ORIGINAL ARTICLE Surgery and inhibitor development in hemophilia A: a systematic review C. L. ECKHARDT,*  J. G. VAN DER BOM, à M. VAN DER NAALD,  M. PETERS,* P. W. KAMPHUISEN   andK.FIJNVANDRAAT* *Department of Pediatric Hematology, Emma ChildrenÕs Hospital, Academic Medical Center, Amsterdam;  Department of Vascular Medicine, Academic Medical Center, Amsterdam; and àJon J. van Rood Center for Clinical Transfusion Research and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands To cite this article: Eckhardt CL, van der Bom JG, van der Naald M, Peters M, Kamphuisen PW, Fijnvandraat K. Surgery and inhibitor development in hemophilia A: a systematic review. J Thromb Haemost 2011; 9: 1948–58. Summary. Background: Although the association between intensive treatment and the formation of inhibiting antibodies towards factor VIII (FVIII) in hemophilia A has been demonstrated, the contributing effect of surgery is presently unclear. The release of immunological danger signals resulting from tissue damage during surgery in the presence of a high FVIII antigen load may elicit the formation of FVIII antibod- ies. The aim of this systematic review was to investigate the role of surgery in the inhibitor risk associated with intensive treatment as compared with treatment for bleeding and prophylactic administration of FVIII. Methods: A comprehen- sive literature search was performed that identified four cohort studies and three case control studies, comprising 342 inhibitor patients among a total of 957 hemophilia A patients. Results: Intensive treatment increased the inhibitor risk, most pro- nounced with intensive treatment of ‡ 5 exposure days (EDs) compared with < 3 EDs (OR, 4.1; 95% confidence interval, 2.6–6.5). Pooled odds ratio for inhibitor development in severe hemophilia patients that received intensive treatment for surgery at first exposure was 4.1 (95% confidence interval, 2.0–8.4) compared with treatment for bleeding or prophylaxis. Information on continuous infusion, previously treated patients and non-severe hemophilia A was insufficient for valid meta-analyses. Conclusions: Intensive FVIII treatment for surgery at first exposure leads to a higher inhibitor risk in hemophilia A patients compared with intensive treatment for bleeding. Keywords: antibody, hemophilia A, intensive FVIII exposure, risk factor, surgery, systematic review. Introduction The development of factor VIII (FVIII) inhibiting antibodies (inhibitors) is the most severe complication of treatment with clotting factor concentrates for hemophilia A. Inhibitors compromise the ability to manage hemorrhage in affected patients, resulting in a considerable increase in complications, disability and costs [2,3]. About one in four severe, and one in 15 non-severe hemophilia A patients develop inhibitors during their treatment [4]. The reason why these patients develop inhibitors is not completely known, and this hampers the development of an effective strategy to reduce the risk. The etiology of inhibitor development is a complex process in which multiple genetic and environmental factors interact dynamically [5]. Patients who develop inhibitors are likely to have high-risk genotypes. Inhibitor development is triggered by certain environmental factors during their treatment, such as intensive treatment with clotting factor concentrates, inflam- mation and infection [6,7]. Inflammation may provoke anti- body formation by the concurrent presence of cytokine release arising from injured tissues, so called Ô danger signalsÕ [8]. Although the association between intensive treatment and the formation of inhibiting antibodies towards FVIII in hemophilia A has been demonstrated, it is presently unclear through which mechanism this severe complication is elicited [9]. Moreover, the influence of reason for treatment (surgery vs. bleeding) is indistinct. Not only may tissue damage and injury elicit immunological danger signals during surgery, several other factors such as anesthetic drugs and inflammation may contribute to antibody formation. In addition, administration of FVIII concentrates by continuous infusion has been suggested to contribute to a higher incidence of inhibitors perioperatively. Several conditions related to continuous infu- sion, such as subcutaneous leakage of FVIII concentrate, FVIII protein modification during storage in infusion pumps, or concomitant thrombophlebitis at the infusion site, may lead Correspondence: Karin Fijnvandraat, Department of Pediatric Hematology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Tel.: +31 20 566 2727; fax: +31 20 691 7735. E-mail: C.J.Fijnvandraat@amc.uva.nl Presented in abstract form at the 29th meeting of the World Federation of Haemophilia, Buenos Aires, Argentina, 13 July 2010 [1]. Received 20 April 2011, accepted 2 August 2011 Journal of Thrombosis and Haemostasis, 9: 1948–1958 DOI: 10.1111/j.1538-7836.2011.04467.x Ó 2011 International Society on Thrombosis and Haemostasis