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Certain F8 mutations increased inhibitor formation in hemophilia A
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Nineteen specific mutations in the Factor VIII gene were associated with inhibitor development in patients with nonsevere hemophilia A, according to the results of a retrospective cohort study.
The results demonstrate the value of Factor VIII genotyping in this patient population, researchers wrote.
“The inhibitor incidence in nonsevere hemophilia A patients with certain F8 mutations approaches the inhibitor incidence in severe patients,” Corien de Groot-Eckhardt, MD, a pediatric resident and PhD student in the department of pediatric hematology and department of vascular medicine at Emma Children’s Hospital in Amsterdam, told HemOnc Today. “These findings are highly relevant for clinical practice as they facilitate identification of high-risk patients based on their F8 genotype.”
De Groot-Eckhardt — along with Karin Fijn van Draat, MD, PhD, of the department of pediatric hematology at Emma Children’s Hospital in Amsterdam, and colleagues — conducted the multicenter INSIGHT study to analyze risk for inhibitor development after treatment with Factor VIII concentrates in 1,112 patients with nonsevere hemophilia A. Researchers identified the F8 genotype in 895 (81%) patients.
Prior studies have demonstrated that the risk for inhibitor development in patients with severe hemophilia A is less than 1% after 50 days of exposure to Factor VIII concentrates. However, most adults with nonsevere hemophilia A haven’t been exposed for this length of time, and thus are still at risk for inhibitor development and resulting complications, researchers wrote.
Nonsevere hemophilia was defined as baseline Factor VIII activity of 2 IU/dL to 40 IU/dL . Eligible patients had Factor VIII concentrate treatment between 1980 and 2011.
The observation period encompassed 25,700 patient-years 44,800 exposure days.
Each patient was exposed for a median of 24 days (interquartile range [IQR], 7-90). At follow-up, exposure did not exceed 50 days in 755 (68%) patients, with 517 of those having less than 20 days of exposure.
Researchers used two positive Bethesda Inhibitor Assay titers of ≥1.0 BU/mL to define inhibitor development. If the inhibitor titers were between 0.6 BU/ml and 1.0 BU/mL, patients also had to have at least a 50% decrease in Factor VIII plasma from baseline or a reduction in half-life after less than 6 hours of treatment for classification of new inhibitors.
Fifty-nine patients (median age, 46 years; median exposure days, 28) developed inhibitors, equating to a cumulative incidence of 5.3% (95% CI, 4.0-6.6; median peak titer, 9 BU/mL). The researchers found no association between inhibitor development and ethnicity or disease severity.
The majority of inhibitors developed between 2000 and 2010 (n=37; 64%), with a median of 32 days of exposure (IQR, 21-75). Seventeen inhibitors (29%) developed between 1990 and 1999, with a median of 12 days of exposure (IQR, 8-41), and four inhibitors (7%) developed between 1980 and 1989, with a median 11 days of exposure (IQR, 6-75).
Researchers calculated the inhibitor risk at 50 exposure days as 6.7% (95% CI, 4.5-8.9), and the risk at 100 exposure days was 13.3% (95% CI, 9.6-17).
“Importantly, the risk of inhibitor development in patients with nonsevere hemophilia approaches the risk of severe hemophilia patients when inhibitor development is evaluated as a function of exposure to Factor VIII concentrates,” the researchers wrote. “This highlights the substantial risk of inhibitor development in nonsevere hemophilia A patients that has been previously underestimated.”
Of the 59 patients who developed inhibitors, researchers reported increased bleeding tendency at detection in 30 (51%) of them, and 47 (80%) needed treatment for bleeding.
After a median of 45 weeks (IQR, 13-108), inhibitors could no longer be detected in 42 (71%) of patients, 12 of whom had undergone inhibitor eradication therapy. Fourteen patients still had inhibitors at the end of follow-up.
Fifty-one (86%) of patients who developed inhibitors had the F8 genotype. At 50 exposure days, the risk for inhibitor development with specific F8 mutations varied from 0% to 42%.
The researchers found that 19 out of 214 F8 mutations, each located in the A2 domain of the heavy chain and the A3, C1 and C2 domains of the light chain, were associated with inhibitor development. Two of those mutations, Phe1775Val and Stop2333Cys, had not previously been reported in the HaMSTERS or CHAMP database, according to researchers. Five of the mutations — Leu412Phe, Arg1781Gly, Phe2101Cys, Arg2159Cys and His2309Asp — had not been previously reported as related to inhibitor development.
“Our study highlights the potential of F8 genotyping to estimate individualized risks of inhibitor formation for those mutations with sufficient data,” the researchers wrote. “It can inform the patient–doctor consultation, contributing to the decision whether to proceed with an elective intervention and how to manage it, and may therefore be of immediate clinical relevance.”
Disclosure: See the study for a full list of the researchers’ relevant financial disclosures.
Perspective
Back to TopNigel Key, MD
This study is important for several reasons. First, it emphasizes that Factor VIII inhibitors are more common than previously appreciated in patients with moderate and mild hemophilia A. Clinicians should be aware that these patients may develop inhibitors after intense Factor VIII exposure, such as can occur after surgery or a major bleeding event. Second, the median age of inhibitor development in this cohort (46 years) is consistent with other similar studies; in contrast, the median age of inhibitor development in patients with severe hemophilia A is <5 years of age. Third, this study now establishes that Factor VIII genotyping can help to predict risk of inhibitor development in nonsevere hemophilia. As such, it provides further evidence that Factor VIII/IX genotyping should now be considered to be standard of care in the management of hemophilia.
Perspective
Back to Top
Bruce L. Evatt, MD
Development of an inhibitor to Factor VIII in a hemophilia patient is a serious and challenging complication. It substantially raises the costs of treatment and leads to increased morbidity and mortality. The cause of inhibitors is multifactorial and their identification by testing is complicated by the lack of universal standardization. Because inhibitors are not common and may not be immediately clinically evident, conducting clinical studies on the causes of inhibitors is difficult. Consequently, a number of assumptions about inhibitors in hemophilia patients have been made in the absence of substantiating data.
Despite these problems, investigators are slowly developing an understanding of inhibitors. Studies of inhibitor development in patients with severe hemophilia have shown a relationship to certain mutations of the Factor VIII gene (F8) and the number of days exposed to treatment Factor VIII concentrates. This knowledge is useful in predicting which patients with severe hemophilia are most at risk for developing inhibitors. Nonsevere hemophilia patients receive treatment less frequently and no tools are currently available to predict their inhibitor risk. This study has identified a higher incidence of inhibitor development in nonsevere patients than previously appreciated and relates this to nonsense mutations in F8. In addition, inhibitor development appears to be cumulative over the lifetime of the patient. This suggests that if patients respond to desmopressin, an alternative treatment for mild and moderate hemophilia patients, then such patients should be treated with desmopressin administration rather than Factor VIII concentrates. The current study should encourage other investigators to undertake further investigations on patients with nonsevere hemophilia using multiple cooperating centers.
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