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.

The immunogenicity of ReFacto AF (moroctocog alfa AF-CC) in previously untreated patients with haemophilia A in the United Kingdom.

INTRODUCTION: Factor VIII inhibitor development is currently the most serious complication of the treatment of haemophilia A. Differences in manufacturing and the molecular structure of brands of recombinant factor VIII have led to speculation that concentrates may differ in immunogenicity. This has led to a regulatory focus on the immunogenicity of factor VIII concentrates both before and after licensure. AIM: To investigate the immunogenicity of ReFacto AF post licensure in a real-world setting in previously untreated patients (PUPs) treated exclusively with this product until at least 50 exposure days (EDs). METHODS: The United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) National Haemophilia Database (NHD) identified a consecutive cohort of patients with severe haemophilia A (<0.01 IU/L) whose first treatment was with ReFacto AF, monitored time to inhibitor development and described associated risk factors. RESULTS: One hundred and three boys reached 50 EDs within the study period, of whom 35 developed an inhibitor (P(t ≤ 50) = 0.33, [95% CI: 0.25-0.43]), of which 15 (P(t ≤ 50) = 0.16, [95% CI: 0.10-0.25]) were high titre. Inhibitors arose after a median (interquartile range) 11 (7-16) EDs. Inhibitors were significantly associated with high-risk mutations and non-significantly associated with non-white ethnicity. Inhibitors were negatively associated with a family history of haemophilia A. High-titre inhibitors were significantly associated with a family history of inhibitors. CONCLUSION: Inhibitor incidence in a single country population of ReFacto AF PUPs was similar to that previously described. Low- and high-titre inhibitors were detected after a similar number of EDs, contrasting with previous data, probably reflecting standardized inhibitor monitoring within the United Kingdom.

Intracranial haemorrhage in children with inherited bleeding disorders in the UK 2003-2015: A national cohort study.

INTRODUCTION: Intracranial haemorrhage in children with inherited bleeding disorders is a potentially life-threatening complication and presents a significant therapeutic challenge. AIM: To define the characteristics, management and outcomes of intracranial haemorrhage presenting in UK children ≤16 years of age with inherited bleeding disorders from 2003 to 2015. METHOD: Retrospective analysis of children treated at UK haemophilia centres. RESULTS: Of 66 children presenting with Intracranial haemorrhage (ICH), 82% had haemophilia A or B, 3% VWD and 15% a rare IBD. The IBD was a severe phenotype in 91%. The rates of ICH were 6.4 and 4.2 per 1000 patient years for haemophilia A and B, respectively. Median age at presentation was 4 months (33% neonates; 91% children <2 years of age). In neonates, delivery was spontaneous vaginal (SV) in 11, instrumental in 6, caesarean in 4 and unknown in 1. In children with haemophilia, the risk of ICH after instrumental delivery was 10.6 times greater than after SV delivery. Trauma was more common in children >2 years (67%) than in children 1 month to 2 years (18%; P = .027). Prior to ICH, only 4.5% of children were on prophylaxis. 6% of haemophiliacs had an inhibitor. The median duration of initial replacement therapy was 15 days. Mortality was 13.5%. Neurological sequelae occurred in 39% of survivors, being more common following intracerebral bleeding. In haemophilia survivors, 52% subsequently developed a FVIII inhibitor. CONCLUSION: Intracranial haemorrhage occurs most frequently in children with severe IBDs, during the first 2 years of life and in children not receiving prophylaxis. Intracranial haemorrhage often occurs without documented trauma.

The use of enhanced half-life coagulation factor concentrates in routine clinical practice: guidance from UKHCDO.

Enhanced half-life factor VIII and IX products are being introduced into routine clinical practice. Published data report on clinical trials and there are limited data available on how to use these products in routine clinical practice. Many patients, for example, those with a past history of an inhibitor, have been excluded from clinical trials and there are limited data published on children. This guidance document is a consensus statement from the UK Haemophilia Centres Doctors' Organisation and aims to give pragmatic advice on the use of these products in routine practice.

Intraoral 3D Scanning or Dental Impressions for the Assessment of Dental Arch Relationships in Cleft Care: Which is Superior?

OBJECTIVE: This study was undertaken to evaluate intraoral 3D scans for assessing dental arch relationships and obtain patient/parent perceptions of impressions and intraoral 3D scanning. MATERIALS & METHODS: Forty-three subjects with nonsyndromic unilateral cleft lip and palate (UCLP) had impressions taken for plaster models. These and the teeth were scanned using the R700 Orthodontic Study Model Scanner and Trios® Digital Impressions Scanner (3Shape A/S, Copenhagen, Denmark) to create indirect and direct digital models. All model formats were scored by three observers on two occasions using the GOSLON and modified Huddart Bodenham (MHB) indices. Participants and parents scored their perceptions of impressions and scanning from 1 (very good) to 5 (very bad). Intra- and interexaminer reliability were tested using GOSLON and MHB data (Cronbach's Alpha >0.9). Bland and Altman plots were created for MHB data, with each model medium (one-sample t tests, P < .05) and questionnaire data (Wilcoxon signed ranks P < .05) tested. RESULTS: Intra- and interexaminer reliability (>0.9) were good for all formats with the direct digital models having the lowest interexaminer differences. Participants had higher ratings for scanning comfort (84.8%) than impressions (44.2%) (P < .05) and for scanning time (56.6%) than impressions (51.2%) (P > .05). None disliked scanning, but 16.3% disliked impressions. Data for parents and children positively correlated (P < .05). CONCLUSIONS: Reliability of scoring dental arch relationships using intraoral 3D scans was superior to indirect digital and to plaster models; Subjects with UCLP preferred intra-oral 3D scanning to dental impressions, mirrored by parents/carers; This study supports the replacement of conventional impressions with intra-oral 3D scans in longitudinal evaluations of the outcomes of cleft care.

The incidence of factor VIII inhibitors in severe haemophilia A following a major switch from full-length to B-domain-deleted factor VIII: a prospective cohort comparison.

Although it has been suggested that switching of factor VIII (FVIII) products may increase inhibitor formation this is disputed. Half of UK patients changed rFVIII brands because of national contracting in 2010, presenting an opportunity to compare inhibitor incidence of switchers with non-switchers. Centres were requested to test all the patients for inhibitors prior to the switching date and 6-monthly thereafter. Positive and negative inhibitor test data were also collected to analyse for testing bias. A total of 1198 patients with severe haemophilia A and treated with Advate, Kogenate/Helixate or Refacto AF preswitch were included in the analysis, of whom 516 switched to Refacto-AF and 682 did not switch products. Five new inhibitors were reported amongst previously treated patients (>50 exposure days) with a median titre at the time of detection of 1.25 BU mL(-1) (IQR 0.7-23.05). One inhibitor occurred in a non-switcher using Kogenate, an incidence of 1.5 per 1000 treatment-years (95% CI 0.2-10.5). Four inhibitors arose in patients who had switched from Kogenate (two) or Advate (two) to ReFacto-AF, an incidence of 7.8 per 1000 treatment-years (95% CI 2.9-20.8). These incidence rates did not differ significantly from one another (incidence rate ratio 5.3 (95% CI 0.5-260.3) or from the historical rate of 6.05 inhibitors/1000 treatment-years (95% CI 5.18-7.06). Only one inhibitor (non-switcher) persisted. Non-switchers were significantly older (P = 0.03), and used significantly less FVIII per year (P = 0.005) prior to switching. Following switching, factor usage increased similarly (P = 0.53) in both groups. Switching from FLRFVIII to Refacto-AF (BDDRFVIII) was not associated with an increased inhibitor development.

Purpura fulminans: recognition, diagnosis and management.

Purpura fulminans (PF) is a haematological emergency in which there is skin necrosis and disseminated intravascular coagulation. This may progress rapidly to multi-organ failure caused by thrombotic occlusion of small and medium-sized blood vessels. PF may complicate severe sepsis or may occur as an autoimmune response to otherwise benign childhood infections. PF may also be the presenting symptom of severe heritable deficiency of the natural anticoagulants protein C or protein S. Early recognition and treatment of PF is essential to reduce mortality and to prevent major long-term health sequelae. However, management strategies require accurate identification of the underlying cause. This review focuses on the clinical features, differential diagnosis and laboratory features of the range of PF disorders and includes expert consensus opinion about immediate and on-going management.

Treatment related factors and inhibitor development in children with severe haemophilia A.

With the advent of modern factor replacement therapy the most important remaining obstacle to successful treatment in haemophilia A is the development of inhibitory antibodies against Facto VIII (FVIII). This retrospective case control study examined genetic variables and early treatment patterns in severe haemophilia A patients who subsequently developed clinically significant inhibitors to FVIII compared with matched controls who did not. Seventy eight inhibitor patients were identified from 13 UK centers over 25 years (1982-2007). For each case an age matched control was selected. Data on potential genetic and treatment related risk factors were collected for cases and controls. Treatment related data was collected for the first 50 exposure days (EDs) for controls or up to inhibitor development for cases. Risk factors were compared for significance by univariate and multivariate analysis. Of the genetic risk factors, major defects in the FVIII gene and non-caucasian ethnicity were each responsible for approximately 5-fold increases in inhibitor risk. When treatment related variables are considered, high intensity treatment increased inhibitor risk around 2.5 fold whether represented by the presence of peak treatment moments or by high overall treatment frequency. This finding was significant regardless of the timing of the high intensity treatment. Periods of intense treatment associated with surgery for porta-cath insertion were however not found to be associated with increased inhibitor risk. No association was shown between inhibitor development and age at first FVIII exposure, type of FVIII product, or the use of regular prophylaxis. This study confirms treatment-related factors as important risks for inhibitor development in Haemophilia A.

Clinical prediction models for inhibitor development in severe hemophilia A.

Clinical prediction models for factor VIII inhibitor development may potentially facilitate the identification of patients at high risk of this complication. In particular, recognition of early intensive FVIII replacement therapy as a significant risk factor for inhibitor development has defined a clear clinical decision point that influences patient care. To assess the effect and potential acceptance of a prediction tool for FVIII inhibitor development in clinical practice, a 15-item survey was developed to assess whether these included items were accepted as potential risk factors by the health care providers taking care of these patients. The rating of these items was on a 5-point linear scale, with '1' representing it to be very unlikely and '5' very likely. Responses from 42 centers were available for analysis. These centers were responsible for taking care of 2642 children <18 years with severe hemophilia A. In addition to genetic factors (mean score approximately 4.5), early intensive treatment was considered important for inhibitor development (mean score 4.07). Other factors likely to reduce inhibitor development were early onset of prophylaxis (mean score 3.68) and avoidance of early surgery (mean score 4.05). Physicians also agreed that institution of early prophylaxis and avoidance of elective surgery are important management strategies to reduce inhibitor development (mean scores 3.54 and 4.32, respectively).

Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A.

Recent reports have suggested that the incidence of inhibitors in haemophilia is the highest in those first exposed to factor VIII under 6 months of age. In this study, we investigated inhibitor development in children first exposed to FVIII as neonates and also examined the effect of other genetic and environmental variables. Three hundred and forty-eight children with severe haemophilia A were investigated. Inhibitors developed in 68 of 348 (20%), with 34 of 348 (10%) high titre inhibitors. The incidence in relation to initial FVIII exposure was: <1 month nine of 35 (26%), 1-6 months 13 of 51 (25%), 6-12 months 27 of 130 (21%), 12-18 months 13 of 66 (20%) and >18 months six of 66 (9%). While we observed a significant difference in inhibitor development and age at first exposure across all age groups (P = 0.018), no significant difference was observed in children treated at different time points during the first year of life (P = 0.44). Similar results were obtained for high titre inhibitors. There was also no difference in the incidence of inhibitors in relation to initial FVIII exposure in a subgroup of 144 children with the intron 22 mutation. Inhibitors developed more frequently in those initially treated with recombinant when compared with plasma-derived FVIII (P = 0.006) and in those with a major molecular defect (P = 0.009). In this study, exposure to FVIII during the neonatal period was not associated with a higher incidence of inhibitors than those treated later during the first year of life. Initial treatment with recombinant FVIII and the presence of a major molecular defect were the most important variables affecting inhibitor development.

Fluconazole and itraconazole susceptibilities of Candida spp. isolated from oropharyngeal specimens and blood cultures of paediatric haematology/oncology patients.

This study examined the in vitro susceptibilities to fluconazole and itraconazole of isolates of Candida spp. from surveillance oropharyngeal specimens and blood cultures from paediatric patients with malignancy. The species distribution of 100 isolates from oropharyngeal specimens was C. albicans 86%, C. glabrata 7%, C. lusitaniae 4%, C. parapsilosis 2% and C. tropicalis 1%. From a total of nine isolates from blood cultures the species distribution was C. albicans 33.3%, C. parapsilosis 33.3 % and C. guilliermondii 33.3%. Only three of the oropharyngeal isolates were resistant to fluconazole (MIC > or = 64 mg l(-1)) and only two were resistant to itraconazole (MIC > or = 1 mg l(-1)). None of the blood culture isolates was resistant to either agent. At this centre, C. albicans is the predominant species from oropharyngeal specimens, but non-albicans Candida species predominate in blood cultures. Although resistance to fluconazole and itraconazole is rare at present, continued surveillance is warranted to monitor trends in species distribution and antifungal susceptibility.

Challenges in preventing pyelonephritis in pregnant women in Indigenous communities.

AIM: To measure the quality of antenatal care in rural and remote regions of the Northern Territory, using asymptomatic bacteruria as an indicator. BACKGROUND: Indigenous Australian women and their babies have a greater frequency of adverse outcomes in pregnancy than their non-Indigenous counterparts. It is well established that asymptomatic bacteriuria may have serious outcomes in pregnancy, including an increased risk of pyelonephritis and a strong association with preterm and low birth weight delivery. Ensuring good quality antenatal care can reduce the individual risks of pregnancy for mothers and their babies. In the Northern Territory there are well established guidelines for antenatal care in rural and remote Indigenous communities. These are documented in the Women's Business Manual. Audit and feedback is one method that has been shown to have a small to moderate effect in changing clinician behaviour, in this case improving compliance with guidelines. METHODS: A retrospective chart audit of antenatal clients was conducted at 10 rural and remote primary health care clinics in the Northern Territory, Australia. The audit reviewed all the available charts (n = 268) of pregnant women, from the participating communities, who gave birth in 2002 or 2003. The diagnosis and management of asymptomatic bacteriuria was chosen as the indicator of quality antenatal care, as it is one of five areas of antenatal care where there is evidence that appropriate management improves outcomes. The quality of care was measured against the local guidelines, the Women's Business Manual. RESULTS: Women frequently had urine tests with where the dipstick showed an abnormal result, with 75% (95% CI [0.70,0.80]) of women having at least one episode of abnormal urinalysis during pregnancy. Six hundred and twenty episodes of abnormal urinalysis in pregnancy were identified. The incidence of bacteriuria at first visit was 16%, (95%-confidence interval = 95% CI [0.10, 0.21]). Compliance with the guidelines was poor. Fifty-six percent (95% CI [0.52,0.60]) of those samples testing positive on urinalysis were not sent to pathology for microscopy and culture, as recommended in the guidelines. Of those with a positive culture, 32% (95% CI 0.28,0.39) were appropriately treated with antibiotics. When antibiotics were given, good compliance of 82% (95% CI 0.76,0.87) with antibiotic guidelines was demonstrated. The positive predictive value of dipstick urinalysis in diagnosing asymptomatic bacteriuria was low in this study at 33.5%. There were 13 episodes of confirmed or probable pyelonephritis. No women with recurrent urinary tract infections were followed up according to protocol. CONCLUSION: Aboriginal women have worse pregnancy outcomes than the non-Indigenous population of Australia. Pyelonephritis is a preventable condition in pregnancy. In these rural and remote communities, pyelonephritis has not been prevented due, in part, to a failure to follow the local guidelines. Structural problems were identified and need to be addressed in order to improve compliance with guidelines and hence pregnancy outcomes for rural and remote Indigenous women.

Neonatal coagulation problems.

Bleeding problems often occur during the neonatal period. Although thrombocytopenia is the most common cause, coagulation problems often occur, and the two problems may co-exist. The causes, diagnosis, and management of coagulation problems in newborn infants are reviewed.

The rare coagulation disorders--review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation.

The rare coagulation disorders are heritable abnormalities of haemostasis that may present significant difficulties in diagnosis and management. This review summarizes the current literature for disorders of fibrinogen, and deficiencies of prothrombin, factor V, FV + VIII, FVII, FX, the combined vitamin K-dependent factors, FXI and FXIII. Based on both collective clinical experience and the literature, guidelines for management of bleeding complications are suggested with specific advice for surgery, spontaneous bleeding, management of pregnancy and the neonate. We have chosen to include a section on Ehlers-Danlos Syndrome because haematologists may be consulted about bleeding manifestations in such patients.

Heritable thrombophilia and childhood thrombosis.

Thrombotic problems are rare during childhood but are increasingly recognized, particularly in tertiary care paediatric populations, and represent a different spectrum of disorders to those seen in adults. An understanding of the aetiological factors involved in the pathogenesis of these events is important both for prevention and management. A number of inherited prothrombotic defects have been shown to be independent risk factors for thromboembolism in adult studies, and may also contribute to thrombotic events in childhood. Homozygous deficiencies of naturally occurring inhibitors of coagulation are clearly associated with major prothrombotic disorders, often presenting in the perinatal period. The association of other inherited prothrombotic disorders with thrombosis in childhood is less well defined. The prevalence of heritable thrombophilia varies in different clinical settings and the risks associated with individual defects has only been addressed in a small number of studies to date. Additional acquired risk factors are also present in a high percentage of cases and again differ from those seen in adult thrombosis. Further studies are required to assess the risks associated with heritable thrombophilia during infancy and childhood, and to define the place of thrombophilia screening in paediatric practice.

Roles and activities of the Commonwealth Government University Departments of Rural Health.

Since 1996, University Departments of Rural Health (UDRH) have been established at Broken Hill, Mount Isa, Shepparton, Launceston, Whyalla, Alice Springs and Geraldton. Each UDRH is underpinned by Commonwealth funding for an initial period of 5 years. The role of the UDRHs is to contribute to an increase in the rural and remote health workforce through education and training programs, as well as a reduction in the health differentials between rural and urban people and between indigenous and non-indigenous peoples. A strong population health focus involving partnerships between existing health providers in a targeted region and the university sector underpins their operation. While UDRHs have been established as a means of addressing a national workforce problem, their organisational arrangements with universities and local service providers vary widely, as does the program mix of activities in education, research service development, facilitation and advocacy. This article outlines some of the activities and progress of the UDRHs to date.