Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A

In mild hemophilia A (MHA; median baseline factor VIII activity [FVIII:C] level 5%), the development of inhibitors is an infrequently reported complication (3% to 13%). Little is known about the risk factors for inhibitor development in MHA, particularly with regard to the role of factor VIII (FVIII) exposure (the amount and intensity of exposure, and the context in which exposure occurs). Recent case reports and small case series, usually involving adults, implicate intense exposure—particularly by continuous infusion (CI) in inhibitor development in MHA. Our group at The Hospital for Sick Children in Toronto, Canada, undertook a review of FVIII exposure and inhibitor development in a population of boys (n 54; age, 0 to 18 years) with MHA who were treated at our institution from 1996 to 2001. All 54 boys were prospectively followed with yearly inhibitor screening. Twenty-nine of these 54 boys (54%) had been exposed to FVIII at some time during their childhood. Mean age at initial exposure to any FVIII was 5.4 years (range, 5 days to 16.3 years). For the 29 FVIII-exposed boys, the mean number of cumulative exposure days (an exposure day [ED] being defined as a day in which a patient receives at least one dose of FVIII regardless of the amount or method of administration, ie, bolus infusion [BI] v CI) was 16.3 days (range, 1 to 46 days). Of 16 boys who received an intense exposure to FVIII (defined as receiving FVIII daily for 6 consecutive days), seven received exposure by CI and 9 by BI. Four of the seven boys (57%) exposed to a CI developed inhibitors (high titer in three). These patients developed a severe and unusual bleeding pattern reminiscent of that seen in acquired hemophilia. None of the other boys with MHA, including the nine boys exposed to daily BI (6 consecutive days), developed inhibitors (P .02 by Fisher’s exact test), suggesting that CI of FVIII may be associated with an increased risk of inhibitor development. The mechanism and incidence of inhibitor development in MHA following intense FVIII exposure is not known. Recently, some hemophilia treatment centers have recommended against the use of CI in MHA patients. Given the potential benefits of CI, it may be premature to cease using this modality of treatment in patients with MHA. Based on our single-center experience, we are in the process of evaluating all MHA patients in Canada to determine the incidence of inhibitor development in such patients following intense exposure (including CI) to FVIII. Conceivably, there may be a group of MHA patients at high risk of developing inhibitors in the setting of CI and other intense exposures to FVIII. For such patients, consideration may need to be given to alternatives to intense FVIII exposure in the context of management of bleeds or surgical bleeding prophylaxis.