Management of Bleeding In Acquired Hemophilia: Results of the European Acquired Hemophilia Registry (EACH2)

Acquired hemophilia (AH) is a hemorrhagic syndrome, caused by autoantibodies inhibiting coagulation FVIII. The optimal hemostatic therapy is not clear. This analysis aimed to describe the first-line management of bleeding in AH within Europe.

Data from the EACH2 registry, a multicentre, international, web-based registry, were used to analyze the use of recombinant activated factor VII (rFVIIa), activated prothrombin complex concentrates (APCC), FVIII concentrates, and DDAVP as first line hemostatic therapy. There was no predefined treatment protocol, each center was free to follow local clinical practice. Response rate is the number of bleeds resolved as judged by each investigator. Data on demographics, pregnancy and immunosuppression will be presented in other abstracts. Data are given as medians and interquartile ranges (IQR) or odds ratios (OR) and 95% confidence intervals (CI).

Data of 501 patients (pts) (235 male, 266 female, median age 74 years (range 14–104)) were prospectively collected between 2003 and 2009 in 90 centers of 11 European countries. In 474 pts at least one bleeding episode is reported; 159 pts had 2 episodes (the second bleeding episode a median 26 (13/67) days after the first), 51 pts had 3 episodes, 16 pts. more than 3 bleedings. Of the 474 initial bleeding episodes, 70.3% were reported as severe (criteria prospectively defined), 50.2% had deep musculoskeletal or retroperitoneal bleeding, 53.2% skin hematomas, 31.6% mucosal bleeding, and only 4.9% hemarthroses. In 77.4% the bleedings occurred spontaneous, 8.4% after trauma, 8.2% after surgery. Median FVIII activity at the time of bleeding was 0.02 U/mL (0.01/0.05 U/mL), the inhibitor titer 19 BU/mL (5.5/64 BU/mL). There was no significant association between FVIII activity or inhibitor titer and severity of bleeding. Hemostatic therapy was given in 70.5% of the bleedings. First line therapy is presented in the table:

Desmopressin was given in 6%, antifibrinolytic drugs in 18%, and high dose immunoglobulin infusions in 11.1%; immunoadsorption was performed in 5.4%, plasmapheresis in 0.6%. Overall bleeding resolved in 76.4%, in median after 4 days (IQR 2–10 days). Second line therapy with an alternative substance was applied in 23.6% (in 17.4% because bleeding did not resolve). The use of bypassing agents (rFVIIa or APCC) resulted in a significant higher rate of bleeding control (91.2 %) than the use of FVIII or desmopressin (71.0 %) (p<0.001), there was no difference between rFVIIa (90.9 %) and APCC (94.3 %). To minimize bias, propensity score matched data analysis (1) based on age, gender, FVIII level, inhibitor titre, hemoglobin level, site, severity and cause of bleeding was carried out. It confirmed that first line treatment with a bypassing agent resulting in a better control of bleeding compared to FVIII or desmopressin (OR 0.25, 95% CI 0.12–0.53; p=0.004). There was no difference in efficacy between rFVIIa and APCC (OR 1.0, 95%CI 0.24–4.18). No other patient- or disease-related parameters affected response rate. Deaths due to bleeding occurred in 3% of the patients, only few serious adverse events were recorded: 1.4% myocardial infarction, 0.2% stroke, 1.0% venous thromboembolic events. There was no significant association of death or severe adverse events with a specific hemostatic therapy.

Bypassing agents are the preferred first line hemostatic therapy in AH (70.1% of the episodes) and have a significantly better efficacy than FVIII or DDAVP; rFVIIa was the agent preferred by most clinicians (~50%), rFVIIa and APCC were equally efficacious. Treatment with bypassing agents was safe and highly effective in controlling bleeding in AH.

1. D'Agostino RB Jr: Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998; 17:2265–2281.

Knoebl:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry, Research Funding; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Baudo:NovoNordisk: Consultancy, Honoraria, NovoNordisk fund the EACH2 registry, Speakers Bureau; Bayer Healthcare: Honoraria, Speakers Bureau. Collins:NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Huth-Kuehne:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levesque:NovoNordisk: NovoNordisk fund the EACH2 registry. Marco:Novo Nordisk: Novonordisk fund the EACH2 registry. Nemes:Novo Nordisk: Novonordisk fund the EACH2 registry. Pellegrini:Novonordisk: Consultancy, Honoraria, Speakers Bureau, The EACH2 registry is funded by Novonordisk. Tengborn:Novo Nordisk: Novonordisk fund the EACH2 registry.