Inhibitor development in mild and moderate hemophilia A seems to be associated with an increased mortality risk

Introduction: Mild/moderate hemophilia A (MHA) usually presents as a mild/moderate bleeding disorder and may be successfully treated or prevented by administration of Desmopressin or Factor VIII (FVIII) concentrates. The development of inhibiting antibodies (inhibitors) towards FVIII may dramatically change the clinical outcome of these patients, as their endogenous FVIII levels may decrease to levels below 2 IU/dL and the associated severe bleeding. The life expectancy of MHA patients without hepatitis or HIV equals the life expectancy of the non-hemophilic population. However, data on mortality in MHA patients with inhibitors are scarce. The aim of this study is to investigate mortality in inhibitor patients with MHA. Methods: The INSIGHT study is an international cohort study of all MHA patients treated between 1980 and 2010 in 34 participating centers across 10 European countries and Australia. Mortality was analyzed using a Cox regression model adjusted for calendar year and age at inclusion in the study and for cumulative exposure days to FVIII. Figures are median (interquartile range), or number (percentage). Results: This cohort includes 2627 MHA patients (113 with inhibitors) with a median age of 36 (18-54) years and a median FVIII baseline level of 11 IU/dL (6-18). During the 30 year follow-up period 120 patients (4.6%) died at a median age of 61 (42-75) years, including 16/113 inhibitor patients (14%). Inhibitor patients had an almost fourfold increased risk of all-cause mortality (adjusted HR 3.8; 2.1-6.8) as compared to non-inhibitor patients. Cause of death was reported in half of the patients (n = 59; 49%). In the majority of patients the cause of death was malignancy (n = 19; 32%), viral infections (HIV and hepatitis C; n = 16; 27%) or intracranial bleeding (n = 13; 22%). Conclusion: In this large cohort of MHA patients inhibitor development seems to be associated with an almost four times higher risk of all-cause mortality as compared to non-inhibitor patients.