ABSTRACT
Intracranial haemorrhage (ICH) is the most serious bleeding symptom in haemophiliacs, resulting in high rates of mortality and disabling sequelae. The Association of Italian Haemophilia Centres carried out a retrospective survey (1987-2008) of ICH occurring in haemophiliacs with the goals to establish: (i) incidence, location of bleeding, death rate and disabling sequels; (ii) risk factors for ICH; and (iii) treatment used during the acute phase of ICH and for recurrence prevention. A total of 112 ICH episodes had occurred in 88 patients (78 haemophilia A, 10 haemophilia B), 24 of whom experienced recurrences. The cumulative hazard of ICH for the whole cohort over the entire follow-up period was 26.7 per 1000 patients, and the annualized rate of ICH was 2.50 events per 1000 patients (95% CI 1.90-3.31). The risk of ICH was higher in the youngest children (24.4 per 1000, 95% CI 12.7-47.0 in the first year of age and 14.9, 95% CI 7.1-31.4 in the second year of age) and then progressively rose again after the age of 40. Univariate, bivariate (age-adjusted) and multivariate analysis investigating the effects of patient characteristics on ICH occurrence showed that haemophilia severity and inhibitor status were strongly associated with ICH [severe vs. mild, HR 3.96 (2.39-6.57); inhibitor vs. non-inhibitor 2.52 (1.46-4.35)]. HCV infection was also associated with the risk of ICH [HR 1.83 (1.25-2.69)]. Therapeutic suggestions based upon our experience to control ICH recurrence are provided.
Subject(s)
Hemophilia A/complications , Hemophilia B/complications , Intracranial Hemorrhages/epidemiology , Adolescent , Adult , Age Distribution , Aged , Autoantibodies/blood , Blood Coagulation Factors/therapeutic use , Child , Child, Preschool , Cohort Studies , Hemophilia A/immunology , Hemophilia B/immunology , Humans , Incidence , Infant , Infant, Newborn , Intracranial Hemorrhages/prevention & control , Italy/epidemiology , Male , Middle Aged , Prevalence , Retrospective Studies , Risk Factors , Surveys and Questionnaires , Young AdultSubject(s)
Factor IX , Factor VIII , Hemophilia A , Hemophilia B , Factor IX/administration & dosage , Factor IX/economics , Factor VIII/administration & dosage , Factor VIII/economics , Female , Hemophilia A/economics , Hemophilia A/prevention & control , Hemophilia B/economics , Hemophilia B/prevention & control , Humans , Italy , Male , Surveys and QuestionnairesSubject(s)
Codon, Nonsense , Exons , Factor IX/genetics , Hemophilia B/genetics , Family , Female , Genetic Testing , Hemophilia B/diagnosis , Hemophilia B/therapy , Humans , Infant , Male , Pedigree , Recombinant Proteins/therapeutic useABSTRACT
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.
