Understanding Rebalancing Agents

Until fairly recently, hemophilia treatment typically worked by replacing missing clotting factors in the body. Balancing agents are a newer method of treatment designed to rebalance the body’s coagulation abilities. Director of Classical Hematology Bethany Samuelson Bannow, MD, MCR, recently shared insights about this emerging class of medications and how community providers and academic medical centers can work together to treat patients with this bleeding disorder.

Advances in hemophilia treatment

Commonly, patients with hemophilia had to frequently receive clotting factor concentrates via IV. Then the monoclonal antibody emicizumab was introduced in 2017. It was the first therapy to successfully prevent bleed progression and clinically apparent joint damage progression in patients who lacked factor VIII inhibitors. This subcutaneous medication mimics the coagulation function of factor VIII to help blood clot normally.

“There's always the concern, of course, that these medications can be associated with thrombosis,” says Dr. Samuelson Bannow. “There are certain settings that you don't want to give this medication in. For example, you don't want to give the combined clotting factor FEIBA to someone who is on emicizumab because it can generate abnormal, and potentially dangerous, clotting.”

In early 2024, the FDA approved the first rebalancing agent. Instead of replicating the behavior of the clotting factor like emicizumab, it decreases anti-clotting factors in the blood. The concept is that it can restore balance in the body’s clotting process to reduce the rate of bleeding episodes.

Fitusiran, marstacimab and concizumab are medications now available for lowering the body’s natural blood-thinning proteins to restore balance of the clotting system and stop abnormal bleeding. All of these medications are administered subcutaneously.

Diagnosing bleeding disorders

Although diagnosing hemophilia itself isn’t particularly challenging, there are some nuances involved. For cases where there’s a suspicion of mild hemophilia, for example, the most commonly used tests for factor VIII activity aren’t quite as precise as some of the more advanced diagnostics. “If you have a patient with a borderline case of hemophilia, this can be a bit difficult to identify,” explains Dr. Samuelson Bannow. “It can also be tough to identify carriers of hemophilia.”

In instances where the provider is unsure of the cause of bleeding, it’s beneficial to work with a health center well versed in advanced testing. The most commonly diagnosed bleeding disorder is von Willebrand disease, which can be difficult to diagnose.

“The nuances and testing are incredibly finicky,” explains Dr. Samuelson Bannow. “If a community provider doesn’t have its own reference lab to handle testing, they have to freeze and ship the sample. A lot can go wrong during that process. Working with a center that has access to advanced diagnostics such as platelet aggregation tests — as well as the experience with these tests — will help ensure accurate results.”

Partnering with community providers

With the emergence of rebalancing agents, patients can benefit from the specialized support of an academic medical center along with the convenience of receiving treatment with their community provider. Cleveland Clinic works with referring providers to either take over cases or to partner together in the care of the patient.

“I’m a big proponent of patients having a specialist here and also having a local doctor,” says Dr. Samuelson Bannow. “There a strong role for both types of providers in caring for patients with bleeding disorders.”

“There are some situations, such as when a patient needs immediate support for a bleed, where they need a local provider, and other situations, such as preparing for a major surgery, where you’ll want a specialist who can monitor factor levels in real time,” she says. “Most community hospitals don’t have the capacity for that type of monitoring.”

In the case of patients with hemophilia, the best approach is to consult with an experienced classical hematologist with expertise in bleeding disorders to discuss treatment options and plan for any major issues, such as surgeries. Once the plan is set, the patient may be able to receive the rebalancing agent in the community setting, including self-administering at home. If desired, the classical hematologist can equip the local hematologist to actively prescribe medications, see the patient on a more regular basis, and handle first-line questions, generally supported by an annual check-in with the classical hematologist.

In the meantime, as its population of patients with hemophilia and other bleeding disorders increases, Cleveland Clinic is looking at opening clinical trials to identify opportunities to further advance treatment options.