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Hemophilia A: FAQ
Experts Answer Frequently Asked Questions on Hemophilia A Management

Released: February 16, 2021

Expiration: February 15, 2022

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In this commentary, hemophilia experts Michael Callaghan, MD; Rebecca Kruse-Jarres, MD, MPH; and Miguel A Escobar, MD, answer questions on the management of hemophilia A posed by the audience during 2 online live CCO symposiums in December 2020 and January 2021.

Factor VIII Prophylaxis
When you repeat laboratory testing for factor VIII (FVIII) levels in a patient, do you see variation in the half-life or pharmacokinetic values, or do they remain fairly consistent?

Michael Callaghan, MD:
Pharmacokinetic levels of FVIII are generally intrinsic to the patient. For example, a patient with a half-life of 30 hours may have a half-life of 36 hours sampled on one day or 24 hours on another. By contrast, in a patient with a typical half-life of 6 hours, half-life may vary between 4 or 8 hours. Pharmacokinetics will change with aging, specifically, half-lives are longer than when that same patient was younger. They also vary to some extent according to von Willebrand factor levels, which can be stress induced.  

How can I determine which patients with hemophilia A are suitable candidates for extended half-life (EHL) products (given once or twice weekly)?

Michael Callaghan, MD:
In our practice, we measure pharmacokinetics of a patient’s standard half-life product (SHL) and after switching to an EHL product. Sometimes the result is a huge increase in the half-life, but other times, there is no meaningful difference. Patients with a very short half-life may have a 50% increase in the half-life, but this is typically insufficient to affect dosing. Clinicians must also engage in empiric trial and error; if a patient is switched from an SHL product to an EHL product and does not have the expected response based on the pharmacokinetics, the treatment strategy can be subsequently adjusted. This requires regular monitoring and a plan that works for the patient that may need to be updated over time as the patients activities change.

Rebecca Kruse-Jarres, MD, MPH:
An example would be patients who have plans for intense exercise. I have patients who go snowboarding every day in the winter, which is a high-risk activity. Even if their baseline factor level is 15%, my goal is to increase this while they are performing intense activity. They do not need to be on an EHL product because they are going to go every day, but it is important to take their SHL right before they go out. Even though their level may drop to approximately 50% after 3-5 hours of snowboarding, I still usually prefer the daily boost with an SHL product over the EHL product.

Miguel A. Escobar, MD:
Absolutely. For very active patients, it is quite important to identify their activities and the factor level that is likely to be safe to tailor their factor replacement therapy appropriately.

Emicizumab: Considerations

Is prophylaxis with emicizumab equally effective with every-4-week vs every-2-week dosing?

Michael Callaghan, MD: 
The emicizumab (a bispecific antibody to coagulation factors IX and X) studies were not designed or powered to answer that question, and the studies used different dosing and different regimens. However, in some of the studies, the bleed rate with every-4-week dosing is slightly higher than with every-2-week dosing, but still quite low. In Japan, the HOHOEMI study compared every-2-week vs every-4-week dosing of emicizumab in 13 pediatric patients with severe hemophilia A without inhibitors. Results showed that both schedules were effective and that bleeding rates were lower with every 4-week dosing. Therefore, although the pharmacokinetics of every-4-week emicizumab would suggest lower trough levels with less-effective protection, it is still effective and a reasonable option.

In my practice, I often use every-4-week dosing of emicizumab, given in clinic, in patients with poor adherence. In young children, a lowest dose, single vial can be used as an every-4-week dose. Our patients receiving emicizumab every 4 weeks do very well, with no breakthrough bleeding.

Miguel A. Escobar, MD:
This is also a good option for patients who live very far from the clinic.

Do patients become resistant to emicizumab or develop antibodies to it?

Michael Callaghan, MD: 
On the HAVEN clinical trials, there was routine testing for antibodies and that has the potential to pick up antibodies that are probably not clinically relevant. They identified 3 patients who had decreased plasma levels of emicizumab with positive antibody test. Therefore, it appears that those antibodies were at least partially neutralizing or clearing. In the HAVEN 2 study, there was 1 patient who had a completely neutralizing antibody, undetectable levels of emicizumab, and breakthrough bleeding at approximately 5 weeks.

I am aware of at least 1 postlaunch neutralizing antibody that has been reported. But now there are several thousand patients receiving emicizumab plus approximately 400 patients in the clinical studies, so the rate of antibody formation and especially neutralizing antibody formation is low, but it is possible.

As for resistance, that does not seem to be the case, and I think there are 2 reasons. The first reason, a biological effect, is that individuals have less bleeding and less joint inflammation, making bleeds less likely in the future. The second reason is that people have become more comfortable with emicizumab and when they have pain, they may wait to treat and it turns out not to be a bleed. Early on, we were worried that could be false confidence and those could actually be bleeds that go untreated with long-term sequelae from that.

Miguel A. Escobar, MD:
I think you might suspect neutralizing antibodies when a patient who has been steady on treatment begins to have breakthrough bleeding. Then you might suspect the possibility of an antibody against the drug itself.

Comorbidity Management

In older patients with hemophilia A receiving prophylaxis, is there a concern for thrombosis when using SHL FVIII at high therapeutic levels?

Rebecca Kruse-Jarres, MD, MPH:
We have very little data to answer this question. I am cautious about giving a patient high doses of recombinant FVIII if I know they have existing cardiovascular risk factors or have had a cardiovascular event. I am also very cautious in choosing the prophylaxis dose for older patients, including perioperative prophylaxis, due to the concern for thrombosis.

There is strong evidence that FVIII, von Willebrand factor, and thrombin are all required for normal bone mineral density (BMD). How do we ensure that patients without inhibitors on emicizumab maintain long-term bone health as they are not receiving FVIII?

Michael Callaghan, MD: 
We have increasing data about this, and we know that people with inhibitors have worse bone health. Even patients receiving FVIII replacement therapy have problems with BMD. We also see this in hemophilia B.

I think, with new therapies, it is definitely something we need to track. The new therapies probably maintain a higher level of hemostasis and thrombin generation and maybe, in the case of gene therapy, even normalize levels. I would expect some benefit to bone health.

Rebecca Kruse-Jarres, MD, MPH:
It is an important question with nonfactor replacements. I am not sure that it is really FVIII that is affecting BMD but more the thrombin generation. But we do not know that. So we need to track it.

Miguel A. Escobar, MD:
One as-yet unanswered question is whether the use of FVIII in infants with hemophilia A will affect their bone density and growth.

Because patients with hemophilia can have osteopenia, should we be monitoring BMD and vitamin D levels?

Rebecca Kruse-Jarres, MD, MPH:
We definitely should screen for and monitor BMD and vitamin D levels, but with the caveat that the corresponding treatment suggestions are based on nonhemophilia literature. I do not actually know how helpful vitamin D, or calcium, or a bisphosphonate would be in a patient with hemophilia. There are suggestions in the literature that BMD is lower in hemophilia vs controls. Over time, I hope that we will see whether real-world use of these approaches in hemophilia is effective or not. Right now, we just do not know enough.

To help answer this question, an ongoing retrospective/prospective study is longitudinally evaluating the effect of emicizumab on bone health compared with factor replacement therapy over 3 years in patients with hemophilia A (NCT04131036). I have noted that my patients who are receiving both FVIII prophylaxis and emicizumab prophylaxis feel safer being more physically active. As physical activity helps minimize BMD loss, among many other benefits, this supports use of both approaches to prophylaxis.

For patients with hemophilia who have a history of coronary or cardiovascular disease, can they be managed with aspirin or antiplatelet agents? How would you balance that risk vs bleeding risk in patients with atrial fibrillation, for instance?

Rebecca Kruse-Jarres, MD, MPH:
I appreciate the first question as we are all struggling with this issue. I think aspirin and anticoagulation are probably a little bit different; usually, aspirin is given for its antiplatelet effect. For a patient with hemophilia and cardiovascular disease, I start with a low-dose aspirin rather than a full-dose aspirin that, in clinical trials, seems to be adequate. If they have increased bleeding, either initiate prophylaxis or increase doses of existing prophylaxis. It is important to remember that there is abundant evidence of the benefit from antiplatelet agents in patients with cardiovascular disease, such that this should be considered an option even if a patient has hemophilia.

Regarding atrial fibrillation, this is becoming increasingly more common as patients are getting older, and those patients should be on anticoagulation therapy. It is important to use the CHADS2 score to determine whether a patient actually needs to be on anticoagulation therapy or if aspirin is sufficient. It is possible that some patients may need prophylaxis and anticoagulation therapy at the same time, which seems a little counterintuitive, but I think we are getting at different targets. I am particularly excited about emicizumab because it provides more steady-state concentrations compared with FVIII products, where levels will reach a peak and then decline. This results in less thrombin burst and allows patients to remain at a lower prophylactic dose, which may make anticoagulation safer, but we do not have data yet.

Miguel A. Escobar, MD:
I have begun to encounter patients with moderate hemophilia A who have never been on prophylaxis who now require it because they also need aspirin, clopidogrel, or even anticoagulation therapy. This is likely due to the aging hemophilia population.

Rebecca Kruse-Jarres, MD, MPH:
Some of my patients have stent placements and will receive dual antiplatelet agents for up to 3 months. Even in a patient with mild or moderate hemophilia A, it is appropriate to initiate prophylaxis for that time period.

To hear more answers to questions like these listen to our podcast.

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