Search

Although synovitis is recognized as a marker of joint disease activity, its periodic assessment is not included in routine clinical surveillance of patients with haemophilia (PwH). In order to evaluate the current knowledge and to identify controversial issues, a preliminary literature search by the Musculoskeletal Committee of the Italian Association of Haemophilia Centres (AICE) has been conducted. Statements have been established and sent to the Italian AICE members to collect their level of agreement or disagreement by a Delphi process. Thirty-seven consensus recommendations have been drafted. We found a general agreement on the indication to consider the presence of synovitis as a marker of joint disease activity in PwH. Accordingly, there was agreement on the indication to search for synovitis both in patients reporting joint pain and in asymptomatic ones, recognizing ultrasound as the most practical imaging technique to perform periodic joint screening. Interestingly, after detection of synovitis, there was agreement on the indication to modify the therapeutic approach, suggesting prophylaxis in patients treated on demand and tailoring treatment in patients already under prophylaxis. Whereas the need of an early consultation with a physiotherapist is recommended for PwH affected by chronic synovitis, the exact timing for an orthopaedic surgeon consultation is currently unknown.

Objective: Extrahepatic portal vein thrombosis (EHPVT) is an atypical condition in pediatrics, although rare, it represents an important clinical problem, as it is one of the most common causes of portal hypertension in children. The objective of this study is to identify the main factors associated with portal hypertension in children, with a main focus on umbilical vein catheterization (UVC) in the neonatal period. Methodology: A literature review of the last 10 years was carried out through a bibliographic search in the PUBMED database with the descriptors “umbilical vein catheterization” and “portal vein thrombosis”. In addition, the articles cited in the references of the works selected in the initial research and in the textbooks were consulted. Results and Discussion: The most common risk factors for EHPVT in descending order are: neonatal umbilical vein catheterization (73.2%), bacterial infections (47.62%), thrombophilia (35%), dehydration (19.08%). The UVC, through the mechanism of endothelial injury, and modification of the local flow causing blood turbulence, is the main cause of TEHVP in children. Final Considerations: Neonatal umbilical catheterization, although safe, has been identified as a cause of portal vein thrombosis, leading to portal hypertension syndrome and its complications. Measures such as prevention of neonatal infections and confirmation of the location of the UVC and shorter length of stay of the central catheter seem to influence the outcome of the patient to evolve with TEHVP.

About 5000 people in Italy suffer from hemophilia, the most common coagulation disorder. As for other chronic diseases, even in the case of hemophilia, the engagement of the patient is essential: the patients, in fact, must be empowered and helped to become strong partners of the care team and sensitized with respect to their rights and duties for the successful achievement of the goals set by their healthcare path. Hence the initiative to start a new research-intervention project in the field of hemophilia. The study had different phases of research: a first moment inspired by the principles of narrative medicine, aimed at collecting stories and narratives of patients with hemophilia related to the experience of the disease and therapy and expectations of active involvement in the relationship with the clinician. At the same time, among hematologists and patients has been surveyed the experience of therapeutical relationship and communication, to capture the aspects in which they feel effective and the areas of improvement and unmet needs. Subsequently, a workshop dedicated to patients and hematologists was organized to foster mutual awareness between these two targets and the formation of a better communication and relational skills of clinicians. The results of the project formed the basis for a policy brief document, aimed at disseminating recommendations to support better relationship and empathic communication between clinicians and patients.

Introduction: Haemophilia management and patients’ quality of life significantly improved. However, data on current patients’, caregivers’ and clinicians’ satisfaction and limitations of treatments and haemophilia management are limited. Aim: Assessing the management satisfaction and unmet needs from the perspective of Italian patients with haemophilia (PWH) without inhibitors (or caregivers if children) and of specialist physicians. Methods: Surveys (for patients≥18 years, caregivers of children and haemophilia specialists) were developed by a multidisciplinary working group and conducted from November 2019 to June 2020. Results: Among 275 participants, 120 (43.6%) were PWH without inhibitors, 79 (28.7%) caregivers and 37 (13.4%) clinicians. Patients and caregivers perceived a higher control of the disease compared to clinicians. However, more than 40% of patients and caregivers reported to feel significantly conditioned by the risk of bleeding during their daily life. PWH reported a 6-month mean/median (range) of bleeds 2.3/.0 (0-24) and caregivers 1.3/.0 (0-16) in children. The treatment burden (frequency of administration) was not satisfactory for more than half adults and caregivers of children treated with prophylaxis. A good access to treatment, haemophilia centres and medical service was reported, with issues associated to the multidisciplinary approach and treatment at emergency department. Conclusions: This large national study provides an updated overview of haemophilia care in Italy from different points of views, highlighting positive aspects and unmet needs. This information can guide future interventions to improve haemophilia management and the assessment of impact of new treatment options.

Regular physical activity can increase joint stability and function, reduce the risk of injury, and improve quality of life of people with haemophilia (PwH). However, a recent review of the literature shows that appropriate physical activity and sport are not always promoted enough in the overall management of PwH. A group of Italian experts in haemophilia care undertook a consensus procedure to provide practical guidance on when and how to recommend physical exercise programmes to PwH in clinical practice. Three main topics were identified -haemophilia and its impact on movement, physical activity recommendations for PwH, and choice and management of sports activity in PwH- and ten statements were formulated. A modified Delphi approach was used to reach a consensus. The group also created practical tools proposing different physical activities and frequencies for different age groups, the Movement Pyramids, to be shared and discussed with patients and caregivers. In conclusion, in the opinion of the working group, physical activity can be considered as a low-price intervention that can prevent/reduce the occurrence of chronic diseases and should be further encouraged in PwH to obtain multiple physical and psychological benefits. Future research should include prospective studies focusing on participation in sports, specific risk exposure and clinical outcomes.

Comprehensive evidence-based guidelines and well-validated assessment scales for pain in people with hemophilia (PwH) are needed. Here, we report 28 statements covering five topics on pain assessment and management in pediatric and adult PwH that were developed by 60 Italian hemophilia specialists during a Delphi consensus process. Overall, a clear consensus was achieved for 19 of the 28 statements. Consensus was reached on all statements on the topic of pain assessment and quality of life (QoL), including the need for regular pain assessment on a quantitative scale, the importance of distinguishing between different pain types, and the need to evaluate the impact of pain on patient QoL. The other four topics concerned acute and chronic pain management in adults and in children. Consensus was reached on statements regarding non-pharmacologic treatment and the use of first-line paracetamol (acetaminophen). There was a lack of consensus regarding the use of non-steroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, or opioids.

rVIII-SingleChain is indicated for treatment and prophylaxis of bleeding in patients with haemophilia A (HA). The safety and efficacy of rVIII-SingleChain have previously been shown in the AFFINITY clinical trial programme. This survey evaluated clinical experience following a switch to rVIII-SingleChain from the perspective of both physicians and patients. A web-based survey (July–September 2019) involving 14 Haemophilia Treatment Centres (HTCs) collected data about HA patients who were under treatment with rVIII-SingleChain for ≥ 12 months, as reported by their physicians. In addition, about half of these patients were separately interviewed. Out of 91 patients receiving rVIII-SingleChain in the 14 participating HTCs, 48 had been treated for ≥ 12 months; among those 48, 38% were ≤ 18 years, 37% 19–40 years and 25 % ≥ 41 years; 73% of them had severe HA and 85% were being treated with prophylactic therapy. Twenty-six patients accepted to be separately interviewed: mean age was 30 years; 62% had severe HA and 85% were receiving prophylaxis. Focusing on those patients who were already in prophylaxis with prior FVIII (all but one with recombinant factors), infusion frequency was significantly reduced from 3–2 per week following the switch to rVIII-SingleChain (mean, 2.74 vs. 2.44, respectively; p=0.013), as reported by physicians; the rate of patients needing 3 infusions per week dropped from 74% with previous products to 44% with rFVIII-SingleChain. The annual mean factor consumption was 4740 IU/Kg (median, 4500 IU/Kg; min, 2.215 IU/Kg; max, 7.200 IU/Kg) with prior product and 4320 IU/Kg (median, 4320 IU/Kg; min, 2.215 IU/Kg; max, 6.646 IU/Kg) with rVIII-SingleChain. Both physicians and patients reported a significant reduction in annual total bleeding rates with rVIII-SingleChain compared with prior product (mean 2.15–0.96 and 2.46–0.71 events/year, p = 0.031 and p = 0.018, respectively). Mean satisfaction ratings (from 1; dissatisfied, to 5; very satisfied) for rVIII-SingleChain were quite high for both physicians (4.14, 86% satisfied/very satisfied) and patients (4.18, 86% satisfied/very satisfied). This survey suggested that switching to rVIII-SingleChain allowed patients to reduce their injection frequency without increasing factor consumption or compromising clinical results. Both physicians and patients reported a positive experience with rVIII-SingleChain after 1 year of treatment.

BACKGROUND Immune tolerance induction (ITI) is the only proven strategy to eradicate factor VIII inhibitors in patients with haemophilia A (HA). AIM To identify patients and treatment options with the highest chance of inhibitor eradication by primary ITI. PATIENTS AND METHODS In the frame of the Italian ITI Registry, carried out from 1995 to 2015 (last follow-up 2018), 137 primary ITI courses in severe HA patients (90/137 with poor prognosis) were analysed for predictors of outcome (complete/partial response or failure). Sixty-six of them (48%) were prospectively evaluated. RESULTS ITI was successful in 91/137 patients (66.4%) and 70 (51.1%) achieved complete response within 11 months (median). Historical peak titres ≤200 BU/ml (P = .033), inhibitor titres ≤5 BU/ml at ITI start (P = .001), peak titres ≤100 BU/ml during ITI (P

Hemophilia is associated with a high financial burden on individuals, healthcare systems, and society. The development of inhibitors significantly increases the socioeconomic burden of the diseases. This study aimed to review and describe the burden of hemophilia with inhibitors, providing a reference scenario to assess the impact of new products in the real word. Two systematic literature reviews were performed to collect data on (i) health economics and (ii) health-related quality of life evidences in hemophilic patients with inhibitors. The costs associated with patients with hemophilia and inhibitors are more than 3 times greater than the costs incurred in those without inhibitors, with an annual cost per patient that can be higher than €1 000 000. The costs of bypassing agents account for the large majority of the total healthcare direct costs for hemophilia treatment. The quality of life is more compromised in patients with hemophilia and inhibitors compared to those without inhibitors, in particular the physical domains, whereas mental domains were comparable to that of the general population. The development of an inhibitor has a high impact on costs and quality of life. New treatments have the potential to change positively the management and socioeconomic burden of hemophilia with inhibitors.

Background: Bypassing agents are the first line therapy in patients with acquired haemophilia A (AHA). Activated prothrombin complex concentrate (aPCC) proved to be effective as initial treatment, but 20% of patients (pts) had relapses. aPCC as short-term prophylaxis to reduce subsequent bleeds is still not clear. Aim: To evaluate whether a short-term prophylaxis with low dose of aPCC can reduce bleeding relapses after initial AHA treatment, maintaining safety. Methods: The FAIR Registry is a retrospective-prospective study started on December 2012, that collected data on all pts with AHA treated with aPCC in 12 Italian Haemophilia Centers. All statistical analyses were carried out in the 56 pts included in the registry. Results: 31 retrospective and 25 prospective pts were evaluated.101 bleeds requiring treatment were reported, 84.1% spontaneous, 71.3% involving muscles or skin. Major bleeds were 38,6%. Low-dose aPCC as short-term prophylaxis was started after the first resolved episode in 15/56 pts, 58% of whom prospective, in a mean dose of 54.2 ± 23.0 IU/kg, higher (61.4 ± 23.4 IU/kg) in the prospective group than in the retrospective one (44.3 ± 19.7 IU/kg) and it was continued up to a mean of 20.5 ± 17.6 days, similar in both groups. A total of 32 bleeding relapses were reported, 87.5% in the retrospective group. Only 9.4% occurred during short-term prophylaxis (p < 0.05). In our Registry no thromboembolic events were found. Conclusion: Initial AHA treatment with aPCC proved to be highly effective, but a consecutive low dose as short-term prophylaxis seems to demonstrate a significant reduction in bleeding relapses maintaining safety.

Background: The appearance of inhibitors is the most serious complication in haemophilia A (HA) patients. The primary objective is their eradication. Up to date, immune tolerance induction (ITI) was the only therapeutic option to achieve this. Aim: To assess the efficacy of moroctocog-alpha as an ITI regimen in a population of HA patients with high-titre inhibitors. Methods: The REF.IT Registry is a retrospective-prospective study that collected data on all patients with HA and high-titre inhibitors treated with moroctocog-alpha as an ITI regimen at twelve Italian Haemophilia Centres. Results: We enrolled 27 patients, 85.2% were children. All patients were high responders, 88.9% had severe HA. We found 69.3% of them had one or more risk factors for poor ITI prognosis, 14.8% were ITI rescue. Overall 59.3% achieved a complete/partial success (complete in 51.9%). ITI failed in 11 patients, 63.6% of them with poor-prognosis risk factors. Inhibitors appeared after a mean of 27 exposure days. Mean historical peak was 78.8BU/mL. The primary ITIs started on average 20.2months after the diagnosis. A partial or complete success after a mean of 15months of treatment was achieved in 56.6% of the children while the same result was obtained by 75.0% adults after 22months from ITI onset. Patients who were treated with high-dose moroctocog-alpha (200UI/kg/day) were 63.0%. Conclusion: Our Registry showed that the use of moroctocog-alpha in the setting of ITI was effective and safe also in a population of patients with high-titre inhibitors, presenting one or more risk factors for poor ITI prognosis.

The investigation of mental health among persons with haemophilia is mostly focused on negative and disease-related indicators. Literature however shows that psychosocial resources and optimal daily functioning can co-exist with chronic disease. The Dual Continua Model operationalizes positive mental health as 'flourishing', a condition comprising emotional, psychological, and social well-being dimensions. In the present study physical and mental health were comparatively assessed through positive and negative indicators in adults with haemophilia and a control group. Participants included 84 Italian persons with severe haemophilia (M

The development of neutralizing antibodies (inhibitors) against infused factor VIII currently represents the main complication of replacement therapy in patients with severe hemophilia A. Inhibitors, indeed, particularly high-titer inhibitors (>5 BU/mL), greatly complicate the management of bleeding, exposing patients to an increased morbidity and mortality risk, thus representing a significant burden for physicians of Hemophilia Treatment Centers (HTCs). Although bypassing agents (i.e., activated prothrombin complex concentrate [APCC] and recombinant activated factor VII [rFVIIa]) are available for the treatment and prevention of bleeding in inhibitor patients, their efficacy, safety, and cost–benefit outcomes are poorly known in the long term and should be further improved. In the frame of the update of recommendations for the management of inhibitor patients by the Italian Association of Hemophilia Centers (AICE), to collect more information on real-life therapeutic approaches with bypassing agents in this setting, a survey was conducted among the Directors of the Italian HTCs. From questionnaires returned by 55% of them, data on the use of rFVIIa and APCC in children, adolescent, and adult patients with hemophilia A and inhibitors were obtained and are summarized in this article, including information about the implementation of prophylaxis with both bypassing agents, the adopted regimens, and reasons for starting, adjusting, and interrupting such a therapeutic approach.

Background: The aim of this study was to provide an Italian version of the Haemophilia Activities List (HAL) and check its reliability in Italian medical centers. Methods: The Italian version of this assessment was administered to 80 patients (aged 18-65 years) affected by haemophilia A and B (moderate or severe). The validation was accomplished by comparing it to the revised and expanded Arthritis Impact Measurement Scales (AIMS2). Results: The internal consistency of the Italian version of the HAL had statistically high results: Cronbach's α 0.957-0.579. The highest internal consistency was measured in the domains ‘leg functionality' and in the overall points of the HAL questionnaire. The correlation between the AIMS2, which has been translated into Italian, and the version of the HAL questionnaire that we proposed, yielded good results for the following correlations: AIMS2 all and HAL overall (r = 0.64), AIMS2 physical function and HAL overall (r = 0.66), AIMS2 pain and HAL overall (r = 0.66). Conclusion: The Italian version of the HAL questionnaire presents both internal coherence and convergent validity. It can be used in addition to other functional tests to measure outcomes in moderate and severe haemophiliac diseases or to determine the quality of life as observed in the everyday life of patients.

PubMedID: 23731246 Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health-related quality of life (HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate (aPCC) on HRQoL, HRQoL was assessed using the Short-Form (SF)-36 Health Survey and the EQ-5D questionnaire in subjects ?14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on-demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on-demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF-36 dimensions except for vitality/energy and physical functioning. After prophylaxis, 'good responders,' defined as patients experiencing ?50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score (P = 0.021), role - physical (P = 0.042), bodily pain (P = 0.015), and social functioning (P = 0.036). Similarly, the EQ-5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on-demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ-5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on-demand treatment (P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on-demand treatment. © 2013 John Wiley & Sons Ltd.

Analyses of the bleeding tendency by means of the bleeding score (BS) have been proposed until now to confirm diagnosis but not to predict clinical outcomes in patients with inherited von Willebrand disease (VWD). We prospectively followed up, for 1 year, 796 Italian patients with different types of VWD to determine whether the previous BS of European VWD1 is useful to predict the occurrence of spontaneous bleeds severe enough to require replacement therapy with desmopressin (DDAVP) and/or von Willebrand factor (VWF)/factor VIII concentrates. Among the 796 patients included, 75 (9.4%) needed treatment of 232 spontaneous bleeding events. BS10 and VWF:ristocetin cofactor activity10 U/dL were associated with the risk of bleeding, but only a BS10 remained highly associated in a multivariable Cox proportional hazard model (adjusted hazard ratio: 7.27 [95% confidence interval, 3.83-13.83]). Although the bleeding event-free survival was different in VWD types, only a BS10 could predict for each type which patient had bleeding events severe enough to require treatment with DDAVP and/or concentrates. Therefore, BS can be considered a simple predictor of clinical outcomes of VWD and may identify patients needing intensive therapeutic regimens.

Haemophilia A (HA) is an X-linked recessive haemorrhagic disorder caused by a deficiency of coagulation factor VIII. Disease causative mutations are heterogeneous and spread all over the F8 gene sequence, with the exception of intron 22 inversion occurring in about 50% of severe patients. To define the specific mutational repertoire and mutation detection rate, we analysed F8 gene, by polymerase chain reaction and direct sequencing, in 128 unrelated patients from Southern Italy with severe (n = 108), moderate (n = 9) or mild (n = 11) HA. We identified 120 mutations, including 64 cases of intron 22 inversion (53.3%), three of intron 1 inversion (2.5%), one large deletion (0,8%) and 52 point mutations (43.3%). In particular, 19/120 were novel and 7/52 point mutations (13.5%) occurred at CpG sites. We also investigated eight prothrombotic genetic variants in a subgroup of 74 severe HA patients to evaluate their possible protective effect on the severity of clinical expression. Methylenetetrahydrofolate reductase A1298C and plasminogen activator inhibitor-1 4G variants recurred more frequently in HA patients with a less-severe phenotype. Clinical impact of these findings needs large-scale studies to further define the role of these prothrombotic variants as possible modifier factors of HA phenotype.

The management of patients with inhibitors is an important challenge in haemophilia care. The lack of randomized controlled trials means that clinical decisions are generally based on subjective opinions, and purchasers' attention is likely to focus on the costs of treatment. In order to assess the current management of inhibitor patients and use of immune tolerance induction therapy (ITI) in Europe, we performed a survey within a European network of 21 comprehensive care centres from 14 countries (the European Haemophilia Therapy Standardisation Board). The survey identified a total of 381 patients with inhibitors attending the centres, 211 (55.4%) of whom had never been exposed to ITI. Between 1998 and 2003, the centres performed 233 procedures and 114 (48.9%) were successful. The survey demonstrated that dosing, which is the time to start and stop the ITI, the type of concentrate to use and the definition of success varied among the centres. Well-designed trials are warranted to guide decision-making, but in the absence of these studies we have developed consensus guidance for the management of inhibitor patients based on current clinical practice, as identified by the survey, and review of the literature.

Nowadays, patients with hemophilia A receive a high standard of care; therefore, the most challenging complication of factor VIII (FVIII) replacement therapy has become the development of FVIII inhibitors, which render the concentrate infusion ineffective and expose patients to an increased risk of morbidity and mortality. Among environmental risk factors influencing inhibitor development, the type of FVIII products has always drawn the attention of investigators. Conflicting results are reported in the literature concerning rates of inhibitor development after either plasma-derived or recombinant FVIII concentrates. To help elucidate this controversial issue, we have performed a systematic review and meta-analysis of prospective studies evaluating the incidence of inhibitors in previously untreated patients with severe hemophilia A receiving plasma-derived or recombinant FVIII products. The quality of the studies was assessed using the Newcastle-Ottawa Scale (NOS), the STrenghtening the Reporting of OBservational studies in Epidemiology and an ad hoc quality score. Overall, 28 prospective studies, including 1,421 patients with hemophilia A, fulfilled our selection criteria and were included in the systematic review. No statistically significant differences were observed in the inhibitor incidence between plasma-derived and recombinant FVIII concentrates considering all (weighted means: 23%, 95% CI: 15-33% vs. 29%, 95% CI: 26-32%) and high titer (16%, 95% CI: 10-26% vs. 18%, 95% CI: 15-21%) inhibitors. Similarly, no significant differences were found in the inhibitor incidence among the different classes of recombinant products. In conclusion, the results of our meta-analysis show that the different types of FVIII products are not associated with different risks of inhibitor development.

Randomized and cohort studies have provided evidence confirming the hypothesis, based on in-vitro observations, that the use of very high-purity factor VIII (FVIII) concentrates, either immuoaffinity chromatography purified or produced by recombinant DNA technology, may slow immunological deterioration in human immunodeficiency virus (HIV)-infected haemophiliacs, while high-purity concentrates, produced by ion-exchange chromatography, did not produce a benefit. Even though these data clearly indicate that very high-purity concentrates should be preferred for the replacement therapy of HIV-positive haemophiliacs, there are little data, based on direct comparison, supporting the use of very high-purity concentrates rather than high-purity preparations, which are less expensive. In an attempt to address this issue, we prospectively compared CD4 cell counts and changes of clinical status in 18 HIV-positive haemophiliacs, randomly assigned either to receive the treatment with a very high-purity FVIII concentrate, purified by immunoaffinity chromatography, or a high-purity product, produced by ion-exchange chromatography. All patients had CD4 lymphocyte counts below 300 μL(-1) , were negative for the hepatitis B surface antigen and the HIV p24 antigen, and were receiving antiretroviral treatment with Zidovudine for at least 6 months. There were no significant changes of CD4 cell counts over the 96-week follow-up period or between the two groups. No signficant differences between the two groups were detected in the occurrence of AIDS-defining diagnoses (one in each group). On the whole, no striking benefit is conferred to the immune status of asymptomatic HIV-positive haemophiliacs by using either of these high-purity and very high-purity FVIII concentrates for 96 weeks. Larger prospective randomized trials are needed to establish definitely whether it is necessary to resort to very high-purity concentrates or it is sufficient to use high-purity concentrates to slow the fall of CD4 cell counts that occurs in HIV-positive haemophiliacs. Randomized trials, based on clinical end-points, are also needed to demonstrate whether slowing the fall in CD4 cells results in clinical benefits, delaying the occurrence of AIDS.

Birth is the first haemostatic challenge for a child with haemophilia. Our aim was to examine the association between perinatal risk factors and major neonatal bleeding in infants with haemophilia. This observational cohort study in 12 European haemophilia treatment centres (HTC) incorporated 508 children with haemophilia A or B, born between 1990 and 2008. Risk factors for bleeding were analysed by univariate analysis. Head bleeds occurred in 18 (3·5%) children within the first 28 d of life, including three intraparenchymal bleeds, one subdural haematoma and 14 cephalohaematomas. Intra-cranial bleeds were associated with long-term neurological sequelae in two (0·4%) cases; no deaths occurred. Assisted delivery (forceps/vacuum) was the only risk factor for neonatal head bleeding [Odds Ratio (OR) 8·84: 95% confidence interval (CI) 3·05-25·61]. Mild haemophilia and maternal awareness of her haemophilia carrier status seemed to be protective (OR 0·24; 95%CI 0·05-1·05 and OR 0·34; 95%CI 0·10-1·21, respectively), but due to the low number of events this was not statistically significant. We found no association between neonatal head bleeding and country, maternal age, parity, gestational age or presence of HTC. Maternal awareness of carrier status protected against assisted delivery (unadjusted OR 0·37; 95%CI 0·15-0·90; adjusted OR 0·47 (95%CI 0·18-1·21).

Over the last few decades, clinical follow-up of patients with haemophilia has become more complex as a result of the introduction of new treatment strategies, the presence of comorbidities related to haemophilia or ageing, as well as the emergence of new tools to evaluate the medical and social consequences of haemophilia. This publication describes the parameters and information that should be documented and the tests, examinations and interventions required for optimal follow-up of a patient with haemophilia. In the absence of formal studies, the present recommendations have been established as result of a series of consensus meetings in the frame of the European Haemophilia Therapy Standardization Board (EHTSB). The following 11 domains were identified: Baseline information, Current status, Treatment, Inhibitor status, Bleeding, Joint status and pain, Comorbidities, Dental care, Physical activities, Social participation and Quality of life. For each domain, details are proposed for the relevant parameters to be captured and monitored as well as the relevant tools that facilitate data collection. Adopting these recommendations should help the individual care of patients and, even though this is not the primary objective of this article, it should also help at national and international level to shape a new approach to haemophilia by working towards a more standardized outcome assessment. Greater standardization should have implications for data collection, improvements in treatment evaluation and optimizing resources.

SUMMARY: The development of inhibitors to the infused factor in patients with haemophilia is a serious clinical problem. Recent evidence suggests that alongside the strong genetic contribution to inhibitor formation, there are a number of non-genetic factors--perceived by the immune system as danger signals--which promote formation of inhibitors. This study provides a comprehensive review of clinical studies relating to these factors and also presents a survey of opinion concerning their importance and clinical influence, conducted among the members of the European Haemophilia Treatment Standardisation Board (EHTSB). Taken together, this information highlights the lack of robust data concerning the influence of several non-genetic risk factors on inhibitor development, and an urgent need for prospective, well-conducted studies that adhere to recommendations made by the European Medicines Agency (EMEA) for studying inhibitors. Based on current literature, the EHTSB formulated consensus recommendations. It is desirable to minimize intensive treatment wherever possible, given the clinical situation. Prophylaxis should be offered to all children, although we still need to determine optimal dosing with respect to inhibitor development, and age for starting treatment. Vaccinations should be given subcutaneously and concomitant factor concentrate infusions avoided. According to the board, there is no evidence in the literature supporting suggestions that the type of concentrate influences inhibitor risk; but all patients should be monitored during their first exposures. Furthermore, there is no evidence to support an association between pregnancy-related issues, breast feeding and treatment-related factors (e.g. route of administration, or use of blood components) and inhibitor development.

To study the effect of 1,8 cineole components of the essential oil of Croton nepetaefolius--plant of North-East of Brasil, used in the popular medicine for riots of the gastrointestinal tract--on the motor behavior of the gut of Wistar rats.Used 16 male animals under jejun of 24h weighing 300-350 g. The effect of 1.8 cineole (1 or 3mg/Kg) on gastric compliance had been lead in anaesthetized rats. The variations of the gastric volume (GV), had been measured by plethysmography, while AP, HR and CVP had been monitored continuously by a digital system of data acquisition.Observe reduction of the GV, which was significant on 30, 40, 50 and 60 min after treatment (2.0 +/- 0.1; 1.9 +/- 0.1; 1.8 +/- 0.1 and 1.7 +/- 0.1mL, versus 2.1 +/- 0.2mL). The AP presented significant fall after the administration of 1.8 cineole, remaining thus during 60min of monitorization (87.9 +/- 7.7; 87.6 +/- 7.1; 87.9 +/- 6.4; 87.8 +/- 5.7; 86.0 +/- 5.5 and 87.7 +/- 6.0mmHg, respectively versus 94.4 +/- 6.2 mmHg), as well as the HR (366.3 +/- 13.4; 361.7 +/- 11.5; 357.3 +/- 10.4; 353.0 +/- 10.4; 348.3 +/- 11.1 and 350.4 +/- 13.7bpm, respectively versus 395.2 +/- 11.1bpm). The CVP did not suffer significant variations after treatment.Observe the 1.8 cineole reduces the gastric compliance in anaesthetized rats besides presenting effect hypotensor and bradycardia; probably for direct action on the gastrointestinal and vascular smooth muscle and moduling the autonomic nervous system.

The ultimate goal of treatment for patients with inhibitory antibodies should be to permanently eradicate the inhibitor by immune tolerance induction therapy (ITI). However, ITI procedures fail in a substantial number of patients and in many countries ITI is not even offered owing to its high cost. How patients with inhibitors are managed in different European countries is evaluated with a special focus on the use of by-passing agents, i.e. recombinant FVIIa (rFVIIa) and activated prothrombin complex concentrates (aPCC), as well as the type of monitoring performed. Investigators from 22 large haemophilia centres participating within the network of the European Haemophilia Therapy Standardisation Board (EHTSB) were asked to complete a questionnaire. rFVIIa was routinely used in all centres for both children and adults at dosages ranging from 90 to 250 mug kg(-1) at an interval of 2-4 h. aPCC was used in 85% of the centres in adults and in 25% of the centres in children with haemophilia A at dosages of 50-100 IU kg(-1) every 6-12 h. The corresponding figures for children and adults with haemophilia B were 40% and 15% of the centres, respectively. Higher dosages of both agents were considered in the case of life-threatening bleeds. General recommendations were developed, based on the information provided by the survey. The results clearly indicate the need for well-designed comparative studies to optimize the use of by-passing agents.

Although current treatment guidelines recommend prophylaxis in paediatric patients with haemophilia, specific indications for and barriers to the prescription of prophylaxis in the paediatric haemophiliac population have not been established. The aim of this web-based survey of clinicians at Haemophilia Treatment Centres in Italy was to identify factors for and against the initiation of prophylactic coagulation factor replacement therapy in paediatric patients with haemophilia.A literature search was conducted to identify factors to include in the survey. Seventeen clinicians from Italian Haemophilia Centres were invited to complete the web-based survey and to rank factors in favour of and those that acted as barriers to prophylaxis in terms of "importance" and "influence" on a numerical scale (0=not important to 100=very important). Any factors for which there was a large discrepancy in results from the survey were further "ranked" by clinicians at an interactive question and answer session at a symposium.A total of 13 web surveys were returned; the most highly scored factors favouring prophylaxis were "bleeding frequency", "bleeding severity" and "presence of target joints", and the most highly scored barriers were "parents' acceptance", "venous access" and "compliance to therapy". Other important factors favouring prophylaxis were "severity of coagulation defect" and "orthopaedic score".This survey gives helpful clinician-derived information for people treating haemophiliacs in Italy, to help the treatment-providers orient themselves better regarding the prescription of prophylaxis for paediatric patients.

Hepatocellular carcinoma (HCC) is an increasingly frequent cause of mortality in hemophiliacs with chronic viral hepatitis. Early diagnosis of the tumor at an initial stage is known to improve the outcome of HCC treatment. Because all HCC cases detected in a previous study based upon annual ultrasound (US) surveillance of hemophiliacs with elevated alanine aminotransferase levels were multinodular, this study was designed to evaluate if a more intense surveillance with US and alphafetoprotein (AFP) serum levels of all the patients infected with the hepatitis C virus (HCV) improved the identification of single nodule tumors. A multicenter cohort of 559 HCV-infected hemophiliacs was divided into 2 arms, one followed up at 6-month intervals and one at 12-month intervals depending on the choice and available facilities of each treatment center. During a 6-year surveillance period, HCC was diagnosed in 5 (2.4%) of 210 patients in the 6-month group and in 3 (0.9%) of 349 patients in the 12-month group. The overall incidence rate of HCC was 239 per 100 000 per year (397 per 100 000 per year in the 6-month group and 143 per 100 000 per year in the 12-month group; differences not statistically significant). By multivariate analysis, HCC risk was increased 12.9-fold with alcohol intake more than 80 g/d and 15.2-fold with AFP levels higher than 11 ng/mL. Liver-related death occurred in 8 cases (1.4%), including 3 with HCC. Still alive and tumor free after 24 to 34 months from diagnosis are 3 patients with multinodular tumors treated with repeat chemoembolization followed by orthotopic liver transplantation. In conclusion, 6-month surveillance with US did not increase the chances of detection of single nodule tumors, but it is reasonable to assume that successful treatment of multinodular tumors based upon debulking with chemoembolization and liver transplantation was facilitated by this approach. (Blood. 2003;102:78-82)

The development of alloantibodies neutralising therapeutically administered factor (F) VIII/IX (inhibitors) is currently the most severe complication of the treatment of haemophilia. When persistent and at a high titre, inhibitors preclude the standard replacement treatment with FVIII/FIX concentrates, making patients’ management challenging. Indeed, the efficacy of bypassing agents, i.e., activated prothrombin complex concentrates (aPCC) and recombinant activated factor VII (rFVIIa), needed to overcome the haemostatic interference of the inhibitor, is not comparable to that of factor concentrates. In addition, the therapeutical response is unpredictable, with a relevant inter-individual and even intra-individual variability, and no laboratory assay is validated to monitor the efficacy and safety of the treatment. As a result, inhibitor patients have a worse joint status and quality of life compared to inhibitor-free subjects and the eradication of the inhibitor by immune tolerance induction is the preeminent therapeutic goal, particularly in children. However, over the last decades, treatment with bypassing agents has been optimised, allowing home treatment and the individualisation of regimens aimed at improving clinical outcomes. In this respect, a growing body of evidence supports the efficacy of prophylaxis with both bypassing agents in reducing bleeding rates and improving the quality of life, although the impact on long-term outcomes (in particular on preventing/reducing joint deterioration) is still unknown. This review offers an update on the current knowledge and practice of the use of bypassing agents in haemophiliacs with inhibitors, as well as on debated issues and unmet needs in this challenging setting.

von Willebrand disease (VWD) is the most common hereditary bleeding disorder affecting both males and females. It arises from quantitative or qualitative defects of von Willebrand factor (VWF) and causes bleeding of mucous membranes and soft tissues. The aim of treatment is to correct the dual defect of haemostasis caused by the abnormal/reduced VWF and the concomitant deficiency of factor VIII (FVIII).This document contains evidence-based recommendations for the management of VWD compiled by AICE (the Italian Association of Haemophilia Centres). All the evidence supporting these recommendations are based on non-randomised comparative studies or case series, because randomised controlled clinical trials or meta-analyses are not available for this disease.Desmopressin (DDAVP) is the treatment of choice for patients with type 1 VWD with FVIII and VWF levels of 10 U/dL or more, while VWF/FVIII concentrates are indicated for those who are unresponsive or insufficiently responsive to DDAVP (severe type 1, type 2 and 3 VWD). VWF concentrates devoid of FVIII, not yet licensed in Italy, may be considered for short-term prophylaxis in elective surgery or for long-term secondary prophylaxis.

Introduction: Data on APCC´s effectiveness, safety and quality of life are relatively poor because of the rarity of patients with FVIII or FIX inhibitors, the small populations included in clinical trials and the relatively short follow-up available. The FEIBA-GO study was designed to capture long-term outcomes on effectiveness, safety and health-related quality of life (HR-QoL) in subjects receiving APCC in different settings in routine clinical practice. Primary objective is to describe the hemostatic effectiveness of APCC in different settings (prophylaxis and on demand, including patients on immune tolerance induction); most relevant secondary objectives aim at describing joint functionality outcomes, safety, HR-QoL, daily activity level, acute and chronic pain associated with hemophilia, as well as healthcare resources used. Methods: The study is a prospective, non-interventional, multicenter cohort study in patients with hemophilia A or B and high-responding inhibitors treated with APCC. A hundred subjects are targeted for enrollment; treatment regimens are at the discretion of the attending physicians in accordance with routine clinical practice, either on early, secondary or tertiary prophylaxis or on demand, including patients treated with APCC during immune tolerance induction. The observation period per subject will be 4 years. Results: As of June 1, 2016, 40 centres have been qualified in 14 countries and 16 centres have been initiated. 27 patients have been enrolled at 14 open sites in 7 countries. Demographic data are available for the 27 patients enrolled so far and are presented for the first time. All patients have severe hemophilia A: 23 are caucasian, 1 african (3 missing). At the enrolment, 18 of them were on prophylaxis and 6 treated on demand (3 missing). Overall median age is 19 years (min-max: 3-71), 17.5 years in patients on prophylaxis (min-max: 3-71) and 39.5 years in patients on demand (min-max: 22-65). Overall median inhibitor titer at enrolment was 8 BU (min-max: 1-2410), 8 BU for prophylaxis (min-max: 1-92) and 12 BU in patients on demand (min-max: 3-35). Nijmegen modified Bethesda assay was used in 18 centres, while 4 used non-modified Nijmegen Bethesda assay (5 missing). Six subjects (3 on prophylaxis, 2 on demand and 1 unknown) have been reported to have overall 13 target joints. Assessment for acute pain was performed in 12 patients and for chronic pain in 9 patients. Two of 12 patients assessed reported acute pain (both on demand). Two of the 9 patients in whom the assessment was performed reported chronic pain (treatment regimen missing). For one patient, information is not available and for another one it has been reported that pain assessment is not routine examination. Gilbert Score was assessed in 6 patients at screening. Discussion/Conclusion: This study will further enhance the information on long-term effectiveness, HR-QoL and safety of APCC across and beyond Europe in the real world on hemophilia A and B patients with high-responding inhibitors under a variety of prescribing regimens in routine clinical practice. Disclosures Cid: Baxalta Innovations GmbH, now part of Shire: Other: Investigator Clinical Studies. Escuriola:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding. Hermans:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies. Holme:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies. Negrier:LFB: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; SOBI: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Alnylam: Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Rangarajan:Baxter: Research Funding; Grifols: Consultancy, Research Funding; Biogen: Consultancy; Pfizer: Research Funding; Baxalta, now part of Shire: Other: Investigator Clinical Studies, Research Funding; Novo Nordisk: Research Funding; Biotest: Research Funding. Rocino:Baxalta, now part of Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. Windyga:Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Other: Speaker's honorarium; Biogen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Nordisk: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Baxalta, now part of Shire: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Patents & Royalties, Research Funding, Speakers Bureau. Gringeri:Shire: Employment, Equity Ownership. Crea:Shire: Employment, Equity Ownership.

SummaryA multicenter prospective study of recombinant activated factor VII (rFVIIa) given by continuous infusion (CI) to treat severe hemorrhages and to handle surgical procedures was carried out.Relations between clinical efficacy, dosages used and levels of FVII coagulant activity (FVII:C) achieved in plasma were also evaluated. Case material included 25 patients with hemophilia (9 children and 16 adults) with high-responding inhibitors and 3 patients with acquired factor VIII inhibitors. Overall, 35 CI courses were given for 10 spontaneous bleeding episodes, 11 major surgical procedures and 14 minor surgical procedures. Bolus doses of 90 to 150 μg/kg (median: 100) were followed by CI given at median rates of 20 μg/kg/h for major surgery and of 17 and 16 μg/kg/h for minor surgery and spontaneous hemorrhages. Satisfactory hemostasis was obtained in 30 of 35 courses (88%). rFVIIa CI was ineffective in 2 hemophiliacs undergoing surgical operations and in another hemophiliac with hemoperitoneum who had to be switched to other treatments (high doses of porcine or human factor VIII concentrates). rFVIIa CI was partially effective in 2 hemophiliacs who had mild local bleeding after minor surgery. The CI rates and the corresponding FVII:C levels in plasma were similar in effective, partially effective and ineffective courses (median rate: 17, 20 and 20 μg/kg/h, respectively; median FVII:C: 14, 18 and 18 IU/ml, respectively). A single adverse event was observed, superficial thrombophlebitis. This study confirms that rFVIIa given by CI is effective in a high proportion of patients with factor VIII inhibitors. It also demonstrates that FVII:C levels attained in plasma do not always predict efficacy because similarly high levels were attained during successful treatments and in those that failed.

SummaryProthrombin deficiency is an autosomal recessive disorder associated with a moderately severe bleeding tendency. In this study, 13 patients with prothrombin deficiency were screened for the presence of alterations in the prothrombin gene, and nine novel candidate mutations were identified. Of 11 patients with hypoprothrombinemia, ten are homozygous for five mutations and one patient is a compound heterozygote. The two patients with dysprothrombinemia are homozygous for two mutations. Eight of nine mutations are missense ones associated with single amino acid substitutions in the propeptide (Arg-1Gln, Arg-2Trp), the kringle-1 (Asp118Try) and kringle-2 (Arg220Cys) domains and the catalytic serine protease domain (Gly330Ser, Ser354Arg, Arg382His and Arg538Cys). The ninth mutation is an in-frame deletion of 3 bp that results in the omission of one amino acid (del Lys 301/302). The combination of these missense mutations with crystal structures for α-thrombin and the prothrombin fragments 1 and 2 resulted in new insight into the function of α-thrombin. The hypoprothrombinemia mutations were inferred to affect either the cleavage of the propeptide from the Gla domain, the stability of the kringle-1 and −2 domains, or the close association of the A and B chains of the serine protease domain. The dysprothrombinemia mutations were inferred to directly affect catalytic function through their location at the active site crevice or exosite 1 within the serine protease domain.

Haemophilia A is the most common inherited bleeding disorder caused by defects in the F8C gene that encodes coagulation factor VIII. This X-linked recessive disorder occurs in approximately 1:5000 males. Haemophilia A is diagnosed based on normal pro-thrombin time, altered activated partial thromboplastin time and reduced factor VIII activity in plasma. Carrier females are usually asymptomatic and can be identified only by molecular analysis. The most frequent mutations in F8C are intron 22 and 1 inversions, which occur in approximately 50% and 5% of patients, respectively, with a severe phenotype. Large gene deletions are observed in approximately 5% of alleles from patients with severe haemophilia A. The remaining severe cases and all moderate and mild cases result from numerous point mutations and small insertions/deletions, which are de novo mutations in one-third of cases. Thus, molecular diagnosis of carrier status and prenatal diagnosis in families without intron 22 or 1 inversions is based on scanning techniques or gene sequencing. When the disease-causing mutation cannot be identified, molecular diagnosis is performed by linkage analysis of several DNA polymorphic markers linked to F8C. Given the clinical heterogeneity among haemophilic patients, many groups, including our own, have examined the relationships between prothrombotic gene variants and haemophilic phenotype to investigate whether prothrombotic gene variants modify clinical expression of the disease.

A total gastrectomy with omentectomy and resection of the distal oesophagus in a 69-year-old haemophilia A patient with high inhibitor of 128 Bethesda units is described. Surgery was successfully performed after infusion of 112 microg kg-1 bw of recombinant FVIIa. Ninety-two microg kg-1 were given thereafter at time intervals of 2 h until 12 h, then every 3 h until 24 h, and every 4 h until 48 h after surgery. Doses were gradually reduced in the following days and finally discontinued on day 28 after surgery. The complete treatment schedule required the administration of a total of 708 mg of recombinant FVIIa. Using this approach, we observed normal haemostasis, and there were no signs of excessive postoperative bleeding or wound haematoma. No clinical side-effects or evidence of systemic activation of coagulation occurred during the treatment. As judged from the clinical course of this major surgery, recombinant FVIIa appears to be highly efficacious and safe and should be used as first line treatment in high titre inhibitor patients with cross-reactivity to porcine factor VIII, undergoing surgery.

This study presents the final report of a long-term psychological assessment of men with haemophilia and HIV infection. The knowledge, emotional impact regarding HIV infection and prospective changes over time and the need for psychological support were evaluated. The study group comprised 118 men with haemophilia, 66 HIV seropositive and 52 seronegative, from the Haemophilia Centres in Bari, Florence, Milan and Naples. All subjects performed psychological tests (STAI: state and trait anxiety inventory; SDS: self-rating depression scale) and completed questionnaires to ascertain their knowledge and the emotional impact of AIDS. After enrollment (1992-93) the assessment was repeated twice over a 2-year period. A high percentage of subjects in both groups answered the questionnaire on knowledge correctly and, more specifically, all (100%) admitted knowing that sexual intercourse was a risk factor for HIV infection, adding that sexual partners of haemophiliacs with HIV should be regularly tested. The percentage, however, decreased for seropositives who admitted to always using a condom during sexual intercourse (86%) and for those who declared that partners were periodically tested for HIV (60%). The most important feature of the study is that, contrary to predicted expectations, seropositive and seronegative subjects presented the same degree of emotional involvement: there are no statistically significant differences in average scores between groups either on the anxiety or depression scales. Moreover, for certain aspects, seronegatives revealed greater emotional involvement: at baseline evaluation, they felt more fear and unhappiness with statistically significant differences compared to asymptomatics. Furthermore, seronegatives more than seropositives continue to feel reluctance towards infusion and avoid blood products after learning of AIDS. These results emphasize the importance of paying due attention to the emotional status of seronegatives. Their reluctance towards the use of blood products (despite present safety) is a very important issue for the possible consequences of treatment with the risk of worsening the clinical condition. In conclusion, we believe that counselling on HIV infection/AIDS needs to address every person with haemophilia regardless of HIV status.

Summary This article describes prenatal diagnosis (PND) of haemophilia B (HB) within the framework of Italian haemophilia centres and genetics laboratories. The study details the experience from six haemophilia genetic centres (three in the North, one in the Centre and two in the South of Italy) and summarizes the different techniques used to perform PND of HB during the last 15 years. To date, the Italian HB database includes 373 characterized unrelated patients and their genetic information has permitted the identification of 274 carriers of childbearing age. This database represents the main instrument for timely and precise PND. Sixty-six prenatal diagnoses were performed on 52 HB carriers whose average age at the time was 34 (ranging from 24 to 44 years). In 44 cases, genetic counselling for carrier status determination was performed before pregnancy, while eight were not studied prior to pregnancy. Foetal samples were obtained by chorionic villus sampling in 52 cases, by amniocentesis in 12 while two were diagnosed by analysis of free foetal DNA obtained from maternal peripheral blood. In 35 (53%) pregnancies the foetus was female. For 31 men (47%), haemophilia status was determined by analysis of previously determined informative markers or familial mutations (12 affected and 19 unaffected). There may be more than one laboratory involved in the PND diagnostic pathway (providing DNA extraction, karyotype analysis, gender determination, maternal contamination detection, molecular diagnosis and sequencing). Good communication between all the parties, coordinated by the haemophilia centre, is essential for a successful and rapid process.

Capri (NA).

Summary. Background: Inhibitor development is influenced by several factors and the type of factor VIII (FVIII) products may play a role. Objectives: In order to explore such a role, we designed a cohort study whose novelty resides in the classification of products not only according to the source of FVIII (plasmatic, pd, or recombinant, r) but also to their degree of purity (expressed as specific activity). Patients/Methods: Treatment data up to inhibitor development or 150 exposure days were collected in 377 patients with hemophilia A. Results: Inhibitors developed in 111 patients (29%; 96 high-responders, 25%). The cumulative incidence was progressively higher from patients treated with low/intermediate-purity pdFVIII compared with those treated with high-purity pd and rFVIII. The adjusted hazard ratio of inhibitor development was 4.9 with rFVIII and 2.0 with high-purity pdFVIII (95% CI, 2.9–8.3 and 1.1–4.0), taking as reference low/intermediate-purity pdFVIII. There was no difference in the frequency of inhibitor testing between treatment groups. Sensitivity analyses (in patients who never switched product type, previously untreated patients, those treated on-demand and those with high-risk F8 mutations) confirmed an increased inhibitor risk with rFVIII and high-purity pdFVIII. Conclusions: This study shows that the degree of purity of FVIII products influences inhibitor development independently from other risk factors, and emphasizes that differences exist within pdFVIII products.

Over the last few decades, clinical follow-up of patients with haemophilia has become more complex as a result of the introduction of new treatment strategies, the presence of comorbidities related to haemophilia or ageing, as well as the emergence of new tools to evaluate the medical and social consequences of haemophilia. This publication describes the parameters and information that should be documented and the tests, examinations and interventions required for optimal follow-up of a patient with haemophilia. In the absence of formal studies, the present recommendations have been established as result of a series of consensus meetings in the frame of the European Haemophilia Therapy Standardization Board (EHTSB). The following 11 domains were identified: Baseline information, Current status, Treatment, Inhibitor status, Bleeding, Joint status and pain, Comorbidities, Dental care, Physical activities, Social participation and Quality of life. For each domain, details are proposed for the relevant parameters to be captured and monitored as well as the relevant tools that facilitate data collection. Adopting these recommendations should help the individual care of patients and, even though this is not the primary objective of this article, it should also help at national and international level to shape a new approach to haemophilia by working towards a more standardized outcome assessment. Greater standardization should have implications for data collection, improvements in treatment evaluation and optimizing resources.