Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database.

Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD.

Efficacy and safety of von Willebrand factor concentrate almost devoid of factor VIII (Wilfactin) in paediatric patients under 6 years of age with severe von Willebrand disease.

Background: Plasma-derived von Willebrand factor (VWF) (Wilfactin, LFB, France) was developed for prophylaxis and treatment of haemorrhages in both adults and adolescents with von Willebrand disease (VWD). Replacement therapy in paediatric patients is a key element of the clinical trial programme.

Material And Methods: Patients aged <6 years with severe VWD were enrolled in a multinational, open-label study to evaluate the in vivo recovery for Wilfactin, and its efficacy in preventing and treating bleeding episodes and during surgery.

The factor VIII treatment history of non-severe hemophilia A.

Background: In patients with non-severe hemophilia A, we lack detailed knowledge on the timing of treatment with factor VIII (FVIII) concentrates. This knowledge could provide information about the expected treatment timing in patients with severe hemophilia A treated with non-replacement therapies.

Objective: To assess the FVIII treatment history in patients with non-severe hemophilia A.

ITI Treatment is not First-Choice Treatment in Children with Hemophilia A and Low-Responding Inhibitors: Evidence from a PedNet Study.

Background:  Limited data exist on the clinical impact of low-responding inhibitors and the requirement for immune tolerance induction (ITI) treatment to establish tolerance, reduce bleeding, and improve outcome. The aim of this article is to describe the therapeutic management of children with severe hemophilia A and low-responding inhibitors and its effect on bleeding phenotype.

Methods:  The REMAIN (Real-life Management of Inhibitors) study is a satellite study of the PedNet registry.

Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study.

The incidence of FIX inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date were small, including patients with different severities, and without prospective follow-up for inhibitor incidence. Study objective was to investigate inhibitor incidence in patients with SHB followed up to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes.

Impact of target joint and FVIII inhibitor οn bone properties in children with haemophilia A: A peripheral quantitative computed tomography study.

Background: Haemophilic children are prone to low bone mass accrual.

Objective: To assess bone properties in haemophilic children, using peripheral quantitative computed tomography (pQCT) and to correlate findings with clinical data.

Subjects/methods: Peripheral quantitative computed tomography scan of both radii and tibiae were performed in 31 haemophilic A children (severe 24, mean age 11.

Desmopressin in moderate hemophilia A patients: a treatment worth considering.

Desmopressin increases endogenous factor VIII levels in hemophilia A. Large inter-individual variation in the response to desmopressin is observed. Patients with a lower baseline factor VIII activity tend to show a reduced response, therefore, desmopressin is less frequently used in moderate hemophilia A patients (baseline factor VIII activity 1-5 international units/deciliter), even though factor VIII levels may rise substantially in some of them.

Vaccinations are not associated with inhibitor development in boys with severe haemophilia A.

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.

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment.

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH.

Continuous infusion of recombinant factor VIII formulated with sucrose in surgery: non-interventional, observational study in patients with severe haemophilia A.

In haemophilia A, continuous infusion (CI) of FVIII perioperatively provides a more constant FVIII level than conventional bolus injections, avoiding low trough levels that could increase bleeding risk. Due to the low number of surgical cases in clinical trials, especially in haemophilia, more information on the clinical practice of CI from observational studies is helpful. We aimed to evaluate the effectiveness and safety of CI with recombinant factor VIII formulated with sucrose (rFVIII-FS) in a typical surgery practice setting.

Cochlear implantation is safe and effective in patients with MYH9-related disease.

Background: MYH9-related disease (MYH9-RD) is a rare syndromic disorder deriving from mutations in MYH9, the gene for the heavy chain of non-muscle myosin IIA. Patients present with congenital thrombocytopenia and giant platelets and have a variable risk of developing sensorineural deafness, kidney damage, presenile cataract, and liver abnormalities. Almost all MYH9-RD patients develop the hearing defect, which, in many individuals, progresses to severe to profound deafness with high impact on quality of life.

Spectrum of the mutations in Bernard-Soulier syndrome.

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin.

Prospective observational cohort studies for studying rare diseases: the European PedNet Haemophilia Registry.

Haemophilia is a rare disease. To improve knowledge, prospective studies of large numbers of subjects are needed. To establish a large well-documented birth cohort of patients with haemophilia enabling studies on early presentation, side effects and outcome of treatment.

Venous thromboembolism at uncommon sites in neonates and children.

We retrospectively analyzed the data of 24 children (whereof 11 neonates), with non-central venous line-related and nonmalignancy-related venous thromboembolism (VTE) at uncommon sites, referred to our Unit from January 1999 to January 2012. Thirty patients who also suffered deep vein thrombosis, but in upper/low extremities, were not included in the analysis. The location of rare site VTE was: portal (n=7), mesenteric (n=2) and left facial vein (n=1), spleen (n=3), lung (n=3), whereas 10 neonates developed renal venous thrombosis.

MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations.

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families).

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL).

Impact of HLA alleles and cytokine polymorphisms on inhibitors development in children with severe haemophilia A.

Human Leucocyte Antigen (HLA) alleles, cytokine polymorphisms and the type of factor VIII (FVIII) gene mutation are among predisposing factors for inhibitors (inh) development in children with severe haemophilia A (HA). The aim was to investigate the correlations among (i) FVIII gene intron-22 inversion, (ii) HLA alleles and haplotypes and (iii) certain cytokine polymorphisms, with the risk for FVIII inhibitors development in 52 Greek severe HA children, exclusively treated with recombinant concentrates. We performed Long-Range PCR for detection of intron-22 inversion and PCR-SSP, PCR-SSO for genotyping of HLA-A, B, C, DRB1, DQB1 alleles and also for cytokine polymorphisms of TNF-α, TGF-β1, IL-10, IL-6 and IFN-γ.

Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study.

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.

Deep vein thrombosis and pulmonary embolism in a child with diabetic ketoacidosis and protein s deficiency: a case report.

Introduction: Diabetic ketoacidosis (DKA) is considered a hypercoagulable state, which may be exacerbated in patients with thrombophilia and lead to thrombosis.

Case Report: We report on a 5.5-year-old boy, who was admitted to the pediatric department with DKA due to newly diagnosed type 1 diabetes.

Replacement therapy for bleeding episodes in factor VII deficiency. A prospective evaluation.

Patients with inherited factor VII (FVII) deficiency display different clinical phenotypes requiring ad hoc management. This study evaluated treatments for spontaneous and traumatic bleeding using data from the Seven Treatment Evaluation Registry (STER). One-hundred one bleeds were analysed in 75 patients (41 females; FVII coagulant activity <1-20%).

MYH9-related disease: five novel mutations expanding the spectrum of causative mutations and confirming genotype/phenotype correlations.

MYH9-related disease (MYH9-RD) is a rare autosomal dominant syndromic disorder caused by mutations in MYH9, the gene encoding for the heavy chain of non-muscle myosin IIA (myosin-9). MYH9-RD is characterized by congenital macrothrombocytopenia and typical inclusion bodies in neutrophils associated with a variable risk of developing sensorineural deafness, presenile cataract, and/or progressive nephropathy. The spectrum of mutations responsible for MYH9-RD is limited.