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Treatment Decisions in Hemophilia A
Internal Medicine, Hematology and Oncology, and Adult Hemophilia
University of California, Davis
What are the most pressing complications of hemophilia A and how do you answer them?
Although deficiency in factor VIII (hemophilia A) or factor IX (hemophilia B) may result in bleeding anywhere in the body, the most common complication is bleeding into the joints. Joint bleeds are not necessarily provoked by trauma but can result from normal everyday activities like walking. For patients with hemophilia, this is the most common and debilitating type of bleed. Acute bleeding in joints is accompanied by pain and joint stiffness.
Most of the time, patients respond well to treatment within a short period of time. However, any bleed — and definitely repeated bleeds to a joint — can result in permanent joint damage. So patients with hemophilia at age 30 years may have the joints of someone at age 80 years or older. For this reason, prophylaxis is currently a standard of care in the United States. The administration of prophylaxis eliminates or dramatically reduces the number of joint bleeds and preserves the joints’ normal function.
How does the heterogeneity of hemophilia (in terms of bleeding pattern, severity, etc.) affect your treatment decisions?
Depending on the severity of the patient’s clotting factor deficiency, it is quite predictable how the patient will behave. Patients with severe hemophilia have the highest risk for bleeding and joint damage. Patients with mild disease and, for example, a factor level of 30% may be diagnosed later in life with no significant previous bleeds. Having said that, even for patients with exactly the same baseline factor activity, therapy needs to be individualized depending on age, history of previous bleeds, and physical activity level.
For instance, if the patient is a boy in high school or college who wants to take part in a sport, he will need higher levels of factor, and thus would need to be infused more often or with slightly higher doses. If the patient is a person who, like me, works in an office and would not exercise too much, then they would likely do very well clinically with lower doses of factor or with less frequent infusion.
Treatment decisions also depend on the degree of the joint damage a patient has already experienced. Unfortunately, if a patient’s joints are already damaged, it perpetuates the vicious cycle where the patient bleeds more into those joints and may need more therapy.
I think the big breakthrough was the realization that men with severe hemophilia need prophylaxis. We’ve started telling patients with hemophilia that they need to infuse factor every other day, or every third day, so that their lowest level of factor — their trough level — before the next dose will be above 1% or above 5%. Currently, the recommendation is to keep the trough level above 1%. However, some clinicians argue that the trough level should be kept above 5%, 15%, or even 50%. This directive has to be augmented by both economics, because factor is extremely expensive, and the availability of factor.
Because the coagulation cascade is complicated and everybody is a little different, we have to ask the patient, “On this type of regimen, on this prophylaxis, do you have bleeds?” If a patient is continuing to bleed despite prophylaxis, their treatment may need to be adjusted.
Something that is very difficult to advise patients about — and I have to rely on their familiarity with and understanding of their disease — is when and how to introduce changes to their prophylaxis. I’ll tell my patients, “There are weeks when you’re not exercising, so maybe you can do prophylaxis less often. But then, if a neighbor calls you and wants you to help with moving furniture, you need to infuse before that. You have to remember, even if your scheduled infusion date is the day after, that you actually need to infuse earlier because you need to protect yourself.”
What steps do you take to evaluate and, if necessary, improve your patients’ health-related quality of life?
This is a very important question. Most of the time I concentrate on a patient’s level of factor or the number of bleeds. Treatment with factor prophylaxis can dramatically decrease the number of bleeds; however, application of the treatment may be a burden on its own. Frequent intravenous infusions take time and skill and may result in possible adverse events.
We recently had some advances in the treatment itself. Factors that work for a longer time (extended half-life products) have become available, so instead of infusing every other day, patients may be infusing every third day or once a week. Also, a new product (emicizumab) was approved that can be injected under the skin (instead of intravenously) every 4 weeks. I share the new therapies with my patients and facilitate switching to new products. I also encourage patients to participate in a variety of clinical trials available at our center, including gene therapy for hemophilia A and hemophilia B.
Recently, we started using musculoskeletal ultrasounds in the clinic to detect joint pathology. For a patient with significant joint changes, it may be difficult to distinguish whether a pain episode is because of arthritis or because of a new acute bleed. Ultrasounds may help distinguish arthritis from acute bleeds. I believe that using this tool in our clinic has already resulted in more patient-directed treatment and has helped us decide between administering factor infusion for bleeds and conducting an orthopedic evaluation for arthritis.
What are the challenges of aging in patients with hemophilia and how do you address them?
Historically, unfortunately, the life expectancy in patients with severe hemophilia was short. It improved dramatically with the use of factor concentrate; then there was the sad period of time when patients were infected and dying because of HIV and hepatitis C, as a result of blood product contamination. Now, when the calculated life expectancy of patients with hemophilia is approaching that of the general population, we have started to see complications that we were not observing before, like cardiac issues and strokes. Cardiovascular diseases are particularly challenging because most of the therapies include anticoagulation or antiplatelet agents, which are contraindicated in hemophilia.
In the future it will be important to have established guidelines for hemophilia treatment in elderly patients. Now, when we have an aging generation of men with severe hemophilia, we are learning that we don’t know what to do when these patients need a coronary artery stent or when they have a stroke and need to be treated with aspirin. There are several initiatives at the International Society on Thrombosis and Haemostasis, and at a variety of societies, that are attempting to create guidelines; there are also several clinical trials and data collection systems attempting to learn more about the aging population of patients with hemophilia.
So, we will have these answers. The guidelines will happen eventually. At the same time, we are getting better treatments and longer-acting medications, so treatment is becoming easier. We can treat patients with factor and, on top of that, apply the treatment for cardiovascular disease. So we are slowly getting there. This is currently an unmet need, but a lot of people are already working on it.
What do you think the role of gene therapy is for hemophilia? Do you see gene therapy becoming a mainstay of hemophilia treatment?
We all hope that it will become a mainstay of treatment. I think it may happen in the future. Initially, the application will be somewhat limited, but it’s extremely exciting. It’s the most exciting therapy that is coming up for hemophilia.
Currently, gene therapy is in phase 3 clinical trials. It shows very promising results and I hope it will be available for clinical use soon. For now, there are a few limitations. One is that patients may have preexisting immunity to the vector (by which the gene therapy is delivered), thereby preventing them from experiencing any results. In addition, the follow-up for gene therapy is currently very time consuming (eg, initial laboratory checkups twice a week). This may become easier when gene therapy is approved. However, the follow-up procedure will likely be substantial. To ensure patients’ safety, follow-up should be performed at experienced centers.
Some patients have a misconception about gene therapy that it will eradicate their disease. Gene therapy is not going to completely eradicate hemophilia, as the gene expressing the missing factor is added only in a particular individual and does not alter the inherited genes. So hemophilia may be still passed on the children.
Gene therapy is in clinical trials, so we are still learning a lot. However, I already believe that it will be an extremely important part of treatment for hemophilia in the future.