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

This work was supported by funding from Biogen, including funding for the editorial and writing support in the the development of this paper

Feasibility, safety and acceptability of select outcome measures in a physiotherapy study protocol for boys with haemophilia.

BACKGROUND: There is a lack of functional performance measures for children and young people with haemophilia (CYPwH) with associated control data from typically developing boys (TDB). The literature advocates development of a core set of outcome measures for different chronic conditions. As medical treatment improves, CYPwH are experiencing better outcomes; therefore, more challenging measures are required to monitor physical performance. Such testing is not performed routinely, due to practical and safety concerns. AIM: Evaluate the feasibility, safety and acceptability of select outcome measures as part of a study protocol testing CYPwH; including myometry, 10 metre incremental shuttle walk test (10-m ISWT), iSTEP (an incremental step test, with data from TDB), and 1 week of accelerometry-wear at home. METHODS: Sixty-six boys aged 6-15 years with mild, moderate or severe haemophilia A or B (including inhibitors) attending routine clinics at Great Ormond Street Hospital were approached to participate. Descriptive statistics and content analysis were used to assess outcomes of feasibility, safety and acceptability, which included recruitment/retention rates, protocol completion within routine appointment timeframes, performance testing without serious adverse events/reactions (SAE/SARs), and acceptability to CYPwH of high-level performance measures. RESULTS: Outcomes were met: 43 boys completed testing at clinic review (Jan-Nov 2018) within a 10-month timeframe, retention was 95% at completion of protocol and no SAE/SARs were reported throughout testing. CONCLUSION: Feasibility, safety and acceptability of the study protocol have been established in this population. Both high-level performance tests, iSTEP and 10-m ISWT, were an acceptable addition to boys' routine clinic appointments and could be safe, acceptable choices of outcome measure as part of a core set of tests for CYPwH. Further investigation of the psychometric properties for the iSTEP is now justified, in order for it to be used as a standardised, validated, reliable outcome measure in clinical or research settings. TRIAL REGISTRATION: Retrospectively registered on September 3, 2019, on ClinicalTrials.gov (ID: NCT04076306 )

Plasma-derived factor X concentrate compassionate use for hereditary factor X deficiency: Long-term safety and efficacy in a retrospective data-collection study.

Background: Coagadex is a high-purity plasma-derived factor X concentrate (pdFX) developed to treat hereditary factor X deficiency (FXD). Objective: Evaluate the efficacy and safety of pdFX administered to patients with hereditary FXD. Methods: This was an open-label, multicenter, retrospective analysis of patients receiving pdFX for compassionate use. Efficacy end points included treatments administered, the number and treatment of bleeds, and investigator assessments. Adverse drug reactions (ADRs) were monitored. Results: Fifteen patients were included: seven received routine prophylaxis, seven received on-demand treatment, and one alternated. Most were aged ≥12 years (n = 13) and had severe hereditary FXD (n = 12). The median follow-up time was 19.2 months (range, 3.5-48.8). The number of infusions per patient per month was higher for the routine prophylaxis group (median [range], 5.4 [1.4-10.1]) than for the on-demand group (0.8 [0.1-2.3]), as was the dose per infusion (27.9 [21.9-53.6] IU/kg vs 20.0 [13.6-27.7] IU/kg). Patients experienced 88 bleeds (34 minor, 7 major, 47 unclassified). The monthly bleed rate per patient was 0.04 in the routine prophylaxis group (based on 17 bleeds in four patients) and 0.8 in the on-demand group (based on 71 bleeds in eight patients). pdFX was used to treat 79 bleeds and was rated effective in all instances. In an overall assessment, investigators rated pdFX as excellent for 14 patients (93.3%) and good for 1 patient (6.3%). No ADRs or safety concerns were reported. Conclusions: This analysis supports the use of pdFX as a safe, effective treatment for hereditary FXD. Routine prophylaxis with pdFX may reduce bleed frequency

Effect of Porcine circovirus 2 (PCV-2) maternally derived antibodies on performance and PCV-2 viremia in vaccinated piglets under field conditions

Background: Nowadays, the most common presentation of PCV-2 is the subclinical infection in piglets after weaning. The success of PCV-2 vaccination is associated with the control of the clinical disease as well as the improvement of production parameters. In consequence, the objective of the present study was to analyse the effect of PCV-2 maternally derived antibody (MDA) levels on vaccine efficacy in piglets vaccinated at three weeks of age with a commercial PCV-2 subunit vaccine. The study was performed analysing a database with 6112 wean-to-slaughter piglets from 4 different European regions. Results: Results showed that the use of the vaccine was able to decrease the PCV-2 viremia calculated as area under the curve (AUC = 60.29 ± 3.73), increase average daily weight gain (ADWG = 0.65 ± 0.01 kg/day) and reduce mortality (7%) in vaccinated piglets compared to non-vaccinated ones (AUC of 198.27 ± 6.14, 0.62 ± 0.01 kg/day and 11% respectively). The overall difference of ADWG between both groups was close to 30 g per day (p < 0.05), also when they were split for low and high levels of MDA titres. Moreover, the animals with the highest ADWG were observed in the group of piglets vaccinated with high or extremely high antibody titres (0.66 and 0.65 kg/day respectively). Considering only animals with extremely high antibody titres, both study groups performed similar, however there was a numerical difference of 10 g/day in favour of vaccinated piglets. Likewise, lack of correlation between ADWG and MDA was observed suggesting that no maternal antibody interference was present with the tested vaccine because the vaccinated animals grew faster compared to unvaccinated control animals, regardless of the level of maternal antibodies present at the time of vaccination. Conclusions: The results of the present study demonstrated that the MDA against PCV-2 transferred through the colostrum intake has a protective effect against this viral infection. The vaccine used in the present study (Ingelvac CircoFLEX®) was effective when applied at three weeks of age and was not affected by the level of MDA at the time of vaccination

Product type and the risk of inhibitor development in nonsevere haemophilia A patients: a case‒control study

Inhibitor development is a major complication of treatment with factor VIII concentrates in nonsevere haemophilia A. It has been suggested that plasma-derived factor VIII (FVIII) concentrates elicit fewer inhibitors than recombinant FVIII concentrates, but studies in severe haemophilia A patients have shown conflicting results. We designed a case‒control study to investigate the clinical and genetic risk factors for inhibitor development in nonsevere haemophilia A patients. We investigated whether the type of FVIII concentrate was associated with inhibitor development in nonsevere haemophilia A patients. This nested case‒control study includes 75 inhibitor patients and 223 controls, from a source population of the INSIGHT study, including all nonsevere haemophilia A patients (FVIII:C 2–40%) that were treated with FVIII concentrates in 33 European and one Australian centre. Cases and controls were matched for date of birth and cumulative number of exposure days (CED) to FVIII concentrate. A conditional logistic regression model was used to calculate unadjusted and adjusted odds ratios. No increased risk for inhibitor development was found for any type of FVIII concentrate; either when comparing recombinant FVIII concentrates to plasma-derived FVIII concentrates (adjusted odds ratio 0·96, 95% confidence interval (CI) 0·36–2·52) or for specific types of FVIII concentrates

Diagnosis, therapeutic advances, and key recommendations for the management of factor X deficiency.

Factor X deficiency is a rare coagulation disorder that can be hereditary or acquired. The typology and severity of the associated bleeding symptoms are highly heterogeneous, adding to the difficulties of diagnosis and management. Evidence-based guidelines and reviews on factor X deficiency are generally limited to publications covering a range of rare bleeding disorders. Here we provide a comprehensive review of the literature on factor X deficiency, focusing on the hereditary form, and discuss the evolution in disease management and the evidence associated with available treatment options. Current recommendations advise clinicians to use single-factor replacement therapy for hereditary disease rather than multifactor therapies such as fresh frozen plasma, cryoprecipitate, and prothrombin complex concentrates. Consensus in treatment guidelines is still urgently needed to ensure optimal management of patients with factor X deficiency across the spectrum of disease severity

A neonatal presentation of factor V deficiency: A case report

BACKGROUND: Factor V deficiency is a rare autosomal recessive coagulation disorder. Awareness of presenting features and management is important to avoid bleeding complications associated with mortality and neurodisability. CASE PRESENTATION: A 6-day-old Pakistani boy was admitted with bleeding from the left nipple. His parents were first cousins. A coagulation screen showed a prothrombin time of 41 s (control 14 s), a partial thromboplastin time of 132 s (control 33 s) and a normal thrombin time of 15 s (control 14 s). Factor V activity was <0.01 IU/ml. Oral tranexamic acid was started. At 5 weeks of age the child presented with irritability, lethargy and reduced feeding and a drop of hemoglobin to 5.6 g/dl. A cranial computed tomography scan showed a right intra-cerebral bleed extending from the frontal lobe to the parieto-occipital region with shift of the midline to the left. A regime of 20 ml/kg of fresh frozen plasma four times a week was instituted and has prevented further bleeds up to the present age of 21 months. Neurodevelopment remained normal. CONCLUSION: This case illustrates that in an unusually bleeding newborn of consanguineous parents rare severe homozygous bleeding disorders need to be considered. Nipple bleeding may be the first presentation of a congenital bleeding disorder. In cases of factor V deficiency where factor concentrates are not available long term use of fresh frozen plasma can prevent potentially life threatening bleeding

Treatment of bleeding episodes in haemophilia A complicated by a factor VIII inhibitor in patients receiving Emicizumab. Interim guidance from UKHCDO Inhibitor Working Party and Executive Committee

Emicizumab is a bispecific antibody that activates FX to FXa in the absence of FVIII. It has been shown to reduce bleeding episodes in people with haemophilia A complicated by a FVIII inhibitor. Despite the protection against bleeds, some breakthrough bleeds are inevitable and these may require additional haemostatic treatment. Emicizumab has been associated with severe adverse events when co‐administered with activated prothrombin complex concentrate. To minimize the risk of adverse events, the UK Haemophilia Centre Doctors’ Organisation issues the following updated interim guidance to its Inhibitor Guidelines for managing patients receiving Emicizumab based on the limit published information available in February 2018

Stand Characteristics and Leaf Litter Composition of a Dry Forest Hectare in Santa Rosa National Park, Costa Rica

One hectare of tropical dry forest in Guanacaste Conservation Area, Costa Rica was mapped and all trees larger than 10 cm diameter at breast height (DBH) identified. The same hectare was sampled for leaf litter and the two data sets, forest and litter, were compared. Dominant and subdominant species of the forest are represented in the leaf litter, whereas rare tree species are highly variable in their representation in the leaf litter. Relative abundance of dominant and subdominant tree species is represented well by the litter although absolute rank-order is nor identical between source forest basal area and leaf litter mass. The litter adds a significant component to the source forest data owing to the presence of vines and lianas, and more rarely small trees or shrubs. This indicates that litter studies may be able to add depth to forest diversity surveys. The source forest also was used to test foliar physiognomic reconstructions of climate that have been proposed recently by paleobotanists as an alternative to taxonomic affinities methods. The observed climate of the area does not conform to the climatic values that were predicted by application of these new methods. RESUMEN Una hectÁrea de bosque seco tropical en el Area de ConservaciÓn de Guanacaste, Costa Rica fue mapeada, y todos los Árboles mayores de 10 cm de dap fueron identificados. En la misma hectÁrea, se tomaron muestras de hojarasca y los dos colecciones de datos. bosque y hojarasca, fueron comparadas. Se encontrÓ que las especies dominantes y subdominantes del bosque estaban representadas en las muestras de hojarasca, mientras que la presencia de especias arbÓreas raras en las muestras de mojarasca fue muy variable. La abundancia relativa de especies arbÓreas dominantesestÁ bien representada en la hojarasca aunque el Área basal del bosque de origen y la masa de hojarasca no heron idÉnticos en rangos absolutos. La hojarasca aÑade un componente significativo a los datos del bosque de origen debido a la presencia de bejucos y lianas en la hojarasca, y mÁs raramente Árboles pequeÑos y arbustos. Estos datos indican que los estudios de hojarasca pueden incrementar la precisiÓn de las estimaciones de la diversidad de los bosques. El bosque de origen fue usado tarnbien para examinar reconstrucciones del clima basados en la fisiognomia foliar recientemenre propuesras por paleobotÁnicas como una alternativa a mÉtodos de afinidad raxonÓmicas. El clima observado en el Área no corresponde con los valores climÁticos que fueron predecidos por la aplicaciÓn de estos nuevos mÉtodos.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73234/1/j.1744-7429.1997.tb00034.x.pd