Improved Prognosis of Acquired Hemophilia A: A 10-Year-Experience

Acquired hemophilia A (AHA) is a rare but significant hemostatic disorder caused by inhibitory autoantibodies against coagulation factor VIII (FVIII:C). The annual incidence of AHA is low with about 1 to 4 cases per million individuals. However, the mortality rate due to severe hemorrhages and comorbidity is high reaching 22% in several series. In the past, only a few patients were reported in whom an association of AHA with respiratory disorders was observed.

We have performed a monocenter study on 35 consecutive patients with AHA A who were referred for diagnosis and treatment to the Düsseldorf Hemophilia Comprehensive Care Center between March 2001 and June 2011. The cohort included 24 males (age: 44–86 years) and 11 females (age: 20–83 years). For laboratory evaluation, a standardized staged protocol of APTT, FVIII:C activity and concentration, mixing studies with patient and normal plasma, and quantitation of inhibitor titers (Nijmegen modification of the Bethesda assay) was used. Diagnostic work-up for any underlying disease was performed according to a standardized protocol of clinical examinations and imaging procedures (including X-ray examination of thorax, sonography of abdomen, retroperitoneum and thyreoidea and, whenever indicated, computerized tomography of thorax, abdomen, or pelvis). Therapy was performed according to a treatment algorithm consisting of (a) acute antihemorrhagic therapy (irrespective of residual FVIII:C activity and inhibitor titer), (b) immediate immunosuppression (individually tailored to the patients’ risks with regard to age and comorbidity), and, if life-threatening bleedings persisted, (c) inhibitor elimination by immunoadsorption or plasmapheresis, and (d) concomitant immunotolerance regimens. Predefined clinical endpoints were control of bleeding, eradication of the inhibitor, complete or partial remission (CR, PR), relapse, or early death (< 30 days). CR was defined as no inhibitor detectable, FVIII:C activity > 80%, and withdrawal of immunosuppressive therapy.

In 21 (60%) of the 35 patients with AHA, an underlying disorder was identified, including 9 patients with respiratory diseases (26%), 8 patients with autoimmune disorders (23%), 3 with malignancies, and one with postpartum state, while in 14 patients (40%) AHA remained idiopathic. Upon admission, 16 of the 35 patients presented with life-threatening hemorrhages. In 13 of these 16 patients, control of bleeding was achieved by high doses of recombinant activated factor VII (rFVIIa; 90–120 μ g/kg every 2–3 h), while 3 patients required combined FVIII bypassing agents (rFVIIa plus bolus injections of activated prothrombin complex concentrates, aPCC; 100 IU/kg every 8–12 h). In the other 19 patients, bleeding also subsided in response to rFVIIa. Concurrent immunosuppression with prednisone alone (2 mg/kg/day) was performed in 11 patients, while 24 patients received cyclophosphamide (2 mg/kg/day) sequentially in combination with prednisone. In 5 patients in whom this first-line immunosuppression failed, 4 doses of rituximab (375 mg/m²) were administered as second-line therapy. Of the 35 patients, 13 required extracorporeal inhibitor elimination procedures due to persisting life-threatening bleeds. Exchange plasmapheresis was performed in 4, daily large-volume immunoadsorption (Ig-Therasorb) for up to 4 weeks in 9 patients. In 3 of them, immune tolerance was concomitantly induced by exogenous FVIII (100 IU/kg/day). Of the 35 patients in total, 28 individuals achieved CR (80%), 3 had PR, one relapsed, and 3 died within 30 days (one of acute myocardial infarction while on antihemorrhagic treatment, one of sepsis while on immunosuppression due to active AHA, one of lung bleeding in assocociation with pre-existing pulmonary sarcoidosis).

This monocenter study demonstrates that control of life-threatening bleeding, eradication of the inhibitor, and induction of immune tolerance to FVIII have clearly improved the clinical outcome of AHA. Our data also suggest a shift in underlying disorders associated with AHA, whereby, in comparison to published studies, a relative increase in the proportion of patients with respiratory diseases is observed. Large controlled multicenter studies are required to confirm these findings.

No relevant conflicts of interest to declare.