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Treatment Decisions in Hemophilia A
Los Angeles, CA
Hemostasis and Thrombosis
University of Southern California Keck School of Medicine
What are the most pressing complications of hemophilia A and how do you answer them?
The most important complication of hemophilia is hemophilic arthropathy or permanent joint damage, which results from repeated bleeds into the same joints. The best approach for preventing this is to treat patients with prophylaxis with factor concentrates. In the case of hemophilia A, there is now the possibility of using emicizumab to prevent bleeding. This preventative approach should be used in all patients with hemophilia with a bleeding phenotype — that is, those with regular (more than once per year) bleeding episodes.
A second important complication is the development of neutralizing antibodies (called inhibitors) to the factor concentrates. Approximately 25% of patients with hemophilia A and 5% of patients with hemophilia B will develop these inhibitors after treatment with factor. These antibodies render factor replacement ineffective and as such, patients must then rely on alternative drugs called bypassing agents that are not nearly as effective as the natural replacement of the missing clotting factor. For patients who develop these inhibitors, they are treated with a regimen of more intensive factor in a treatment approach termed immune tolerance induction with the goal of eradicating the inhibitor. This approach is effective in approximately 70% of the patients who are administered the therapy as prescribed. A novel alternative approach is to put such patients on emicizumab, which does not eradicate the inhibitors but is very effective at preventing bleeding and thus its complications. Still, patients who develop inhibitors should have a trial of immune tolerance if at all possible.
How does the heterogeneity of hemophilia (in terms of bleeding pattern, severity, etc.) affect your treatment decisions?
Patients with hemophilia are very heterogenous in their bleeding phenotype, even those with the same severity per their factor level. The approach to managing hemophilia must be individualized, and those with a bleeding phenotype should be treated aggressively — that is, with prophylaxis — regardless of which category they fall in based on their residual factor level. In other words, for patients with severe or moderate (or even mild) hemophilia who experience frequent bleeding, the appropriate therapy is prophylaxis with factor or emicizumab. Furthermore, patients’ responses to the above treatments vary, and thus, patients on prophylaxis should be monitored carefully for their response to treatment with the goal of having as few bleeds as possible (preferably 0). Treatment should be adjusted depending on the patients’ response and can include changing the dose and frequency of the medication used or even the medication as well.
What steps do you take to evaluate and, if necessary, improve your patients’ health-related quality of life?
In order to maximize the outcomes for patients, regular and detailed evaluations must take place at least every 6 months for patients with severe hemophilia and others on prophylaxis and every 3 months for those with inhibitors. The evaluations include an assessment of the patient’s bleeds — how many, where, and how were they treated — as well as an evaluation of their joints by a qualified physical therapist, preferably using the Hemophilia Joint Health Score (HJHS), a validated tool for evaluating musculoskeletal health and activities. Such frequent follow-up and detailed examinations can uncover subtle changes that may result in a change in treatment, thereby improving outcomes. In addition, an evaluation by a social worker or psychologist can assess overall quality of life, and there are hemophilia-specific instruments that can help with this assessment as well.
What are the challenges of aging in patients with hemophilia and how do you address them?
For aging patients, there are both hemophilia-related and non-hemophilia-related challenges. With respect to hemophilia, the current generation of aging patients did not have the benefits of prophylaxis in most cases when they were young and, thus, they suffer from significant joint disease. The best approach for such patients is, again, to use prophylaxis with factor to prevent further bleeding into deteriorating joints, but moreover, these patients need to have their physical limitations evaluated and treated. This may involve chronic pain management, physical and occupational therapy, and surgery where appropriate. This is best accomplished with a multidisciplinary team approach and in comprehensive hemophilia treatment centers where these services are usually available.
In addition, aging patients present a challenge with respect to management of non-hemophilia-related issues such as cardiovascular disease. These include issues such as determining the appropriate medications to administer to prevent cardiovascular complications but that will not exacerbate bleeding or existing joint disease. In addition, some patients are still living with complications related to receiving factor therapy before the elimination of transmission of infections from blood products and thus may have HIV, Hepatitis C, or both. These patients need to be referred to the appropriate specialist for management of those conditions.
What do you think the role of gene therapy is for hemophilia? Do you see gene therapy becoming a mainstay of hemophilia treatment?
Gene therapy will certainly play a role in the management of patients with hemophilia. Although it holds great promise for potentially eliminating the need for factor and for preventing bleeding, there is much work to be done to determine its short- and (especially) long-term safety. Importantly, gene therapy, at least in the early years after commercialization, will only be available for a subset of patients: adults, those with no prior history of inhibitors, those with no preexisting antibodies to the vector (for most currently studied products), and those who are willing to try a truly novel approach to medical therapy (across all disease types). Thus, in the first 5 to 10 years after gene therapy is available, it is likely that the majority of patients (if we include children in the calculation) will not receive gene therapy and will still rely on factor, emicizumab, and a host of other new nongene therapy approaches. However, thinking further into the future, gene therapy has the potential to ultimately treat all patients and thus eliminate the risk and burdens associated with having hemophilia.