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Managing Hemophilia
Expert Guidance on Non-Factor Approaches to Managing Hemophilia

Released: December 31, 2025

Stacy E. Croteau
Stacy E. Croteau, MD, MMS
Kristin N. Maher
Kristin N. Maher, MD, PhD
Steven Pipe
Steven Pipe, MD
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Key Takeaways
  • Managing hemophilia requires insight into both the patient’s disease characteristics, bleeding frequency, and the patient’s lifestyle and preferences.
  • Non-factor therapies offer subcutaneous administration with good bleeding control for patients requiring or desiring an alternative to intravenous infusions.
  • Gene therapy is an option for some patients and provides a time-limited period of freedom from hemophilia symptoms, but realistic patient expectations must be established via shared decision-making.

The management of hemophilia A and B continues to evolve with many therapeutic options available for patients, but many patients still experience breakthrough bleeding that needs to be managed. There is no one-size-fits-all approach to managing hemophilia. Thus healthcare professionals must engage their patients in shared decision-making to ensure the most effective management approach that fits the patient’s lifestyle and disease.

Hemophilia treatment has moved from focusing on intensive intravenous factor replacement to the use of newer subcutaneous therapies that mimic or rebalance coagulation pathways. These non-factor therapies, including emicizumab, marstacimab, concizumab, and fitusiran, have reshaped our management approach for many patients, including those with limited venous access, adherence challenges, or high treatment burden.

In this commentary, experts describe their management approach for several patient case scenarios and address questions posed by a healthcare professional audience during a live symposium held adjacent to the American Society of Hematology Annual Meeting 2025.

Patient Case 1: The “Difficult-to-Treat” Patient
The patient is a 42-year-old man with severe hemophilia B and high-titer inhibitors. He has scarring from years of intravenous access. He has moderate hepatic impairment related to previous infection with hepatitis C virus. He has cleared the infection but has some residual fibrosis.

Currently, he uses on-demand bypassing agents for bleed treatment. He has frequent visits to the emergency department for venous access issues for assistance with bleed treatment. He strongly desires a subcutaneous prophylaxis option. 

Kristin N. Maher, MD, PhD:
The patient population with severe hemophilia B with inhibitors has had limited treatment options until very recently. Now, both concizumab and fitusiran are approved by the FDA for patients 12 years of age or older with hemophilia A or B with or without inhibitors, so I would definitely offer this patient subcutaneous prophylaxis. Fitusiran is less appealing here because of the need to avoid this treatment in patients with hepatic impairment, so I would likely suggest concizumab. 

Stacy E. Croteau, MD, MMS:
I agree with that approach. Concizumab and fitusiran are the subcutaneous prophylaxis options in this setting, and given his concern for hepatic impairment, concizumab may be the preferred option. I also agree that this is the patient population with the highest unmet need. Marstacimab is currently only approved by the FDA for patients with hemophilia A or B without inhibitors, and emicizumab is only approved by the FDA for patients with hemophilia A with or without inhibitors. Other non-factor therapies may be approved in the future, but currently, concizumab would be the preferred option.

Historically, we would think about central access to allow more effective, potentially even prophylactic, bypassing agent therapy for him. An agent that improves hemostasis, that provides a consistent, improved hemostatic capacity, and that can be administered subcutaneously will change his quality of life. 

Steven Pipe, MD:
I would note that although the presence of clinically significant liver disease limited patient eligibility for the fitusiran studies leading to its FDA approval, there were patients who had a history of hepatitis C, and there was no indication that they had any differing outcomes. Hepatic toxicities with fitusiran are a dose-dependent effect, and the incidence of hepatic toxicities was reduced once the fitusiran dosing regimen was changed to allow for dose modification based on each patient’s antithrombin activity levels.

We are still learning about the underlying mechanism for hepatotoxicity with fitusiran and other siRNA therapies and understanding if hepatic impairment remains to be an issue with fitusiran. Obviously, hepatic impairment has implications for any therapy that is liver targeted, such as fitusiran, and we have ongoing studies to evaluate the potential for hepatotoxicity closely using FibroScan and transaminase elevation screenings to assess the severity. 

If the patient agrees to begin therapy with concizumab, what would the next steps be? 

Kristin N. Maher, MD, PhD:
Concizumab therapy requires a loading dose, followed by once-daily dosing for 4 weeks of treatment, and then individualized maintenance dosing. He would start with a loading dose of 1 mg/kg on Day 1, followed by once-daily dosing of 0.2 mg/kg for 4 weeks. Then a plasma concizumab level at 4 weeks would be needed to ensure that the patient is within the acceptable ranges >200 ng/mL to decrease the risk of bleeding episodes.

It is also important to discuss what strategies to use for breakthrough bleeding or surgeries. At our center, we offer emergency letters to patients with hemophilia, stating our protocol for bleeding, in case they go to an emergency department. 

Steven Pipe, MD:
That is a great point. It is important to consider the whole patient: Is he is having some therapy that may be outside the hemophilia treatment center oversight? Will a local emergency department understand the implications of him receiving concizumab? Will they pay attention to the doses of the agents? A lot of centers have emergency cards that the patients take with them when they go to the emergency department so that the emergency medicine professionals understand that there may be some risk mitigation related to breakthrough bleed management. 

Patient Case 2: The Quest for a “Cure”
This is a 38-year-old man with severe hemophilia A without inhibitors. He has mild nonalcoholic fatty liver disease. Otherwise, he is healthy. He is on prophylaxis once weekly with efanesoctocog, and his annualized bleeding rate is 0. Even though he has had no bleeds, he finds that the mental burden of having hemophilia, being a patient, and weekly intravenous infusion are exhausting. He asks for gene therapy so he can be cured and never see a doctor again. 

How would you approach this situation, and how are you walking him through what he might consider? 

Stacy E. Croteau, MD, MMS:
This patient is potentially a candidate for gene therapy. We presently have 1 commercially available factor VIII gene therapy for hemophilia A: valoctocogene roxaparvovec. Engaging in shared decision-making and understanding his expectations and goals are critical here.

There are some baseline laboratories and imaging that are needed to ensure he is eligible to receive valoctocogene roxaparvovec, including assessing for the presence of anti-AAV antibodies, factor VIII inhibitor presence, and liver health assessments. We will look in more detail at his organ dysfunction, investigating his overall liver health, and potential fibrosis. Valoctocogene roxaparvovec is contraindicated for patients with known significant hepatic fibrosis (stage 3 or 4), or cirrhosis, as well as for active infections, either acute or uncontrolled chronic, or known hypersensitivity to mannitol.

Then it is important to have a discussion to set realistic expectations of what we can deliver with gene therapy. With the available commercial gene therapy, some individuals may achieve normal levels of factor VIII particularly in the first-year post infusion, but most end up in the mild hemophilia A range with continual decline in factor VIII levels each year. This therapy is not expected to provide lifelong efficacy, especially for a patient who receives the therapy at 38 years of age. Patients also need to be aware that it is not as easy as coming in for one outpatient infusion and then “never see a doctor again.” Frequent monitoring and careful communication that must happen after the gene therapy infusion include weekly blood draws and follow-up for the first 6 months after infusion that can taper to monthly by the end of Year 1 and then every 3 months by Year 2.

In many instances, particularly for hemophilia A gene therapy, immunomodulatory agents, such as corticosteroids, for elevated transaminases is needed. Adverse effects, particularly of corticosteroids, and adherence to the steroids can be a challenge. Although individuals with clinically severe hemophilia A can benefit from gene therapy, there are additional care burdens that need to be well recognized by patients and their healthcare professionals in advance. It is important to ensure that patients have very clear expectations of what it means to receive gene therapy and go through those logistics, as well as the likelihood for removing the need for ongoing regular prophylaxis, and the probable durability of that, so each patient does not have unmet expectations moving forward. 

Steven Pipe, MD:
I have had this exact patient scenario. The reality is that we are still doing gene therapy too late. By the time patients are adults and we offer gene therapy, there is accumulated joint damage that is going to have implications down the road. The idea of being able to completely disconnect from the hemophilia treatment center is not good and maybe not be likely either. 

Kristin N. Maher, MD, PhD:
The possibility of curative gene therapy in young children is aspirational. It would be great to have durable, normal factor activity and essentially not have hemophilia. These patients would still require some ongoing clinical follow-up and certainly genetic counseling. However, this is still a long way off and not practical based on current trials. 

FAQ About Hemophilia Management 

Do you need to have baseline antithrombin levels checked before you start fitusiran? 

Stacy E. Croteau, MD, MMS:
Yes, fitusiran should not be initiated if the patient’s baseline antithrombin level is <60%. When fitusiran is administered, antithrombin levels should be monitored at Week 1 and dosing adjusted as needed per the prescribing information. If fitusiran is discontinued, the antithrombin level should be monitored until it returns to the normal range, as the bleed management plan (factor/BPA dosing and frequency) will need to return to normal labeled dosing as the antithrombin returns to normal levels. 

What does measuring concizumab plasma levels tell us about thromboembolic complications since we are not measuring anything pharmacodynamic related to TFPI itself? 

Steven Pipe, MD:
I think we accept this limitation. I do not know any other coagulation parameter that we can measure in routine practice that would really help us there. The decision to keep patients within a range of concizumab concentration was informed from the clinical trial program and then examining patients who did have thrombotic complications and whether that was a contributing risk factor. 

Are there any data about bone health differences in patients whose first therapy is nonreplacement therapy such as emicizumab compared with standard or EHL prophylaxis? What are you discussing with your patients’ families, and what do you know from the data related to bone health outcomes, particularly in small children? 

Kristin N. Maher, MD, PhD:
I do not know of any current data, although data are expected on bone health in children who initiated emicizumab as previously untreated patients. We are counseling our older children on bone health, but not as it relates specifically to emicizumab. 

Steven Pipe, MD:
The HAVEN 7 trial enrolled young infants with hemophilia A and they received emicizumab. The first wave of patients who enrolled are now having their bone assessments. The whole cohort of 55 patients will have MRIs starting approximately 5 years after initiating therapy. That will give us our first cohort of infants who have exclusively been treated on emicizumab and a look at their bone health. From a physiologic perspective, there is no question that bleeding, effects on joint function, and limitations on activity have the greatest negative impact on bone health. Anything that reduces bleeding and improves activity levels is likely to have a positive impact on joint health.

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Which of the following non-factor therapies have you used for your patients with hemophilia?

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