Surgery as a risk factor for inhibitor development in haemophilia A:A systematic review

Introduction: Surgery is a risk factor for the development of factor VIII inhibiting antibodies (inhibitors) in haemophilia A. This may be due to the combination of danger signal release resulting from tissue damage and intensive exposure to factor VIII (FVIII) concentrate. The purpose of this systematic review was to compare the inhibitor risk following intensive treatment for surgery in comparison to both prophylactic administration of FVIII concentrate and intensive treatment for bleeding in patients with haemophilia A. Methods: A comprehensive search was performed in MEDLINE, EMBASE, and the Cochrane databases (1966 to 2009), to identify cohort or case control studies in which risk of inhibitor development in relationship to surgery and treatment was reported. Results: Eighteen studies (n = 2547) reporting 675 surgical procedures in 526 patients met the inclusion criteria. Because of heterogeneity in study populations, missing data, and limited methodological study quality, we assessed the effect of surgery only in patients with a first treatment, leaving three studies for further analysis. Pooled OR for inhibitor development in patients undergoing surgery was 4.6 (95% CI, 2.1 - 10.2) compared to treatment only. Limited information was available for continuous infusion, previously treated patients, and those with mild/moderate haemophilia A. Conclusion: Surgery at first exposure to FVIII concentrate seems associated with a 4.6-fold increased risk of inhibitor development in patients with severe haemophilia A. There is a clear need for robust well-designed studies assessing the association between surgery and inhibitor development, in which potential confounding factors are taken into account