The development of anti-factor VIII inhibitors in mild/moderate hemophilia A (MHA) patients was described as an uncommon event. The largest cohort reported so far included 26 MHAI patients (Hay et al, 1998) and with other anecdotic reports underlined a special pattern of the bleeding reminiscent of acquired hemophilia, a generally poor response to immune tolerance protocol compared to severe patients, and potential factors contributing to a high-risk of inhibitor development such as the FVIII genotype, family related factors and intense substitutive therapy. The optimal therapeutic strategy in MAHI remains unknown. A retrospective data collection was therefore conducted. To date 45 MHAI patients from 29 french and belgian centers were included, with a median FVIII:C baseline level of 0.08 IU/ml (1–28). More than a half of the cases were detected within the last 4 years (y) for a total study period of 20 y. The median age for MHA diagnosis, first FVIII treatment and inhibitor disclosure was respectively 5-y (0 to 73-y),10.5-y (0 to 73-y) and 22.5-y (1 month to 81-y). One splice and 22 different missense mutations were identified for 34 patients (8 already described including 5 with inhibitor, and 15 new). Before the inhibitor appearance, patients received plasma derived (13) or recombinant (12) products only, or both (20). The median number of cumulative exposure days before inhibitor diagnosis was 29 (3–150). History of intense substitutive therapy (≥4 consecutive days or prophylactic treatment every other day for ≥8 days) was observed in 35 (77%) patients, and history of intracranial bleeding in 6/45 (13%). The median maximum historical titer was 6.6 UB (0.5 – 288). In 19 out of 45 (42%) patients FVIII:C baseline level was less than 0.01 IU/ml, while decreased but still detectable (0.01 IU/ml or higher) in 16 (35%), stable in 4 (9%), and unknown in the 6 others. No specific treatment to eradicate the inhibitor was used in 24 patients, while 19 received either an immune tolerance protocol (14 patients, including 6 with combined immunosuppressive drugs), either immunosuppressive agents alone (5 patients); specific treatment was unknown in 2. Apart 2 deaths unrelated to MHA and 3 unknown outcomes, the inhibitor disappeared for 30 patients with a median of 8 months, persisted as a plateau in 2, and was still decreasing in 7 after a median follow-up of 5 months. Anamnestic response defined as an increase of at least 30 % of the inhibitor titer after FVIII or aPCC concentrates was observed in 17 out of the 29 (65%) patients that were rechallenged, but none after recombinant factor VIIa (Novoseven®) or DDAVP. When an anamnestic response occured the median delay for inhibitor eradication increased from 3 to 11 months. This survey underlines: i) that MAHI is not rare, but likely better recognized nowadays, ii) the need for systematic inhibitor assessment after substitutive therapy in MHA, iii) the role of FVIII genotype, intense treatment and possibly inracranial bleeds as contributing factors for inhibitor development, iv) how treatment of bleeds in MHA have to be carefully discussed to limit the risk of respectively appearance or anamnestic response in patients without or with inhibitors.

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