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Keywords: intracranial haemorrhage; neonatal haematology; children; haemophilia; \sequelae EN intracranial haemorrhage neonatal haematology children haemophilia \sequelae e101 e104 4 07/20/20 20200715 NES 200715 Intracranial haemorrhage (ICH) in neonates with severe haemophilia is a potentially life-threatening complication and has been reported to occur in about 2-4% of boys with severe haemophilia; around 44-60 times higher than that expected in a non-haemophilia population.1,2 ICH requires intensive replacement therapy with factor concentrates, which has been identified as a risk factor for inhibitor development in patients with haemophilia A (HA).3 Death and neurological sequelae (motor function problems, seizures and developmental delay) are the most feared complications and have been reported to affect 50-60% of children with ICH.4 The aim of this paper was to study the incidence and symptoms of ICH in neonates with severe haemophilia and the impact of early diagnosis and treatment of ICH on long-term outcomes. The case report form registered patients' type of haemophilia, mode of delivery, ICH, and in cases of ICH, neurological signs and symptoms at presentation, treatment and sequelae. To be able to compare neonatal ICH incidences to ICH incidences later in life, the 450 neonatal months were added up to 34-52 patient years, resulting in an incidence of 0-26 ICH/patient year. The neonate might not be diagnosed as having haemophilia if there is no family history of haemophilia, symptoms like lethargy and vomiting are non-specific and not all cases of ICH are detected. [Extracted from the article]

Background Genomic inversions are usually balanced, but unusual patterns have been described in haemophilia A ( HA) patients for intron 22 (Inv22) and intron 1 (Inv1) inversions leading to the hypothesis of more complex rearrangements involving deletions or duplications. Aim To characterize five abnormal patterns either in Southern blot and long-range PCR for Inv22 or in PCR for Inv1. Materials and methods All patients were studied using cytogenetic microarray analysis ( CMA). Results In all cases, CMA analysis found that each inversion was associated with complex Xq28 rearrangement. In three patients, CMA analysis showed large duplication ranging from 230 to 1302 kb and encompassing a various number of contiguous genes among which RAB39B. RAB39B duplication is a strong candidate gene for X-linked intellectual disability ( XLID). Surprisingly, none of the severe HA patients with RAB39B duplication reported in this study or in the literature exhibited XLID. We hypothesise that F8 complex rearrangement down regulated RAB39B expression. In the two remaining patients, CMA analysis found Xq28 large deletion (from 285 to 522 kb). Moyamoya syndrome was strongly suspected in one of them who carried BRCC3 deletion. Conclusion Because several F8 neighbouring genes are associated with other pathologies such as XLID and cardiovascular disease, all HA patients where complex Xq28 rearrangement was suspected should be referred to a geneticist for possible utility of a pangenomic study. Such investigation should be carefully considered in genetic counselling in female carriers to assess the risk of transmitting severe HA with a 'contiguous gene syndrome'. [ABSTRACT FROM AUTHOR]

Lymphomas or hepatocarcinomas related to blood-borne transmitted diseases are well-known malignancies in persons with haemophilia ( PWH). However, rising life expectancy has increased the number of PWH suffering from other malignancies. This study aimed to collect cancer occurrence data in PWH followed in five European haemophilia treatment centres (Brussels, Geneva, Marseille, Montpellier and Paris-Bicêtre) over the last 10 years and to analyse some particular features of cancer occurring in PWH. In total, 45 malignancies were diagnosed in 1067 PWH. The most common malignancies were hepatocellular carcinoma (12/45) and urogenital tract tumours (9/45). Bleeding at presentation or changes in bleeding pattern was indicative of cancer in four patients. Three patients with mild haemophilia developed anti-factor VIII inhibitors after intensive substitution therapy prior to surgery or invasive procedures. There was no bleeding associated with chemotherapy or radiotherapy. A few bleeding complications occurred following invasive (3/39) or surgical procedures (2/27) as a result of insufficient hemostatic coverage or in spite of adequate substitution. No bleeding was noted after liver or prostate biopsies. Following cancer diagnosis, five patients were switched from on-demand to prolonged prophylaxis substitution. In the majority of cases, the standard cancer treatment protocol was not modified on account of concomitant haemophilia. Thus, oncological treatments are not contraindicated and should not be withheld in PWH assuming that adequate haemostasis correction is undertaken. As shown by our study results, a change in bleeding pattern in adult PWH should raise suspicion of a malignancy. Intensive substitution must be considered a risk factor for inhibitor development. [ABSTRACT FROM AUTHOR]

The ONE Registry ( OR) was an international prospective observational study of on-demand recombinant factor VIIa (rFVIIa) treatment for mild to moderate bleeds in haemophilia A/B patients with inhibitors. To describe real-world use of single and multi dose rFVIIa and to compare outcomes, including effectiveness, safety, quality of life and treatment satisfaction associated with treatment. Baseline data included demographics, treatment, medical and bleed history and patient/caregiver-reported outcomes regarding bleeds. rFVIIa was prescribed according to routine practice; regimens varied and initial dose was categorized as low ( LD, ≤120 μg kg−1), intermediate ( ID, >120 and <250 μg kg−1) or high ( HD, ≥250 μg kg−1). OR included 102 patients and 85 (83%) reported 494 bleeds overall. Mean age was 23 years ( SD 16.4), with 52% ≥18 years. Majority of bleeds ( n = 350, 71%) involved ≥1 joints; 46% involved a target joint. Median initial dose was 90 μg kg−1 in LD (range 87-120, n = 156), 174 μg kg−1 in ID, (range 121-249, n = 127) and 270 μg kg−1 in HD, (range 250-375, n = 211). For spontaneous bleeds, effective haemostasis rate at 9 h was 63% LD, 60% ID and 56% HD. Rates of combined partially effective/effective haemostasis was 85% LD, 96% ID and 86% HD. Median number of doses in HD was one (range 1-7), compared with two in LD (range 1-17) and ID (range 1-23). No thromboembolic events were reported in 1145 doses given. These observational data in real life are consistent with previous studies which have shown similar overall effectiveness of rFVIIa and similar effectiveness and safety across different patterns of standard initial dosing. [ABSTRACT FROM AUTHOR]

Although most surgical and invasive procedures can be performed safely in patients with haemophilia, the optimal level and duration of replacement therapy required to prevent bleeding complications have not been established conclusively. For providing more insight into optimal therapy during invasive procedures, a literature review of surgical procedures in patients with haemophilia was conducted. Concomitantly, current practice was surveyed in 26 European Haemophilia Comprehensive Care Centres, representing 15 different countries. The review identified 110 original papers published between 1965 and 2007. Of these, only two studies were randomized controlled trials. Target levels and the duration of replacement therapy in the published studies were as follows. For major orthopaedic surgery: preoperative targets were 80–90%; postoperative targets showed a high degree of variation, with trough levels ranging from 20% to 80%, duration 10–14 days; for liver biopsy, 70–100%, 1–7 days; tonsillectomy: 90–100%, 5–11 days; indwelling venous access device insertion: 100%, 3–10 days; circumcision: 50–60%, 2–4 days; dental surgery: 30–50%, single treatment. With the exception of dental surgery, current practice in Europe, as assessed by the survey, was largely in agreement with published data. In conclusion, this study provides both a comprehensive review and a large survey of replacement therapy in patients with haemophilia undergoing invasive procedures; these data have informed the consensus practical treatment recommendations made in this paper. This study highlights the need for better-designed studies in order to better define minimal haemostatic levels of replacement therapy and optimal treatment duration. [ABSTRACT FROM AUTHOR]

Surgery in infants and young children with haemophilia, when preceded by accurate diagnosis and accompanied by safe and effective factor prophylaxis, is not associated with a significant risk of haemorrhage. Haemophilic newborns undergoing circumcision or major surgery prior to diagnosis and in the absence of appropriate haemostatic prophylaxis remain as a concern. Inhibitor development has replaced haemorrhage as the major surgical complication in the developed world, largely because of the intensity of treatment used to secure haemostasis. For that reason only, essential surgery should be performed. Intracranial haemorrhage (ICH) during the neonatal period affects 3.5–4.0% of all haemophilia boys in countries with a good standard of health care, which is considerably (40–80 times) higher than expected in the normal population. Because of the high frequency of sporadic cases, ICH in the neonatal period can only be partially prevented by improved carrier diagnosis and counselling. Infections and thrombosis are the major serious complications of central venous lines. Large differences are seen in the frequency of these complications, the most plausible explanations are probably related to the protocol used for device care, the quality of education and the compliance of the users, an issue addressed in an on-going study. [ABSTRACT FROM AUTHOR]

In the early nineties, the occurrence of hepatitis A outbreaks in some patients with haemophilia in some countries led French health authorities to recommend hepatitis A virus (HAV) vaccination in HAV-seronegative haemophiliacs. The French ‘Suivi thérapeutique National des Hémophiles’ cohort permitted to assess the implementation of this recommendation by the analysis of the vaccinal process, i.e. HAV seropositivity assessment and vaccination of HAV-seronegative patients, in a survival approach. In a subgroup of 812 patients diagnosed earlier than 1990 (prevalent cohort), the implementation of vaccinal process increased quickly from 0% in 1993 to 41.8% in 1994 and to 71.2% in 1996, suggesting a ‘notification effect’. The vaccinal process was associated to three cofactors in a Cox model analysis (age, severity of haemophilia, centre of treatment). No infection was observed during the survey in this group. In another subgroup of 201 boys born since 1993 (incident cohort), 27.5% and 15.4% patients remained exposed to the risk at 3 and 5 years from diagnosis respectively, again with a ‘centre effect’, which might be linked to various factors such as regain in confidence for products or economic reasons. Only five infectious seroconversions were assessed over the 7-year survey, which represents 14.5 cases per 1000 person-year incidence without any relationship with products. Our data combined with the contemporary hepatitis A epidemiology and the current safety of anti-haemophilic concentrates, should lead to a new assessment of the risk of hepatitis A in haemophiliacs. We suggest that among patients with bleeding disorder, as well as in other populations, HAV prevention policy might be stressed on those who already suffer from chronic liver disease and/or travel in endemic countries. [ABSTRACT FROM AUTHOR]

A survey of 21 haemophilia doctors, throughout Europe, who care for a total of approximately 5000 patients with bleeding disorders addressing practice and opinions regarding prophylaxis in patients aged 16–24 years and adults aged over 50 years, is presented. The outcome of adolescent patients who reduced or stopped prophylaxis was recorded. Eighteen of 19 respondents would consider modification of established prophylaxis in the adolescent age group, principal considerations being avoidance of risks of further concentrate exposure, predicted poor compliance and treatment costs. The preferred age for modification was 16–20 years, but there was very little consensus on the particular prophylactic regime recommended. Approximately, half of a cohort of 218 patients with severe haemophilia successfully reduced or stopped prophylaxis when they reached adolescence. Only 26 of 92 (28%) of the patient cohort who stopped prophylaxis, required reintroduction of a prophylactic regime and 12 of 59 (20%) of those who reduced the intensity of prophylaxis had to reintroduce a more intensive regime. A majority of respondents would consider starting prophylaxis in those over 50 years. There was no consensus as to indications for this practice or the nature of the prophylaxis protocol. We conclude that there is an absence of consensus on the management of patients with severe haemophilia, as they pass through adolescence and young adulthood, and reach the age of 50. Aggregate outcome data suggest a significant proportion of patients in the 18–22 years age range may be able to reduce or stop prophylaxis. A substantial number of older patients are on prophylaxis. [ABSTRACT FROM AUTHOR]

Abstract: Major molecular and genetic findings over the last decades and subsequent applications for diagnosis and therapeutic concerns have dramatically improved the evolution of severe haemophilia in countries with high economic resources. Another major factor of progress consisted in the setting of comprehensive care centres coordinating the care at a regional level. The early involvement of paediatricians for this rare and potentially serious chronic disease, which may be symptomatic from birth, is relevant in this context. Indeed, the early diagnosis of severe haemophilia and the involvement of expert caregivers in a multidisciplinary approach, are essential to make the acceptance of the disease easier. The diagnosis announcement should go together with a therapeutic project, which is nowadays based on long-term prophylaxis. Awaiting for likely curative treatments in the future, such as gene therapy, early implementation of prophylaxis and observance of this gold standard treatment during all the period of growth are critical to prevent the haemophilic arthropathy, to favour the future social and work-related integration and overall to improve the quality of life. The occurrence of an inhibitor represents the major residual complication of replacement therapy, especially for young children with severe haemophilia A. Even though new therapeutic resources brought substantial improvements for inhibitor patients, a better understanding of risk factors is a key issue since more accurate replacement regimen might induce tolerance during the first exposures and subsequently might prevent this complication. Prophylaxis and inhibitors that represent major concerns in paediatric care of severe haemophilia are included as main research objectives for the national registry " FranceCoag Network". [Copyright &y& Elsevier]

Intracranial haemorrhage (ICH) is known to be a severe although uncommon complication of haemophilia. A national survey has been conducted in France in order to collect information about ICHs which occurred in haemophiliacs between 1991 and 2001 and to propose recommendations for the diagnostic and treatment of ICH. Within this period, 123 episodes of ICH were recorded from 106 patients. Two-thirds of ICH concerned patients with severe haemophilia. Half of the cases occurred in patients under 15 years of age, 67.2% of which were post-traumatic. Ten cases occurred in neonates with three fatal outcomes. Overall mortality was high (21.9%) suggesting that availability of clotting factor concentrates has not improved the prognosis of this event. Morbidity was also high with 60% of long-term sequelae. The following parameters have been identified as prognostic factors for death: thrombocytopenia, HCV infection, intraventricular or intraparenchymatous haemorrhage. A delay in diagnosis was mentioned in 43.3% of cases, often related to the lack of recognition of the initial symptoms, which may be very common (apathy, tearfulness in young children and headache in elder patients). Delayed replacement therapy was recorded in 37.2% of cases. Emergency units initially dealt with half of these patients. Information concerning recognition and management of these episodes, not only in severe haemophilia, but also in moderate and mild forms, should be regularly supplied to paediatricians in maternity and physicians from emergency units, as well as to patients and their relatives. [ABSTRACT FROM AUTHOR]

Haemophilia management is not uniform among countries, even within western Europe, that have close economic, social and cultural relationship. The European Paediatric Network PedNet aims to share experiences in the field of the care of boys with haemophilia. In 1998, a PedNet survey has shown significant disparities in 20 centres from 16 countries, particularly as regards the implementation of prophylaxis regimen. This survey has been updated in 2003 to describe the current status of haemophilia management in 22 centres and the changing pattern of care of boys with severe haemophilia in western Europe. Regular, continuous long-term prophylaxis is provided in all PedNet centres, more than 50% and 80–100% of boys being treated this way in 20/22 and 15/22 centres respectively. Twenty of the 22 centres (91%) recommend continuous prophylaxis (primary or secondary A) for a new patient. The use of recombinant factor VIII concentrates was already widespread in 1998 and a further expansion of recombinant products has been observed over the last 5 years. Recombinant FVIII is now used exclusively in nine centres and for more than 80% of boys with haemophilia A in nine other centres. The use of recombinant and plasma derived FIX is more balanced: among 18 centres where boys with haemophilia B are treated, 14 use recombinant FIX, and nine administer it to a majority of patients. Other modifications of practice have been stressed in this survey, such as more targeted use of central venous devices in the youngest boys and more extensive characterisation of genetic mutations. [ABSTRACT FROM AUTHOR]

The only form of haemophilia treatment that is able to prevent arthropathy and other consequences of bleeding symptoms in patients with severe haemophilia is prophylaxis started at an early age (primary prophylaxis). It is also highly beneficial for the psychological and social wellbeing of patients and their families. Scientific institutions and international organizations such as WHO, the World Federation of Hemophilia (WFH) and the National Haemophilia Foundation (NHF) have recommended that prophylaxis be considered optimum therapy. This paper discusses the barriers to prophylaxis, such as the perceived need, costs and availability, and difficulty of venous access, and describes the authors' experiences with the therapy. [ABSTRACT FROM AUTHOR]