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Practical Care Choices for Hemophilia
Individualizing Nonfactor Prophylaxis in Hemophilia: Practical Choices for Community Care

Released: April 10, 2026

Kristin Maher
Kristin Maher, MD, PhD
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Key Takeaways
  • In hemophilia, even subclinical bleeding can drive meaningful arthropathy over time; annual joint assessment and point-of-care ultrasound can detect early changes.
  • Nonfactor therapies, including emicizumab, concizumab, marstacimab, and fitusiran, are all administered subcutaneously on distinct schedules with variable monitoring.

Hemophilia A and B are rare X-linked bleeding disorders caused by a deficiency of clotting factors VIII and IX, respectively. Without adequate prophylaxis, patients face recurrent bleeding into joints and soft tissues that can cause permanent damage and disability over time. Historically, treatment has been intravenous replacement of the missing clotting factor, but the relatively short circulation time necessitates a burdensome regimen, requiring frequent infusions and reliable venous access. For some patients, particularly severe hemophilia A the formation of inhibitors against factor VIII or factor IX that can occur in response to exogenous factor protein complicating the approach to bleed treatment and prevention. The treatment landscape has shifted dramatically with the approval of non-factor therapies: agents that improve the blood’s ability to clot through alternative mechanisms, many of which can be given subcutaneously and less frequently than factor concentrate. As these options have expanded, so have the decisions clinicians and patients must navigate. In this commentary, Dr Kristin Maher of the University of Washington School of Medicine addresses questions from HCPs who attended our meeting series, Individualizing Non-Factor Prophylaxis in Hemophilia: Practical Choices for Community Care, held at community practices across the United States.

When you are thinking about prophylaxis approaches for your patients, what are the most important factors to consider?
In my practice, I return to the same principle for every patient: prophylaxis should be individualized around bleeding risk, activity level, joint status, inhibitor history (inhibitors are antibodies some patients develop against clotting factor replacement, which complicate treatment significantly), venous access, social factors, and patient preference, not severity label alone. Decision-making is tied not only to bleed prevention but also to quality of life and independence.

Early prophylaxis also matters for joint preservation. Even subclinical bleeding can drive meaningful arthropathy over time, and in our clinic we use annual joint assessment and point-of-care ultrasound to detect early changes. A modest annualized bleed rate (ABR) should not be falsely reassuring when a patient reports stiffness, pain, or functional decline.

With the growing number of approved prophylaxis therapies, where does emicizumab fits now?
Emicizumab remains my go-to nonfactor option for hemophilia A with or without inhibitors. Unlike factor replacement, emicizumab is given as a subcutaneous injection rather than an intravenous infusion and works by mimicking the function of factor VIII, bridging 2 clotting proteins (factor IXa to factor X) to restore hemostasis. In the HAVEN 1-4 studies, more than half of the participants had zero treated bleeds across treatment intervals, with rates increasing over time with sustained prophylaxis. HAVEN 7 showed similar results in infants with severe hemophilia A without FVIII inhibitors, and those participants are continuing in a 7-year long-term follow-up. The FDA label confirms the indication for patients ages newborn and older, with maintenance dosing options of weekly, every 2 weeks, or every 4 weeks after loading.

How are the newer rebalancing agents distinct from each other and other prophylactic treatment options?
Concizumab, marstacimab, and fitusiran are typically referred to as rebalancing agents. Rather than replacing or mimicking the missing factor protein, they restore thrombin generation by either inhibiting or decreasing the synthesis of natural anticoagulant proteins: tissue factor pathway inhibitor (TFPI) in the case of concizumab and marstacimab, and antithrombin in the case of fitusiran. These agents are potentially game-changing, particularly when subcutaneous delivery and applicability across hemophilia subtypes are priorities. Rebalancing agents are the first subcutaneous prophylaxis options for patients with hemophilia B, since factor VIII mimetics are not an option for those patients except in very rare circumstances. Each rebalancing agent has a distinct indicated population, monitoring requirement, and safety profile that must be considered before treatment is started.

Concizumab is an anti-TFPI monoclonal antibody approved for routine prophylaxis in adults and pediatric patients 12 years of age or older with hemophilia A or B, with or without inhibitors. It is given daily and dosing requires plasma concentration–guided optimization 4 weeks after starting treatment. Marstacimab is also an anti-TFPI therapy, but its current labeled indication is hemophilia A or B without inhibitors in patients 12 years of age or older. Unlike concizumab, marstacimab is given weekly and does not require laboratory monitoring. Finally, fitusiran is an antithrombin-lowering small interfering RNA (a type of gene-silencing therapy that reduces production of a specific protein) approved for routine prophylaxis in patients 12 years of age or older with hemophilia A or B, with or without inhibitors. Dosing is once a month or every other month and is individualized based on antithrombin activity. Antithrombin activity is measured at week 4 after the starting dose and then subsequently at week 12, 20 and 24, or after dose modifications. Fitusiran carries a risk for gallbladder disease and elevation in transaminases so this should be considered before starting the medication for a patient with a history of liver disease.

What are the recommended monitoring and key safety considerations for each nonfactor replacement therapy?
For emicizumab, the critical safety point is the risk associated with concomitant use of activated prothrombin complex concentrates (aPCCs), bypassing agents used to treat bleeds when standard factor replacement cannot be used because of the presence of an inhibitor. When patients with inhibitors need breakthrough bleed treatment, we start with recombinant activated factor VII when possible. We limit aPCC exposure, so that the cumulative aPCC dose does not exceed 100 U/kg/24 hours for 24 hours or more. For concizumab, monitoring is based on drug level, with plasma concentration checked after 4 weeks of treatment initiation and dosing adjusted accordingly. For breakthrough bleeds that require additional treatment with factor products or bypassing agents, the lowest approved dose and dose interval is recommended.

For fitusiran, antithrombin-based dose titration drives the regimen, with dosing adjusted to maintain antithrombin activity in the target 15% to 35% range. The prescribing information includes a table with specific recommendations for modified breakthrough bleed management, with factor and bypassing-agent doses and frequency substantially reduced from what is typical.  For marstacimab, no thromboembolic events occurred in the core noninhibitor trial program, though 1 deep vein thrombosis was reported in the inhibitor extension cohort. Long-term thrombotic risk remains uncertain and should be framed as evolving experience.

Can you summarize how you put all of this into practice for patients?
First, assess bleeding phenotype, not just factor level. Moderate hemophilia can behave like severe disease. Treatment should match what the patient actually experiences, not the severity label alone.

Second, match the agent to the indication. Emicizumab covers hemophilia A with or without inhibitors. Concizumab and fitusiran cover hemophilia A or B with or without inhibitors. Marstacimab is approved for hemophilia A or B without inhibitors. Each carries distinct monitoring and safety considerations.

Third, plan breakthrough bleed management before starting any prophylaxis agent, not after. How acute bleeds, procedures, and surgeries will be handled on top of each therapy must be considered with the initial selection decision.

Fourth, be ready for the questions families are asking, such as those about long-term bone health with early non-replacement prophylaxis and what home infusion looks like in practice compared to administration of a subcutaneous medication. Also, the dosing frequency of each of these prophylaxis medications can vary significantly. Addressing these directly improves shared decision-making.

Fifth, involve the hemophilia treatment center (HTC) earlier, not later. Limited HTC engagement, lack of emergency factor access, and variable community familiarity with advanced therapies are real barriers. Equitable care means choosing therapies that fit both the patient’s biology and care environment. It’s critical that community HCPs and HTCs work together to provide optimal care for patients.

Your Thoughts?
Share your experiences with and questions about nonfactor prophylaxis for hemophilia; insights from the community help all of us deliver better care.

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