Environmental risk factors for inhibitor development in children with haemophilia A: a case–control study

Authors

  • Elena Santagostino,

    1. Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Department of Internal Medicine and Dermatology, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation and University of Milan, Milan, Italy
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  • Maria Elisa Mancuso,

    1. Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Department of Internal Medicine and Dermatology, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation and University of Milan, Milan, Italy
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  • Angiola Rocino,

    1. Haemophilia and Thrombosis Centre, San Giovanni Bosco Hospital, Naples, Italy
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  • Giacomo Mancuso,

    1. Haemophilia Centre, Haematology Department, Haemostasis and Thrombosis Centre, Haematology Unit, ‘G. Di Cristina’ Children Hospital and University, Palermo, Italy
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  • Maria Gabriella Mazzucconi,

    1. Policlinico Umberto I Hospital and La Sapienza University, Rome, Italy
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  • Annarita Tagliaferri,

    1. Haemophilia Centre, Internal Medicine Unit, Parma Hospital, Parma, Italy
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  • Maria Messina,

    1. Centre for Inherited Bleeding and Thrombotic Disorders, Transfusional Unit, ‘‘Regina Margherita’’ Children Hospital, Turin, Italy
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  • Pier Mannuccio Mannucci

    1. Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Department of Internal Medicine and Dermatology, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation and University of Milan, Milan, Italy
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Elena Santagostino, MD, PhD, Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, IRCCS Maggiore Hospital and University of Milan, Via Pace 9, 20122 Milan, Italy.
E-mail: hemophilia_ctr@policlinico.mi.it

Summary

This case–control study investigated the interactions between genetic and environmental factors and inhibitor development in 108 children with haemophilia A exclusively treated with recombinant factor VIII (FVIII). Sixty patients with inhibitors were compared with 48 inhibitor-free controls. Family history of inhibitors and null mutations in the FVIII gene were more prevalent in cases than in controls (20% vs. 2%, P = 0·001 and 83% vs. 64%, P = 0·04, respectively). On the other hand, there was no difference between cases and controls for such putative risk factors of inhibitor development as amniocentesis/villocentesis, premature/caesarean birth, breast-feeding, treatment during infections/vaccinations, surgical procedures and central nervous system bleeding. A trend was found for an increased risk of inhibitor development in children first treated at a young age (<11 months); however, this was not confirmed after adjusting for genetic factors. The implementation of prophylaxis was evaluated as a putative risk factor in a subgroup of 25 cases: seven who started prophylaxis prior to inhibitor development and 18 potentially eligible for prophylaxis because they were inhibitor-free up to the age of 35 months (i.e. the upper limit of the age range at prophylaxis onset in cases and the median age at prophylaxis onset in controls). Patients who started prophylaxis had a lower inhibitor risk than those treated on demand (adjusted odds ratio 0·2, 95% confidence interval 0·06–0·9). The protective effect on inhibitor development shown by prophylaxis may represent an additional advantage prompting its use in haemophilic children.

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