Beatrice Nolan

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. 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.

Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A

Prophylactic factor replacement, which prevents hemarthroses and thereby reduces the musculoskeletal disease burden in children with hemophilia A, requires frequent intravenous infusions (three to four times weekly).

Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A

The safety, efficacy and prolonged half‐life of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously treated patients with severe haemophilia A was demonstrated in the phase 3 A‐LONG and Kids A‐LONG studies. Here, we report interim safety and efficacy data from the rFVIIIFc extension study, ASPIRE (ClinicalTrials.gov #NCT01454739).

Bleeding before prophylaxis in severe hemophilia: paradigm shift over two decades.

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

Recombinant factor IX Fc fusion protein in children with haemophilia B (Kids B-LONG): results from a multicentre, non-randomised phase 3 study

BACKGROUND Kids B-LONG was a multicentre, open-label, phase 3 study assessing the safety, efficacy, and pharmacokinetics of recombinant factor IX Fc fusion protein (rFIXFc) in previously treated paediatric patients younger than 12 years with severe haemophilia B. METHODS The study enrolled 30 previously treated boys younger than 12 years with haemophilia B (≤2 IU/dL [≤2%] endogenous coagulation factor IX [FIX] activity). All patients were initially given rFIXFc prophylaxis (50-60 IU/kg) once per week with adjustments to dose (≤100 IU/kg per infusion) or dosing frequency (up to two times per week) as needed. The primary outcome measure was development of inhibitors (neutralising antibodies). Secondary outcomes were pharmacokinetics, annual bleeding rate (ABR), spontaneous joint ABR, the number of infusions and dose required to resolve a bleed, time from last infusion of rFIXFc to a bleeding episode, assessment of response to treatment, and total annualised rFIXFc consumption for prevention and treatment of bleeding episodes. All patients underwent sequential pharmacokinetic evaluations of their prestudy FIX and rFIXFc. The completed trial is registered with ClinicalTrials.gov, number NCT01440946. FINDINGS No patients developed inhibitors to rFIXFc; in the 30 enrolled patients the most common adverse events were nasopharyngitis (n=7; 23%) and fall (n=6; 20%); four patients (13%) had serious adverse events. Overall, rFIXFc exhibited a prolonged half-life of 68·6 h (95% CI 61·8-76·0), reduced clearance, and similar recovery compared with prestudy FIX. The median ABR was 2·0 (0·0-3·1) overall and 0·0 (0·0-0·0) for spontaneous joint bleeds; ten (33%) of 30 patients reported no bleeding, and 19 (63%) reported no joint bleeding on-study. The median average prophylactic dose of rFIXFc was 58·6 IU/kg (IQR 52·3-64·8) per week. Throughout the study, 29 (97%) of 30 patients remained on once per week infusions. INTERPRETATION Weekly infusions of rFIXFc were well tolerated and resulted in low bleeding rates in children with severe haemophilia B. FUNDING Biogen, Sobi.

Long-term safety and efficacy of extended-interval prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) in subjects with haemophilia B

The safety, efficacy, and prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) were demonstrated in the Phase 3 B-LONG (adults/adolescents ≥12 years) and Kids B-LONG (children <12 years) studies of subjects with haemophilia B (≤2 IU/dl). Here, we report interim, long-term safety and efficacy data from B-YOND, the rFIXFc extension study. Eligible subjects who completed B-LONG or Kids B-LONG could enrol in B-YOND. There were four treatment groups: weekly prophylaxis (20-100 IU/kg every 7 days), individualised prophylaxis (100 IU/kg every 8-16 days), modified prophylaxis (further dosing personalisation to optimise prophylaxis), and episodic (on-demand) treatment. Subjects could change treatment groups at any point. Primary endpoint was inhibitor development. One hundred sixteen subjects enrolled in B-YOND. From the start of the parent studies to the B-YOND interim data cut, median duration of rFIXFc treatment was 39.5 months and 21.9 months among adults/adolescents and children, respectively; 68/93 (73.1 %) adults/adolescents and 9/23 (39.1 %) children had ≥100 cumulative rFIXFc exposure days. No inhibitors were observed. Median annualised bleeding rates (ABRs) were low in all prophylaxis regimens: weekly (≥12 years: 2.3; <6 years: 0.0; 6 to <12 years: 2.7), individualised (≥12 years: 2.3; 6 to <12 years: 2.4), and modified (≥12 years: 2.4). One or two infusions were sufficient to control 97 % (adults/adolescents) and 95 % (children) of bleeding episodes. Interim data from B-YOND are consistent with data from B-LONG and Kids B-LONG, and confirm the long-term safety of rFIXFc, absence of inhibitors, and maintenance of low ABRs with prophylactic dosing every 1 to 2 weeks.

The prevalence of abnormal preoperative coagulation tests in pediatric patients undergoing spinal surgery for scoliosis.

BACKGROUND CONTEXT Multilevel spinal fusion surgery for deformity correcting spinal surgery in pediatric patients with scoliosis has typically been associated with significant blood loss. The mechanism of bleeding in such patients is not fully understood. Coagulation abnormalities, which may be associated with scoliosis, are thought to play a role. PURPOSE To document and compare the prevalence of preoperative coagulation abnormalities among patients with scoliosis attending a pediatric orthopedic department for spinal fusion surgery with patients attending for minor surgery. STUDY DESIGN An observational study. All patients were recruited from a pediatric tertiary referral center in Dublin, Ireland. PATIENT SAMPLE Coagulation profile results were prospectively collected over a 2-year period from 165 spinal surgery patients. In total, 175 patients were included in the non-scoliosis group. These patients attended the day ward for minor procedures and were recruited over a 4-month period. OUTCOME MEASURES The primary outcome measure was the coagulation profiles, which included prothrombin time, activated partial thromboplastin time (APTT), and thrombin time (TT). Levels of Coagulation Factors II, V, VII, and X were also recorded. METHODS All blood samples were sent to the haematology laboratory to establish the coagulation profile. The primary outcome was the presence of an abnormal coagulation screening test (if any of PT, APTT, or TT were abnormal). Prothrombin time, APTT, and TT were also analyzed as individual continuous variables, as well as Coagulation Factors II, V, VII, and X. Regression analysis was used to compare the coagulation profile of scoliosis patients with that of non-scoliosis patients. There were no outside funding sources or any potential conflict of interest associated with this study. RESULTS The scoliosis patients were more likely to have an abnormal preoperative screening test compared with non-scoliosis patients, with an odds ratio of 2.6. Further analysis showed statistically significant longer clotting times for patients with scoliosis compared with those without; PT (t=3.37, p=.001), APTT (t=4.26, p<.001), TT (t=4.52, p<.001). Of the coagulation factors analyzed, only factor X was significantly different in scoliosis patients compared with non-scoliosis controls (t=-4.41, p<.001). CONCLUSIONS Children with scoliosis have a higher prevalence of preoperative coagulation abnormalities compared with normal healthy patients.

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. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on‐demand‐group, 8% (2/24) children with ICH died and 33% had long‐term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non‐frequent or no prophylaxis.

Transient myeloproliferative disorder in an infant with PTPN11 mutation

A female infant born at 37 weeks gestation with a birth weight of 2 2 kg was noted to have bruising on the nasal bridge. She was the first born of a dichorionic, diamniotic twin pregnancy. Subsequent laboratory data showed thrombocytopenia (platelet count 38 9 10/l) and leucocytosis (white cell count 26 8 9 10/l). Twin 2 had a normal platelet count. The blood film was leucoerythroblastic with anisopoikilocytosis, polychromasia, monocytosis with dysplastic monocytes, basophilia and 8% blast cells (left). She was well and had no clinical or radiological evidence of splenomegaly. Examination of the bone marrow revealed a population of 15% blasts with myelomonocytic differentiation, myeloid hyperplasia and trilineage dysplasia (right). Cytogenetic analysis confirmed a normal female karyotype. Mutation screening by DNA sequencing of the PTPN11 gene revealed heterozygosity for a single nucleotide substitution in exon 3, predicted to result in a threonine-to-isoleucine change at residue 73 (T73I), and a novel variant in intron 12 of the same gene. The same sequence alterations were also present in the DNA of patient hair follicles, thereby confirming a germline mutation. This provided genetic evidence supporting a diagnosis of a myeloproliferative disorder (MPD) associated with Noonan syndrome (NS). No mutations in NRAS, KRAS or CBL were found. The infant had no cardiac or other phenotypic features of NS. Over the following 6 weeks, the platelet count normalised and the white cell count decreased without any intervention. Children with NS are predisposed to a spectrum of haematological abnormalities, including MPDs. These may regress without treatment, or evolve to juvenile myelomonocytic leukaemia (JMML). This case illustrates the spontaneous resolution of an MPD in a neonate associated with a germline PTPN11 mutation. The T73I is a missense mutation that is well recognised in NS-associated MPDs and NSassociated JMML but is rarely seen in sporadic JMML or in NS-PTPN11 without MPD. This case supports the use of a conservative approach to such patients in the absence of critical organ dysfunction or refractory cytopenia.

Unsuspected haemophilia in children with a single swollen joint

A clotting screen to exclude haemophilia is an essential investigation in a child with a single swollen joint