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Hemophilia Rebalancing Agents
Hemophilia Hemostatic Rebalancing Therapies: Insight for Patient Care

Released: April 06, 2026

Angela C. Weyand
Angela C. Weyand, MD
Guy Young
Guy Young, MD
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Key Takeaways
  • Hemostatic rebalancing agents block the body's natural anticoagulants to restore thrombin generation, clot formation, and substantially reduce annual bleeding rates.
  • Approved agents include the siRNA targeting antithrombin fitusiran, and the tissue factor pathway inhibitor antibody antagonists concizumab and marstacimab, all subcutaneously injected from pens.
  • Patient circumstances and preferences play an important part in the choice of a specific hemostatic rebalancing agent.

Hemophilia and Ongoing Needs

Dr Angela Weyand:
Hemophilia is a congenital X‑linked bleeding disorder caused by either factor VIII deficiency, termed hemophilia A, or factor IX deficiency, termed hemophilia B. The core pathophysiology is impaired thrombin generation, leading to reduced clotting and recurrent bleeding, whether it is clinically evident or undiscernible. Untreated hemophilia can cause mucosal nose bleeds, mouth bleeds, bruising easily, and bleeding into the muscles or joints, which causes pain and swelling. Sometimes, life-threatening bleeding into the brain, coughing up blood, or vomiting blood may also occur, making treatment essential. Despite modern prophylaxis, including factor replacement and mimetic therapies, patients may experience breakthrough bleeding, progressive and irreversible joint damage without obvious bleeds, chronic pain, and a reduced quality of life. Therefore, new approaches are necessary to avoid all bleeds and provide patients with hemophilia a similar quality of life to those without hemophilia.

Hemostatic Rebalancing and Approved Rebalancing Therapies

Dr Angela Weyand:
Whereas previous prophylactic approaches replaced missing clotting factors, the new hemostatic rebalancing agents target and inhibit the body's natural anticoagulants to restore thrombin generation. Thrombin will cleave fibrinogen, which creates a fibrin network and stable aggregates of cross-linked clots.

Dr Guy Young:
All 3 new rebalancing agents, concizumab, fitusiran, and marstacimab, are subcutaneous pen‑based therapies, which reduces the burden of patients needing to receive an intravenous infusion. In addition, all of the new rebalancing agents generate substantial reductions in annualized bleeding rates vs on-demand therapy and produce substantial improvements in patients’ quality of life. Many patients using rebalancing agents achieve zero or near-zero bleeds each year.

Fitusiran is an antithrombin-directed, small interfering RNA indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age or older with hemophilia A or B with or without factor VIII or IX inhibitors. Fitusiran is dosed subcutaneously via injection once every 2 months. The antithrombin activity is then monitored using an FDA-cleared test to maintain antithrombin activity between 15% and 35% through adjusting the dose or frequency of fitusiran to reduce the risk of thrombosis. Regarding safety, the most common side effects of fitusiran include viral infection, colds, and bacterial infection, and it has a boxed warning for thrombotic events and gallbladder disease.

Marstacimab is an anti–tissue factor pathway inhibitor (TFPI) antibody targeting the K2 domain of TFPI. It is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age or older with hemophilia A or B without factor VIII or IX inhibitors, respectively. Marstacimab is dosed subcutaneously on the same day each week. It differs from the other rebalancing agents in that there is no required laboratory monitoring. Although drug warnings include thromboembolic events and hypersensitivity, unlike fitusiran, there are no boxed warnings on the drug label. As of early April 2026, marstacimab is not yet approved for patients with inhibitors, although that might change in the future.

Dr Angela Weyand:
Concizumab is another anti-TFPI antibody with the same mechanism of action as marstacimab. It is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age or older with hemophilia A or B with or without factor VIII or IX inhibitors, respectively. Concizumab is dosed subcutaneously via injection and starts with a loading dose on Day 1, followed by once daily dosing. Four weeks after initiation of treatment, concizumab plasma concentrations are measured using an FDA-approved test to determine the appropriate maintenance dose to use. Differences with concizumab when compared to the other rebalancing agents mentioned above include weight-based dosing, a higher injection frequency, and a shorter washout time. There is no boxed warning for concizumab, but the drug warnings include thromboembolic events, hypersensitivity reactions, and increased lab values of fibrin D-dimer and prothrombin fragment.

Clinical Pearls for the Use of Hemostatic Rebalancing Therapies

Dr Guy Young:
When rebalancing agents are indicated, there are several factors to consider before recommending a specific treatment option. The choice of therapy should consider the individual patient’s circumstances and preferences, such as the injection frequency, the need for laboratory monitoring, the distance for the patient to the lab testing facility and whether there is convenient rural access, and the tolerance for uncertainty without biomarker tracking. It is also important to note that all patients still require factor or bypassing agents for breakthrough bleeds.

As examples of this, let’s consider a few different scenarios that you may encounter. First, imagine that you manage a 19-year-old college student for severe hemophilia A without inhibitors, and he is trying to avoid having to take medication with him to his dormitory due to storage and privacy issues. He goes home about every 2 months. When discussing which drug would be the best option for him, the conversation should include fitusiran because it avoids the limitations that he has communicated to you.

In another example, imagine that you manage a 14-year-old with severe hemophilia B without inhibitors who has been managed with an extended half-life FIX concentrate infused through a port. He presents to you because his port is occluded, and you determine that this port is not salvageable. The patient has significant anxiety with venipuncture but has not had issues receiving vaccinations or concerns with needles. For this patient, recommending marstacimab as an option for ongoing prophylaxis is appropriate. The drug has flat dosing and no laboratory monitoring, which makes it an especially good option for patients with limited lab access. Here, the patient has not had any issues with injections, so the weekly administration does not appear to present any upfront concerns.

Finally, let’s consider a 24-year-old with severe hemophilia A without inhibitors who is afraid of bleeding. Although he has avoided many activities out of caution, he still experiences spontaneous joint bleeding. He never learned to infuse factor and states that he is afraid of the infusion. He presents asking about any available alternative options, other than infusing factor for hemophilia A treatment. As you continue discussing his future, he mentions surgery for a total left elbow arthroplasty, which is a priority for him. In his case, there are several options, with concizumab as a consideration. Although concizumab has a higher injection frequency than the other approved rebalancing agents, required lab testing will allow measured feedback on his response for proper dosing, and the drug has a shorter washout time if it should be discontinued prior to his surgery.

Final Thoughts

Dr Guy Young:
To end, I think that with our current therapies we are moving closer to a functional cure for our patients with hemophilia and that our patients are able to live a less restrictive lifestyle. 

Your Thoughts
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