2003; baxter - Supplements - Haematologica

46The MIBS registryTable 1. Characteristics ofthe 528 brother pairs.Table 2. Incidence of inhibitor families stratified accordingto type of hemophilia and ethnicity. The number of familiesin each subgroup is shown in Table 1.ResultsAs of August 2001, data concerning 1,108 subjectsin 528 families had been accrued (451hemophilia A and 77 hemophilia B) from 27hemophilia centers in Europe and North America.The characteristics of these families areshown in Table 1. Twenty-five are twins of whommonozygosity was confirmed in 15 pairs. Twenty-oneof the twins suffer from hemophilia A (17severe and 4 mild) and 4 from hemophilia B (2severe and 2 mild).A history of inhibitors was described in 13.3%of all subjects and in 110 families. Eighty-five ofthese families were of Caucasian origin as shownin Table 2. The inhibitor incidence in all severehemophilia A individuals was 20.6% correspondingto 29.8% of the families.The distribution of low- and high-respondinginhibitors in each family is shown in Table 3. Ahistory of inhibitor was reported in more thanone sibling in 36 of the 110 inhibitor families. In24 of these 36 families the same type of inhibitorresponse was reported. Six of the 25 twins reporteda history of inhibitor. Three of these were confirmedmonozygotic twins, of whom both brothershad a history of a high-responding inhibitorin two cases. In the remaining discordant pair,one brother was a high-responder whereas theother had no history of an inhibitor.The observed inhibitor history within 249 ofthe families with two siblings suffering fromsevere hemophilia was significantly concordantusing expected inhibitor incidences of 20 and30%, (Table 4), corresponding to an overall concordanceof 78.3%. 13 The corresponding figurefor the small group of 17 twins with severehemophilia A was 88.2%. The risk of a siblingwith hemophilia developing antibodies if an olderbrother had a history of inhibitor was found tobe 48% (95% CI 35-62%), whereas the risk inthe case of no previous known inhibitor in thefamily was only 15% (95% CI 11-21%) correspondingto a relative risk of 3.2 (95% CI 2.1-4.9).DiscussionCharacterization of genetic markers affectingthe risk of developing inhibitory antibodies is adifficult but highly warranted task. So far, themost significant factor has been the underlyinggenetic defect, in that large rearrangements havebeen associated with an increased incidence ofinhibitors. 5,6 However, even on this matter contradictorydata exist. 7 In our MIBS registry, wefound significantly more siblings, both twins andnon-twins, with an inhibitor than could beexplained by chance alone. This finding is inagreement with previous reports. 2–4 We alsofound that the risk of a sibling developing aninhibitor was three-times higher in families witha previous known inhibitor (CI 95% 2.1-4.9). Asin all retrospective studies of inhibitor incidence,some transient low-responding inhibitors mighthave been missed and the true number of patientswith inhibitors among the MIBS siblings is probablyunderestimated. The issue of why somepatients develop high- and others low-respondinginhibitors is also unresolved, but is of majorimportance since the clinical and economicimpact, as well as the outcome, is so different.haematologica vol. 88(supplement n. 12):september 2003