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The incidence of factor IX (FIX) inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date have been small, including patients with different severities, and without prospective follow up for inhibitor incidence. The study objective was to investigate the inhibitor incidence in patients with SHB followed up for to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes. Consecutive previously untreated patients (PUP) with SHB enrolled into the PedNet cohort were included. Detailed data was collected for the first 50 ED, followed by the annual collection of the inhibitor status and allergic re-actions. The presence of inhibitors was defined by at least two consecutive positive samples. Additionally, data on FIX gene mutation was collected. One hundred and fifty-four PUP with SHB were included; 75% were followed up until 75 ED, and 43% until 500 ED. Inhibitors developed in 14 patients (seven high-titer). The median number of ED at inhibitor manifestation was 11 (interquartile range [IQR]: 6.5-36.5). The cumulative inhibitor incidence was 9.3% (95% Confidence Interval [CI]: 4.4-14.1) at 75 ED, and 10.2% (95% CI: 5.1-15.3) at 500 ED. Allergic reactions occurred in four (28.6%) inhibitor patients. Missense mutations were most frequent (46.8%) overall but not associated with inhibitors. Nonsense mutations and deletions with large structural changes comprised all mutations among inhibitor patients and were associated with an inhibitor risk of 26.9% and 33.3%, respectively. In an unselected, well-defined cohort of PUP with SHB, the cumulative inhibitor incidence was 10.2% at 500 ED. Nonsense mutations and large deletions were strongly associated with the risk of inhibitor development. The ‘PedNet Registry’ is registered at clinicaltrials.gov; identifier: NCT02979119.

Background: Inhibitor development in previously untreated patients (PUPs) with severe haemophilia A is a multifactorial event. It is unknown whether paediatric vaccinations given in close proximity to factor VIII (FVIII) are associated with inhibitor development. Objective: To assess whether paediatric vaccinations in close proximity to FVIII within the first 75 exposure days (EDs) are associated with inhibitor development in PUPs with severe haemophilia A. Methods: We included 375 PUPs with severe haemophilia A (

International audience; Objectives: To evaluate the applicability and compliance with guidelines for early initiation of long-term prophylaxis in infants with severe hemophilia A and to identify factors associated with guideline compliance.Study design: This real-world, prospective, multicenter, population-based FranceCoag study included almost all French boys with severe hemophilia A, born between 2000 and 2009 (ie, after guideline implementation).Results: We included 333 boys in the study cohort. The cumulative incidence of long-term prophylaxis use was 61.2% at 3 years of age vs 9.5% in a historical cohort of 39 boys born in 1996 (ie, before guideline implementation). The guidelines were not applicable in 23.1% of patients due to an early intracranial bleeding or inhibitor development. Long-term prophylaxis was delayed in 10.8% of patients. In the multivariate analysis, 2 variables were significantly associated with "timely long-term prophylaxis" as compared with "delayed long-term prophylaxis": hemophilia treating center location in the southern regions of France (OR 23.6, 95% CI 1.9-286.7, P = .013 vs Paris area) and older age at long-term prophylaxis indication (OR 7.2 for each additional year, 95% CI 1.2-43.2, P = .031). Long-term prophylaxis anticipation was observed in 39.0% of patients. Earlier birth year (OR 0.5, 95% CI 0.3-0.8, P = .010 for birth years 2005-2009 vs 2000-2004) and age at first factor replacement (OR 1.9 for each additional year, 95% CI 1.2-3.0, P = .005) were significantly associated with "long-term prophylaxis guideline compliance" vs "long-term prophylaxis anticipation."Conclusions: This study suggests that long-term prophylaxis guidelines are associated with increased long-term prophylaxis use. However, early initiation of long-term prophylaxis remains a challenge.

Hemarthroses and muscle bleeds are well-known and well-documented complications in pediatric and young adult hemophilia patients. In contrast, deep bleeds in atypical locations can be a diagnostic challenge, since clinicians and radiologists are often unfamiliar with their clinical and radiological features. Some atypical bleeds, however, can be life-threatening or severely disabling, highlighting the need for prompt, accurate diagnosis. Rare bleeds include central nervous system bleeds (including intracranial and spinal hematomas), urogenital bleeds, intra-abdominal bleeds (mesenteric and gastrointestinal wall hematomas) and pseudo tumors in unusual locations like the sinonasal cavities. Because clinical assessment can be difficult, clinicians and radiologists should be aware of the possibility of these rare complications in their hemophilia patients, so that they can avoid unnecessary invasive diagnostic and surgical procedures and institute prompt, appropriate treatment. The purpose of this review is to illustrate the imaging features of bleeds that occur in rare locations in young (i.e., children and young adults) patients with hemophilia to make the reader more familiar with these conditions.

IntroductionSevere haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life.Methods and analysisWe present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14–17 years) with those from a group of young adults (aged 20–29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants’ views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag.Ethics and disseminationThe study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public.Trial registration numberNCT02866526; Pre-results.

Prophylaxis for hemophilia is the scheduled infusion of the missing clotting factor with pre-specified dose, with the intention of preventing bleeds and subsequent hemophilic arthropathy. It is the treatment of choice for patients with severe hemophilia A in countries with available resources.[1][1

Henoch-Schönlein purpura is a common form of immunological vasculitis in children. Hemophilia A is a genetic disorder, inherited in a X-linked recessive pattern, and characterized by spontaneous hemorrhage or prolonged bleeding due to factor VIII deficiency. The clinical signs depend on the severity of factor VIII deficiency. We herein report the case of a 4-year-old boy admitted to the emergency room for typical rheumatoid purpura, associated with a lengthening of aPTT, whose exploration had uncovered mild hemophilia A. Laboratory assays should explore lengthening of aPTT: firstly the presence of lupus anticoagulant without bleeding risk, in an inflammatory context; secondly a deficiency of VWF and one of the factors involved in the extrinsic coagulation pathway associated with bleeding risk.

The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.

Phenotypic variability is well recognized in severe hemophilia A. A few studies, mainly in adults treated lifelong on demand, suggest that bleeding phenotype correlates with factor VIII gene (F8) mutation type. Because treatment regimens influence outcomes to a large extent, examining bleeding phenotype during the first years of life may be the most suitable way to define this variability. We set out to analyze the very early phenotypic expression of severe hemophilia A in 621 consecutively enrolled, well-characterized previously untreated patients and to correlate this with patients' F8 mutation. Detailed information was collected on bleeds and treatment of the first 75 exposure days or until inhibitor development. F8 mutation type was known for 531 patients; 402 had null mutations and 129 had non-null mutations. Considering only patients who had not started prophylaxis or developed an inhibitor before select bleeding events, we found that patients with null mutations experienced their first bleed and first joint bleed at younger median ages than patients with non-null mutations (9.7 vs 10.9 months and 13.8 vs 16.1 months, respectively). We conclude that F8 mutation type accounts for only a small component of the significant phenotypic variability found among patients with severe hemophilia A.

SummaryMany studies have reported an increased incidence of inhibitors in previously untreated patients (PUPs) with severe haemophilia A after the introduction of recombinant products. It was the objective of this study to investigate whether the inhibitor incidence has increased between 1990 and 2009 in an unselected cohort of PUPs with severe haemophilia A (FVIII < 1 %). Patients were consecutively recruited from 31 haemophilia treatment centres in 16 countries and followed until 50 exposure days or until inhibitor development. Inhibitor development was studied in five-year birth cohorts comparing cumulative incidences. Furthermore the risk for inhibitor development per five-year birth cohort was studied using multivariable Cox regression, adjusting for potential genetic and treatment-related confounders. A total of 926 PUPs were included with a total cumulative inhibitor incidence of 27.5 %. The inhibitor incidence increased from 19.5 % in 1990-1994 (lowest) to 30.9 % in 2000-2004 (highest; p-value 0.011). Low titre inhibitor incidence increased from 3.1 % in 1990-1994 to 10.5 % in 2005-2009 (p-value 0.009). High titre inhibitor incidences remained stable over time. After 2000, risk of all inhibitor development was increased with adjusted hazard ratios 1.96 (95 % CI 1.06-2.83) in 2000-2004 and 2.34 (1.42-4.92) in 2005-2009. Screening for inhibitors was intensified over this 20-year study period from a median of 1.9 to 2.9 tests/year before 2000 to 2.7 to 4.3 tests/ year after 2000. In conclusion, the cumulative inhibitor incidence has significantly increased between 1990 and 2009. The high titre inhibitor incidence has remained stable.

During the last decades, long-term prophylaxis has become the gold standard for the treatment of children with severe haemophilia A or B. Prophylactic replacement regimens modify the natural history of the disease by aiming at the prevention of haemarthrosis, target joints and arthropathy. This treatment represents a constraint and an enhanced exposure to anti-haemophilic concentrates, which means potential increase of related risks and significant additional cost. The context of crisis of confidence due to the blood borne infections in the 1980s, may have delayed prophylaxis as an universal gold standard.In the early 2000s, the French group CoMETH proposed recommendations based on the review of the international experience. At first, specific guidelines of long-term prophylaxis were dedicated to children with severe haemophilia A or B, aged 3 years or less, with no history of target joint or arthropathy. The main concerns of this regimen consist in the early start and the escalating intensification of the treatment. In the French haemophilia care centres, the diffusion of these guidelines has apparently induced a significant turning point in therapeutic practices for haemophilia children. In 2006, more comprehensive recommendations were diffused to take into account all the children with severe haemophilia, whatever the bleeding history and joint status. The analysis of their impact, jointly with the National cohort "France Coag Network", will first assess the widespread implementation of the recommendations and the observance of the prophylactic regimen and identify factors associated to the compliance.

Hemophilia A (HA) is an X-linked hereditary bleeding disorder defined by a qualitative and/or quantitative factor VIII (FVIII) deficiency. The molecular diagnosis of HA is challenging because of the high number of different causative mutations that are distributed throughout the large F8 gene. The putative role of the novel mutations, especially missense mutations, may be difficult to interpret as causing HA. We identified 95 novel mutations out of 180 different mutations responsible for HA in 515 patients from 406 unrelated families followed up at a single hemophilia treatment center of the Bicetre university hospital (Assistance Publique-Hopitaux de Paris [AP-HP], Le Kremlin-Bicetre). These 95 novel mutations comprised 55 missense mutations, 12 nonsense mutations, 11 splice site mutations, and 17 small insertions/deletions. We therefore developed a mutation analysis based on a body of proof that combines the familial segregation of the mutation, the resulting biological and clinical HA phenotype, and the molecular consequences of the amino acid (AA) substitution. For the latter, we studied the putative biochemical modifications: its conservation status with cross-species FVIII and homologous proteins, its putative location in known FVIII functional regions, and its spatial position in the available FVIII 3D structures. The usefulness of such a strategy in interpreting the causality of novel F8 mutations is emphasized.

SummaryRecombinant activated factor VII (rFVIIa) is an effective haemostatic treatment in haemophiliacs with inhibitors. In vitro, FVIIa concentrations corresponding to those obtained with therapeutic doses of rFVIIa have been shown to induce normal thrombin generation and platelet activation in the absence of factors VIII or IX. To further study the in vivo haemostatic changes induced by rFVIIa, circulating procoagulant microparticles (MP) were measured in patients treated with discontinuous injections of Novoseven®. In 6 out of 15 patients, a transient peak of procoagulant MP was observed after injection, occurring 15 min to 2 h after infusion. It was composed primarily of platelet-derived MP and was of very short duration. This peak was not observed in haemophiliacs without inhibitor, who were treated with conventional replacement therapies. Our results provide further in vivo evidence that rFVIIa specifically activates platelets, either directly or as a consequence of a burst of thrombin generation that could account for its haemostatic efficacy.

Objective: The diagnosis of hemophilia was reported as delayed in historic studies. We therefore investigated this issue to provide current epidemiologic data in a large series of patients. Study design: The French cohort provided the opportunity to investigate the age at diagnosis and the circumstances of diagnosis in 599 individuals with hemophilia born between 1980 and 1994. The type and the severity of hemophilia, the family history, and the period of birth were analyzed as potential modifying factors. Results: The median age at diagnosis was 7.7 months, with significant differences among subgroups: 5.8 months in severe hemophilia, 9.0 months in moderate forms, 28.6 months in mild forms, 0.4 months in the case of hemophilic brothers, and 10.1 months in de novo hemophilia, which accounted for 55.3% of cases. In severe forms we observed a trend for earlier diagnosis throughout 3 consecutive periods from 1980 to 1994. Of bleeding epsiode, testing due to family history, or routine testing, bleeding was the main circumstance of diagnosis (59.9%). Conclusions: Diagnosis was made earlier than in historic series, but it remained somewhat delayed. Early diagnosis will require efforts in the fields of genetic counseling and specific diagnosis of early bleeding, even without family history, because of the high incidence of de novo hemophilia. (J Pediatr 2002;141:548-52)

Hepatitis C virus (HCV) is the major etiologic agent associated with non-A, non-B hepatitis. This study was designed to assess virologic and serologic markers in hemophiliacs exposed to non-heat-treated and/or virus-inactivated plasma derivatives. Serial bleeds from 48 hemophilic patients were analyzed for the presence of HCV viral RNA sequences as detected by polymerase chain reaction (PCR) and antibodies to structural (core) and nonstructural (C-100 and 33C) proteins by specific dot immunoblot assay. All patients exposed to non-heat-treated products, and four of six patients exposed only to virus inactivated products, had evidence of HCV infection. However, over the 5-yr study period, six exposed patients (13%) consistently lacked detectable anti-C-100 and seven (15%) lost this antibody. HCV viremia (PCR positive) was found in 91% of exposed patients, and was significantly more frequent in HIV seropositive hemophiliacs (P less than 0.05). Six patients had high antibody level to HCV and elevated ALT, but appeared to clear viremia. Four hemophiliacs were HCV seropositive but lacked detectable viremia. These data indicate that hemophiliacs remain persistently infected by HCV and that antibody to the core antigen of HCV is a reliable marker of this transfusion transmissible agent.

The interaction between thrombin and alpha-2-macroglobulin was studied on human purified materials, either in the presence or in the absence of heparin, by kinetic analysis of thrombin inhibition and polyacrylamide gel electrophoresis. In the absence of heparin, binding of thrombin to alpha-2-macroglobulin, shown by electrophoresis, leads to the loss of the coagulant property of the enzyme. In the presence of heparin the rate of inhibition of thrombin clotting activity by alpha-2-macroglobulin is strongly decreased. Heparin binds to thrombin, impairing the formation of thrombin-alpha-2-macroglobulin complex. These data show that heparin paradoxically protects thrombin from inhibition by alpha-2-macroglobulin whereas it increases the enzyme inhibition by antithrombin III. Such a phenomenon could be of practical interest for treatment of thrombosis in patients with high plasma level of alpha-2-macroglobulin and low level of antithrombin III, such as occurs in the nephrotic syndrome.

The principal obstetrical and paediatric sequelae were studied in 22 heroin addicts who were followed up at Lariboisière Hospital in Paris between 1980 and 1984. The main effects were on the fetus with 45% showing growth retardation below the 10th percentile, 65% fetal distress, 9% prematurity; 33% had infections and 66% had the withdrawal syndrome. Because of this pathology a high number had to be transferred. Considering the period of study, HIV infection could not be evaluated. The most dramatic result seems to be the long-term effect on these children because only a third apparently live with their families and several suffer from abnormalities in psychomotor development.