Anti-factor VIII IgA as a potential marker of poor prognosis in acquired hemophilia A: results from the GTH-AH 01/2010 study.

Neutralizing autoantibodies against factor VIII (FVIII), also called FVIII inhibitors, are the cause of acquired hemophilia A (AHA). They are quantified in the Bethesda assay or Nijmegen-modified Bethesda assay by their ability to neutralize FVIII in normal human plasma. However, FVIII inhibitors do not represent the whole spectrum of anti-FVIII autoantibodies. Here, we studied isotypes, immunoglobulin G subclasses, and apparent affinities of anti-FVIII autoantibodies to assess their prognostic value for the outcome in AHA. We analyzed baseline samples from patients enrolled in the prospective GTH-AH 01/2010 study. Our data suggest that anti-FVIII immunoglobulin A (IgA) autoantibodies are predictors of poor outcome in AHA. Anti-FVIII IgA-positive patients achieved partial remission similar to anti-FVIII IgA-negative patients but had a higher risk of subsequent recurrence. Consequently, IgA-positive patients achieved complete remission less frequently (adjusted hazard ratio [aHR], 0.35; 95% confidence interval [CI], 0.18-0.68; P < .01) and had a higher risk of death (aHR, 2.62; 95% CI, 1.11-6.22; P < .05). Anti-FVIII IgA was the strongest negative predictor of recurrence-free survival after achieving partial remission and remained significant after adjustment for baseline demographic and clinical characteristics. In conclusion, anti-FVIII IgA represents a potential novel biomarker that could be useful to predict prognosis and tailor immunosuppressive treatment of AHA.

Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study.

Acquired hemophilia A (AHA) is caused by autoantibodies against factor VIII (FVIII). Immunosuppressive treatment (IST) results in remission of disease in 60% to 80% of patients over a period of days to months. IST is associated with frequent adverse events, including infections as a leading cause of death. Predictors of time to remission could help guide IST intensity but have not been established. We analyzed prognostic factors in 102 prospectively enrolled patients treated with a uniform IST protocol. Partial remission (PR; defined as no active bleeding, FVIII restored >50 IU/dL, hemostatic treatment stopped >24 hours) was achieved by 83% of patients after a median of 31 days (range 7-362). Patients with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days) than patients with ≥1 IU/dL (89%, 24 days). After adjustment for other baseline characteristics, low FVIII remained associated with a lower rate of PR (hazard ratio 0.52, 95% confidence interval 0.33-0.81, P < .01). In contrast, PR achieved on steroids alone within ≤21 days was more common in patients with FVIII ≥1 IU/dL and inhibitor concentration <20 BU/mL (odds ratio 11.2, P < .0001). Low FVIII was also associated with a lower rate of complete remission and decreased survival. In conclusion, presenting FVIII and inhibitor concentration are potentially useful to tailor IST in AHA.

Long-term efficacy and safety of a pasteurized, plasma-derived factor VIII concentrate (Beriate® P) in patients with haemophilia A.

INTRODUCTION: Beriate(®) P was first introduced in Germany in 1990 as factor VIII (FVIII):C(®) HS Behring and subsequent product improvements yielded an albumin-free formulation with a specific activity of approximately 170 IU/mg protein. In 1992, the concentration was raised to 100 IU FVIII/mL in the reconstituted product, with a mean specific activity of 270 IU/mg protein. Pathogen safety is achieved by careful donor selection and a combination of pasteurization and chromatographic purification steps. MATERIALS AND METHODS: We analysed the efficacy and safety of Beriate(®) P in the clinical setting from 1996 to 2005 with a focus on surgical patients. Of the 36 patients (mean age: 38 years; range 1-72 years), 29 had severe haemophilia A, two had moderate haemophilia, two had mild haemophilia, and three had sub-clinical haemophilia. Most patients (n=28) had more than 100 exposure days, representing a total of 202 patient-years with a consumption of 27,811,500 IU of Beriate(®) P. RESULTS: There was no evidence of seroconversion towards relevant viruses, no inhibitor development (35 previously treated patients, one previously untreated patient), no abnormal immunological findings or allergic reactions. In all 36 patients treated for acute bleeding and prophylaxis, and 24 surgeries (15 total joint replacements, eight orthopaedic procedures, one cholecystectomy) in 16 patients with severe haemophilia A, efficacy of Beriate(®) P was always rated as "excellent" or "good", and no thrombosis was reported. CONCLUSION: Beriate(®) P has an excellent efficacy and safety profile. Many patients who were initiated on Beriate(®) P at our centre remain on the treatment today.