Acquired hemophilia A (AHA) is characterized by neutralizing autoantibodies against FVIII. Typically, AHA incidence is observed in 2 peaks: the first is during pregnancy or within the first year of childbirth, and the second is in old age, defined as over 60 years old. Approximately 50% of AHA patients have comorbidities such as malignancy or other autoimmune disorders.
AHA, in contrast to congenital hemophilia A, is extremely rare. The scarcity of clinical research into AHA reflects this reality. In addition, AHA patients tend to present with more severe symptoms, thus complicating efforts to recruit patients stable enough for clinical studies. This means that treatment decisions are largely dictated by the attending physician’s experience and expertise (as opposed to established guidelines).
There have been some attempts to create a set of international guidelines for use by physicians around the world. Huth-Kühne et al proposed a set of new international recommendations for the treatment of AHA in 2009. The recommendations were made based on the authors’ own experiences treating AHA and encompassed data from both Europe and the US.
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More than a decade has gone by since these guidelines were published, and new evidence regarding AHA treatment has come to light. Hence, a team of researchers sought to publish an updated version in 2020. This was a highly ambitious project, with each author of the study independently reviewing the 2009 guidelines and identifying areas that were ripe for change based on their expertise and knowledge of available literature. Some of the authors who reviewed the 2009 guidelines happened to also be the authors of said guidelines, including Peter Collins, Midori Shima, and Angela Huth-Kühne.
The authors then combined their findings into a single document, which was published in Hematologica. Each of the proposed changes had to be justified, with an emphasis on the data available through AHA registries. Recommendations were made when the authors judged the potential benefits and safety to outweigh any potential risks and burdens. In this article, we will look at some of their findings as they relate to guidelines regarding the immunosuppressive treatment of AHA.
In addition to hemostatic treatment, immunosuppressive therapy aims to reduce bleeding time and induce remission in AHA patients. In the 2009 guidelines, the recommendation was that all patients should be started on immunosuppressive therapy upon AHA diagnosis. This was because bleeding-related mortality was high in patients with AHA, so all reasonable measures were to be taken to reduce bleeding tendencies.
The 2009 guidelines recommended that patients be treated initially with corticosteroids only or in combination with cyclophosphamide for up to 6 weeks. The second-line therapy of rituximab was recommended if there were any contraindications to first-line immunosuppressive therapy.
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The evidence for the immediate use of immunosuppressive drugs is compelling. A study recruited patients within 7 days of being started on immunosuppressive therapy. They were monitored weekly until remission was achieved. The 1-year survival rate was 68%; among the 34 patients who died, the most common cause of death was infection (n=6), while bleeding was the least common (n=3). This means that with immunosuppressive therapy, the risk of dying from infection was higher than bleeding from AHA, thus highlighting the incredible value of immunosuppressive therapy in reducing bleeding-related incidences.
Just as in the 2009 guidelines, the authors of this study recommended immunosuppressive therapy for all patients with AHA, with the caveat that caution should be exercised in frail patients.
Choice of Drugs
Now that we have established that immunosuppressive therapy is essential to AHA management, what do the authors recommend as the first and second-line choice of drugs? In the 2009 guidelines, corticosteroids such as prednisolone or prednisone were recommended as first-line therapy. The dose was 1 mg/kg/day PO for 4−6 weeks. In the updated guidelines, the authors retained this recommendation and left it unchanged.
As for second-line therapy, rituximab was recommended in the 2009 guidelines. Rituximab is not approved by the US Food and Drug Administration for treating AHA in the US, but it is approved for use in treating other immune diseases such as non-Hodgkin lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis.
Having studied the evidence regarding the use of rituximab in AHA, the authors of this study recommended adding rituximab to first-line immunosuppressive therapy in AHA patients with poor prognostic markers at a dose of 375 mg/m2/week for a maximum of 4 cycles. “Rituximab should be considered as second-line immunosuppressive therapy if corticosteroids are contraindicated in AHA patients,” the authors wrote.
Regardless of the regimen of immunosuppressive drugs prescribed, it is important to closely monitor patients for adverse events. Studies have shown that adverse events relating to immunosuppressive therapy occur in about 50% of cases. Therefore, patients should be monitored until complete remission has been achieved and for the few months following that. For detecting recurrence, FVIII:C monitoring has been shown to be a superior method to monitoring activated partial thromboplastin time (APTT).
Hence, with regards to follow-up protocols, the authors of the study wrote, “We recommend follow-up after complete remission, using FVIII:C monitoring monthly during the first 6 months, every 2−3 months up to 12 months, and every 6 months during the second year and beyond, if possible.”
The Necessary Evolution of Guidelines
The bigger picture that this study represents is the necessary evolution of guidelines as new research is conducted and new information emerges. While studies involving AHA are relatively scarce, researchers are still able to recommend a set of guidelines according to the best available evidence. Just as adjustments were made to the 2009 set of AHA treatment guidelines, no doubt new adjustments and recommendations will follow in the years to come.
Tiede A, Collins P, Knoebl P, et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica. Published online May 7, 2020. doi:10.3324/haematol.2019.230771
Huth-Kühne A, Baudo F, Collins P, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica. Published online April 1, 2009. doi:10.3324/haematol.2008.001743