Hemophilia is a bleeding disorder characterized by spontaneous, recurring bleeding that can result in arthropathy and reduced mobility. Patients who have a severe phenotype of the disease tend to experience significant spontaneous bleeding events that often result in a poorer quality of life.
The severity of this disease, aside from its clinical manifestations, can be categorized according to the levels of factor VIII and factor IX activity for hemophilia A and B respectively.
“Disease severity is based on the residual coagulation FVIII/IX level and is classified as severe (<0.01 IU/mL), moderate (0.01-0.05 IU/mL), or mild (>0.05-0.40 IU/mL),” Kloosterman and colleagues wrote in Blood Advances.
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Much research has been devoted to finding new ways to treat patients with severe hemophilia. The reason for this is obvious: patients who experience unexpected and severe bleeding episodes often struggle to fully participate in school, sports, or employment. In other words, there is an urgency attached that is not found in milder cases of hemophilia.
The collective commitment to treating severe hemophilia has resulted in the development of a number of treatment strategies that continue to transform the therapeutic landscape of severe hemophilia: emicizumab, other nonreplacement products, and gene therapy.
Patients who experience mild hemophilia tend to only have bleeding episodes triggered by trauma or surgery. Because medical literature has conventionally placed a greater emphasis on severe hemophilia, we still do not have a firm grip on the frequency and nature of bleeding episodes experienced by patients with mild hemophilia.
A Closer Look at Mild Hemophilia
In the Journal of Thrombosis and Haemostasis, Abdi and colleagues investigated the factor VIII treatment history in patients with nonsevere hemophilia A.
The research team recruited patients with nonsevere hemophilia A, defined as having factor VIII activity between 2 and 40 IU/dL, from the INSIGHT study. Participants in that study had at least one exposure to factor VIII concentrate between 1980 and 2011; Abdi and colleagues only looked at the data of patients born after January 1, 1980. This study yielded important insights into how factor VIII replacement therapy has been administered in patients with mild hemophilia A over the years.
Kloosterman and colleagues conducted a similar study into the bleeding phenotype of patients with nonsevere hemophilia, defined as having a median factor VIII/ factor IX baseline of 0.12 IU/mL. This was an international multicenter cohort study that had the participation of 15 hemophilia centers from across the globe. Patients with mild hemophilia were recruited and had to complete a questionnaire and blood draw, as well as consent to the collection of clinical information.
The researchers discovered that the age of first bleed was known in 69% of cases and that the median age at first bleed was 8 years of age. The age of the first exposure to factor VIII treatment (for hemophilia A) occurred earlier in patients with a family history of hemophilia, regardless of baseline factor VIII activity.
The researchers also discovered that the median annualized bleeding rate was 1.1 and the annualized joint bleeding rate was 0.3 in patients with mild hemophilia. Among the patients who experienced major spontaneous bleeds, only 33% were verified to be spontaneous.
Approximately 67% of bleeds were related to trauma, activity, surgery, or an underlying disease. Bleeding episodes occurred in the joints and muscles around a third of the time.
There also appears to be heterogeneity in terms of the duration between follow-ups for patients with mild hemophilia, ranging from 6 months to 14.8 years. In addition, some bleeding episodes were self-reported by patients with mild hemophilia.
“Because bleeds occur infrequently, self-reported bleeding rates may come with a degree of recall bias and are open for subjectivity,” Abdi and colleagues wrote.
Implications for Clinical Practice
There is enormous value in collecting data on patients with nonsevere hemophilia because it allows physicians to devise appropriate treatment plans for patients with all hemophilia phenotypes.
The goal of treating patients with severe hemophilia is to convert their disease into one that has a milder clinical presentation. However, the risk of the development of inhibitors to factor replacement products remains. Hence, an important consideration in treating patients with both severe and nonsevere hemophilia is to effectively monitor and manage inhibitor development.
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“It has been speculated that improved diagnosis and increased use of FVIII products have increased the reported incidence of inhibitor formation in mild hemophilia A,” Benson and colleagues wrote in Blood Transfusion. “It is therefore useful to keep records of a patient’s exposure to FVIII throughout their life.”
In addition, the studies conducted by Abdi et al and Kloosterman et al demonstrate that bleeding episodes can still occur in patients with mild hemophilia. Data from patients with severe hemophilia indicate that even a small number of joint bleeds can result in joint pathology. This means that patients with nonsevere hemophilia may experience a deterioration in their quality of life if their condition is not managed effectively.
Therefore, it is imperative that patients with mild phenotypes of hemophilia are educated on how to recognize joint bleeds and how certain activities can increase the risk of bleeding. Physicians should not hesitate to initiate prophylactic treatment in patients with moderate hemophilia and relatively high bleeding rates.
Abdi A, Kloosterman FR, Eckhardt CL, et al. The factor VIII treatment history of non-severe hemophilia A. J Thromb Haemost. 2020;18(12):3203-3210. doi:10.1111/jth.15076
Kloosterman FR, Zwagemaker AF, Bagot CN, et al. The bleeding phenotype in people with nonsevere hemophilia. Blood Adv. 2022;6(14):4256-4265. doi:10.1182/bloodadvances.2022007620
Benson G, Auerswald G, Dolan G, et al. Diagnosis and care of patients with mild haemophilia: practical recommendations for clinical management. Blood Transfus. 2018;16(6):535-544. doi:10.2450/2017.0150-17