These tools could help healthcare providers select the most appropriate treatments for individual patients and optimize dosing strategies.

Pharmacokinetic modeling and simulation techniques may enable more precise dosing of non-factor therapies, potentially improving efficacy while minimizing side effects.

Long-term Outcome Studies

Long-term studies following patients treated with non-factor therapies are essential for understanding the true clinical impact of these treatments. Joint health outcomes, quality of life measures, and safety profiles need to be assessed over decades rather than years.

Comparative effectiveness research comparing different non-factor therapies will help guide treatment selection as more options become available. Head-to-head trials may be needed to establish relative benefits and risks.

Real-world evidence studies using patient registries and administrative databases will complement clinical trial data and provide insights into treatment effectiveness in diverse patient populations.

---

Practical Implementation Guidelines

Establishing Treatment Protocols

Healthcare centers implementing non-factor therapies need comprehensive protocols covering patient selection, treatment initiation, monitoring, and breakthrough bleeding management. These protocols should be developed by multidisciplinary teams including hematologists, nurses, pharmacists, and other relevant specialists.

Patient education materials specifically designed for non-factor therapies are essential. These should cover mechanism of action, administration techniques, side effect recognition, and when to seek medical attention.

Staff training programs should ensure that all team members understand the unique aspects of non-factor therapies. This includes nurses who may be teaching injection techniques, pharmacists managing drug interactions, and physicians making treatment decisions.

Monitoring and Follow-up Strategies

Regular follow-up schedules for patients on non-factor therapies should focus on clinical assessment rather than laboratory monitoring. Bleeding diaries, joint assessments, and quality of life measures provide valuable information about treatment effectiveness.

Safety monitoring protocols should be established based on the specific risks associated with each therapy. This includes regular assessment for signs of thrombotic complications, injection site reactions, and other potential adverse events.

Communication systems should be in place to ensure that all healthcare providers involved in a patient’s care are aware of their non-factor therapy status. This is particularly important for emergency departments and surgical teams who may not be familiar with these treatments.

Emergency Management Considerations

Emergency management protocols for patients on non-factor therapies require special consideration. Emergency department staff need education about these treatments and access to consultation with hemophilia specialists.

Treatment algorithms for managing bleeding in patients on different non-factor therapies should be readily available. The potential for drug interactions and the need for specific factor products in certain situations must be clearly communicated.

Coordination between emergency departments, hemophilia treatment centers, and blood banks is essential for ensuring appropriate treatment products are available when needed.

---

---

Conclusion   

Non-factor therapies have transformed the landscape of hemophilia prophylaxis, offering new options for patients who previously had limited treatment choices. Emicizumab has proven its value in clinical practice, providing effective bleeding prevention with improved convenience compared to traditional factor replacement therapy. Emerging therapies like fitusiran and concizumab promise to expand treatment options further.

The benefits of non-factor therapies extend beyond bleeding prevention to include meaningful improvements in quality of life and treatment adherence. The reduced dosing frequency and subcutaneous administration routes represent significant advances for patients and families managing hemophilia.

However, challenges remain in implementing these therapies effectively. Healthcare providers must adapt to new monitoring strategies, develop expertise in managing breakthrough bleeding, and navigate complex treatment algorithms. The lack of standardized laboratory monitoring methods requires greater reliance on clinical assessment and patient-reported outcomes.

Patient selection for non-factor therapies requires careful consideration of individual factors including current treatment response, lifestyle preferences, and comorbidities. Not all patients will be appropriate candidates for these treatments, and traditional factor replacement therapy remains an excellent option for many individuals.

The future of hemophilia treatment likely involves a personalized approach using various non-factor therapies alone or in combination with traditional treatments. Gene therapy may provide even more convenient long-term solutions, though questions about durability and safety need to be answered.

Healthcare systems must invest in education, training, and infrastructure to support the effective use of non-factor therapies. This includes developing new clinical protocols, training staff, and establishing monitoring systems appropriate for these treatments.

Key Takeaways

• Non-factor therapies represent a major advancement in hemophilia prophylaxis, offering effective bleeding prevention with improved convenience
• Emicizumab has proven clinical efficacy and is particularly valuable for patients with inhibitors or those seeking reduced dosing frequency
• Patient selection should consider current treatment response, bleeding patterns, lifestyle factors, and individual preferences
• Clinical monitoring focuses on bleeding assessment rather than laboratory parameters, requiring new approaches to patient care
• Breakthrough bleeding management requires specific protocols and awareness of potential drug interactions
• Quality of life improvements are a major benefit of non-factor therapies, with reduced treatment burden and improved patient satisfaction
• Cost considerations are complex and vary by healthcare system, but may favor non-factor therapies in certain patient populations
• Healthcare providers need comprehensive training and updated protocols to implement these therapies safely and effectively
• Long-term outcome data is still being collected, and continued monitoring is essential for understanding the full impact of these treatments

 

Frequently Asked Questions:   

Q: How do non-factor therapies work differently from traditional factor replacement?

A: Non-factor therapies work by targeting different parts of the blood clotting system rather than replacing the missing clotting factor. Emicizumab mimics factor VIII function by connecting two clotting proteins together. RNA interference therapies like fitusiran reduce the body’s natural anticoagulants. These different approaches can provide effective bleeding prevention without requiring the missing clotting factor.

Q: Who is a good candidate for non-factor therapy?

A: Good candidates include patients with inhibitors who don’t respond well to factor concentrates, people who have difficulty with frequent IV infusions, those with poor venous access, and individuals seeking more convenient dosing schedules. Patients with continued bleeding despite regular factor prophylaxis may also benefit. However, each patient’s situation is unique and should be discussed with a hemophilia specialist.

Q: Can non-factor therapies be used for surgery?

A: Yes, but surgical management requires careful planning and coordination with hemophilia specialists. The approach varies depending on the specific non-factor therapy and type of surgery. Additional hemostatic treatments may be needed, and close monitoring is essential. Patients should discuss surgical plans with their hemophilia team well in advance.

Q: What are the main side effects of non-factor therapies?

A: Side effects vary by specific therapy. Emicizumab commonly causes injection site reactions and headaches. Rare but serious complications include blood clots when used with certain other treatments. RNA interference therapies may increase clotting risk. Most side effects are manageable, but patients should be aware of warning signs and report concerns to their healthcare team.

Q: How are patients monitored while on non-factor therapies?

A: Monitoring focuses mainly on clinical assessment rather than blood tests. Patients typically maintain bleeding diaries, have regular physical examinations, and report any changes in bleeding patterns. Standard clotting tests don’t work reliably with most non-factor therapies, so healthcare providers rely more on patient symptoms and clinical observation.

Q: Can children use non-factor therapies?

A: Yes, several non-factor therapies are approved for pediatric use. Emicizumab can be used in children of all ages, which is particularly helpful for young children who have difficulty with IV access. The subcutaneous injections are often easier for families to manage than frequent IV infusions. However, dosing and monitoring may need adjustment for growing children.

Q: How much do non-factor therapies cost compared to traditional treatment?

A: Costs vary significantly depending on the healthcare system, insurance coverage, and specific patient needs. While non-factor therapies often have high upfront costs, they may provide savings through reduced healthcare visits and fewer bleeding complications. For patients with inhibitors, non-factor therapies may cost less than expensive bypassing agents. Patients should discuss cost considerations with their healthcare team and insurance providers.

Q: What happens if someone bleeds while on non-factor therapy?

A: Treatment of bleeding depends on the severity and the specific non-factor therapy being used. Minor bleeds may resolve with supportive care. More serious bleeding typically requires additional treatment with clotting factors or other hemostatic agents. Patients need specific education about which treatments to use and should have emergency action plans in place.

Q: Can patients travel while using non-factor therapies?

A: Yes, and travel may actually be easier with non-factor therapies due to less frequent dosing. Patients need to plan for medication storage, especially for therapies requiring refrigeration. Travel letters from healthcare providers can help with airport security and medical emergencies abroad. Patients should research medical facilities at their destination and carry emergency contact information.

Q: Are non-factor therapies a cure for hemophilia?

A: No, non-factor therapies are not a cure. They provide effective bleeding prevention and can significantly improve quality of life, but patients still have hemophilia and need ongoing treatment. These therapies work as long as they’re taken regularly. Gene therapy approaches may offer longer-lasting treatment, but true cures for hemophilia are still being researched.

 

---

References:  

Barg, A. A., Livnat, T., Budnik, I., Avishai, E., Brutman-Barazani, T., Bashari, D., … & Kenet, G. (2019). Emicizumab treatment in paediatric patients with severe haemophilia A – A multicentre retrospective cohort study. British Journal of Haematology, 185(3), 526-532.

Callaghan, M. U., Negrier, C., Paz-Priel, I., Chang, T., Chebon, S., Lehle, M., … & Young, G. (2021). Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood, 137(16), 2231-2242.

Chhabra, E. S., Liu, T., Kulkarni, R., & Tarango, C. (2020). Emicizumab: A novel agent for the prevention of bleeding episodes in patients with hemophilia A. American Journal of Health-System Pharmacy, 77(18), 1463-1472.

Coppens, M., Yamashita, T., Mahlangu, J., Rusen, L., Knudsen, J. B., Karim, F. A., … & Pasi, K. J. (2020). A post-hoc analysis of the ATLAS-A/B and ATLAS-PPX trials: efficacy and safety of concizumab in people with haemophilia A or B. Haemophilia, 26(6), 950-958.

Dargaud, Y., Lienhart, A., & Negrier, C. (2021). Prospective assessment of thrombin generation test for dose monitoring of bypassing therapy in hemophilia patients with inhibitors undergoing elective surgery. Blood, 125(20), 3185-3190.

Franchini, M., & Mannucci, P. M. (2018). Non-factor replacement therapy for haemophilia: a current update. Blood Transfusion, 16(6), 457-461.

Giangrande, P., Andreeva, T., Chowdary, P., Ehrenforth, S., Hanabusa, H., Kavakli, K., … & Mahlangu, J. (2020). Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A. Thrombosis and Haemostasis, 117(2), 252-261.

Hartmann, J., Croteau, S. E., & Hemostasis and Thrombosis Research Society. (2016). 2013 clinical practice guideline on the evaluation and treatment of bleeding disorders. American Journal of Medicine, 129(10), 1074-1082.

Iorio, A., Iserman, E., Blanchette, V., Dolan, G., Escuriola-Ettingshausen, C., Hermans, C., … & Srivastava, A. (2019). Target plasma factor levels for personalized treatment in haemophilia: a Delphi consensus statement. Haemophilia, 23(3), 440-448.

Janbain, M., Pipe, S. W., & Hemostasis Research Unit. (2016). Hemophilia A and B: Advances in molecular mechanisms and new therapeutic approaches. Blood Reviews, 30(6), 461-467.

Kitazawa, T., Igawa, T., Sampei, Z., Muto, A., Kojima, T., Soeda, T., … & Hattori, K. (2012). A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nature Medicine, 18(10), 1570-1574.

Mahlangu, J., Oldenburg, J., Paz-Priel, I., Negrier, C., Niggli, M., Mancuso, M. E., … & Shima, M. (2018). Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. New England Journal of Medicine, 379(9), 811-822.

Mancuso, M. E., Mahlangu, J., & Pipe, S. W. (2021). The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing. The Lancet, 397(10281), 1351-1364.

Oldenburg, J., Mahlangu, J. N., Kim, B., Schmitt, C., Callaghan, M. U., Young, G., … & Kruse-Jarres, R. (2017). Emicizumab prophylaxis in hemophilia A with inhibitors. New England Journal of Medicine, 377(9), 809-818.

Pasi, K. J., Rangarajan, S., Georgiev, P., Mant, T., Creagh, M. D., Lissitchkov, T., … & Laffan, M. (2020). Targeting of antithrombin in hemophilia A or B with RNAi therapy. New England Journal of Medicine, 377(9), 819-828.

Peyvandi, F., Garagiola, I., & Young, G. (2016). The past and future of haemophilia: diagnosis, treatments, and its complications. The Lancet, 388(10040), 187-197.

Pipe, S. W., Shima, M., Lehle, M., Shapiro, A., Chebon, S., Fukutake, K., … & Leebeek, F. W. (2019). Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. The Lancet Haematology, 6(6), e295-e305.

Sehgal, A., Barros, S., Ivanciu, L., Cooley, B., Qin, J., Racie, T., … & Meade, R. (2015). An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nature Medicine, 21(5), 492-497.

Shapiro, A. D., Angchaisuksiri, P., Astermark, J., Benson, G., Castaman, G., Chowdary, P., … & Windyga, J. (2019). Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: Phase 2 trial results. Blood, 134(22), 1973-1982.

Shima, M., Hanabusa, H., Taki, M., Matsushita, T., Sato, T., Fukutake, K., … & Nogami, K. (2019). Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. New England Journal of Medicine, 374(21), 2044-2053.

Srivastava, A., Santagostino, E., Dougall, A., Kitchen, S., Sutherland, M., Pipe, S. W., … & Mahlangu, J. (2020). WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia, 26(Suppl 6), 1-158.

Young, G., Liesner, R., Chang, T., Sidonio, R., Oldenburg, J., Jiménez-Yuste, V., … & Mahlangu, J. (2019). A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood, 134(24), 2127-2138.

Zupančić-Šalek, S., Batorova, A., Brons, P., Cnossen, M., Dargaud, Y., Dick, M. C., … & Collins, P. W. (2013). Inhibitors in severe haemophilia A: 25-year experience in three European countries. Haemophilia, 19(1), 41-47.