What FVIII Levels Are Ideal for Preventing Bleeding in Hemophilia A?
Recent studies indicate that target trough levels of factor 1–3% during prophylactic treatment are insufficient to fully prevent clinical and subclinical bleeding. With a sustained FVIII level > 15%, as shown in studies with mild hemophiliacs, spontaneous bleeding is very rare. This raises the question of whether achieving zero bleeding incidence with FVIII replacement therapy is possible and whether it can be a realistic goal. This topic was also explored in a presentation by Dr. Ester Zápotocká from the Clinic of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital in Prague.
Current Definition and Approaches to Prophylaxis
The author first summarized the current approaches to prophylaxis: “We strive for the best possible use of available factor concentrates, individualizing treatment with respect to dose, application intervals, type of concentrate, utilizing pharmacokinetic parameters, and considering bleeding events or risks, which are very individual for each patient”. She added that a certain level of physical activity also requires a certain level of factor, which is considered protective. It is also noted that early joint involvement can impact signs of hemophilic arthropathy, which may develop over several decades of a patient’s life.
The World Federation of Hemophilia (WFH) in the 3rd edition of their guidelines proposed a new definition of prophylaxis. According to them, prophylaxis should be defined as the regular administration of hemostatic agents to prevent bleeding in individuals with hemophilia, enabling these individuals to live active lives and achieve a quality of life comparable to those without hemophilia. The goal of hemophilia care, especially for the most severe cases, should thus be to find the minimally effective treatment, with a great emphasis on its personalization.
PROPEL Study
The PROPEL international multicenter randomized open-label Phase III trial provided some insights into this issue. It compared the effectiveness and safety of pharmacokinetically guided prophylaxis to achieve target trough FVIII levels of 8–12% (first arm, n = 58) vs. 1–3% (second arm, n = 57). It also sought to answer whether increasing trough levels would yield a higher proportion of patients without any bleeding (zero bleeding).
The study was conducted from November 2015 to August 2018 in 62 treatment centers across 19 countries, including 115 patients aged 12–65 years with severe hemophilia A (FVIII level < 1%) and an annual bleeding rate (ABR) ≥ 2 in the past 12 months (with a median ABR of 13 and average ABR of 6 in the cohort). Patients were infused with rFVIII-PEG at a dose of 60 ± 5 IU/kg.
The results showed that achieving target trough levels of 8–12% led to a consistently lower total ABR and a higher proportion of individuals without bleeding compared to the target range of 1–3%. The safety profile of the treatment was similar in both groups, with no new safety risks identified.
The PROPEL study thus confirmed the necessity of a personalized approach to prophylaxis, as diverse dosing regimens and overlapping of the two groups in terms of FVIII dose and frequency were observed during the study.
Conclusion
Dr. Zápotocká concluded that achieving higher sustained trough levels and zero bleeding is possible, particularly with extended half-life (EHL) products, albeit at the cost of increased application frequency and FVIII consumption. Higher trough FVIII levels can be beneficial or necessary for many hemophiliacs, and this needs to be emphasized in individualized treatment. Pharmacokinetics can be used as a tool for personalization, taking into account the clinical condition, the patient’s wishes, and their idea of quality life, including physical activity.
Eva Srbová
MeDitorial Editorial Team
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