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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.

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.

Acquired haemophilia A (AHA) is a rare bleeding disorder due to autoantibodies to coagulation factor VIII that may be secondary to autoimmune diseases, cancer, drugs, pregnancy, infections, or be idiopathic. Recurrent bleeding, often severe, mostly in muscles and soft tissues, and isolated prolonged activated partial thromboplastin time (aPTT), in the absence of personal and family history of bleeding, are typical features that should raise the suspicion of AHA. Poor awareness of the disease results in diagnostic delays and inappropriate treatment.The Italian Association of Haemophilia Centres (AICE) developed consensus recommendations in cooperation with the Italian Society on Thrombosis and Haemostasis (SISET). The document was shared with scientific societies of specialist physicians, laboratory professionals and pharmacists to spread knowledge about AHA and promote appropriate diagnosis/treatment.Ready availability of the aPTT mixing test is crucial, although diagnostic confirmation and optimal management require prompt referral of patients to specialised centres with rapidly available diagnostic and therapeutic facilities. If immediate referral is unfeasible, treatment must be undertaken early, under guidance of specialised centres or based on shared protocols. Recommendations about diagnosis, general management and, in bleeding patients, haemostatic therapy using bypassing agents or replacement treatment, including the recently available recombinant porcine factor VIII, are provided, considering the different clinical settings and laboratory facilities.This consensus document aims to improve the overall healthcare pathways for AHA, harmonise the management and therapeutic approaches to newly diagnosed patients and reduce the still relevant complications and mortality in this setting.

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.

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.

This study aimed to identify the characteristics of patients with hemophilia B eligible for once-weekly treatment with Nonacog alfa. Methods: A survey was conducted in 14 Hemophilia (HCs) of Italy. These centers were given a questionnaire consisting of ten closed multiple-choice questions. The centers were asked: (a) the percentages of their hemophilia B (HB) patients undergoing replacement therapy, “On-demand”, or weekly prophylaxis, (b) the criteria guiding the monitoring of patients, the advantages according to the age of patients, and (c) the obstacles to prophylaxis. The percentage of patients receiving “On-demand” (OD) treatment or continuous prophylaxis (prophy) differed depending on patient age and the severity of the disease. Only 57% of HCs provided “On-demand” therapy to the mild HB patients, about 93% to moderate ones, of whom 43% on prophylaxis. About 78% of patients 65 years old. Many centers assigned a medium-high score to the baseline concentration of FIX level at diagnosis in all age groups. Most HCs attributed a medium-high score to type of genetic mutation in the younger age groups. As for socio-cultural barriers and quality of life, the majority of respondents gave a medium-high score in all age groups. For periodic monitoring of patients receiving continuous prophylaxis, 59% of the centers reported using clinical assessment. With regard to prophylaxis administration method, the majority of hemophiliacs were given infusions twice weekly, while as regards to the dose of FIX concentrate delivered, 50% of the centers reported administering prophylaxis once-weekly at a dose ranging from 5−100 IU/kg in 10−50% of HB patients. Thus, 93% of the centers reported using a dose of 25−50 IU/kg for twice-weekly prophylaxis in 6−100% of the patients. The majority of centers (86%) believe that, in a program of early primary prevention, once-weekly treatment with nonacog alfa may represent an alternative strategy to dose escalation. The results show that patients with mild hemophilia, with functional musculoskeletal status and difficulties with venous access, are candidates for once-weekly prophylaxis with nonacog alfa. For such patients, this regimen can improve treatment compliance and quality of life.

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.

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 inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein.

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.

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.

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.

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.

BACKGROUND: Patients with severe hemophilia A and factor VIII inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Effective strategies to prevent bleeding in such patients have not yet been established. METHODS: We enrolled patients with hemophilia A who were older than 2 years of age, had high-titer inhibitors, and used concentrates known as bypassing agents for bleeding in a prospective, randomized, crossover study comparing 6 months of anti-inhibitor coagulant complex (AICC), infused prophylactically at a target dose of 85 U per kilogram of body weight (±15%) on 3 nonconsecutive days per week, with 6 months of on-demand therapy (AICC at a target dose of 85 U per kilogram [±15%] used for bleeding episodes). The two treatment periods were separated by a 3-month washout period, during which patients received on-demand therapy for bleeding. The primary outcome was the number of bleeding episodes during each 6-month treatment period. RESULTS: Thirty-four patients underwent randomization; 26 patients completed both treatment periods and could be evaluated per protocol for the efficacy analysis. As compared with on-demand therapy, prophylaxis was associated with a 62% reduction in all bleeding episodes (P

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to quantitative and/or qualitative defects of von Willebrand factor (VWF). Despite the improved knowledge of the disease, detailed data on VWD types requiring specific treatments have not been reported thus far. To determine the number and types of VWD requiring therapy with desmopressin (DDAVP) and/or VWF/FVIII concentrates in Italy, a national registry on VWD (RENAWI) was organized. Only 16 of 48 centers included VWD in the RENAWI with diagnoses performed locally. Patients with uncertain results were retested by two expert laboratories using multimeric analysis and mutations of the VWF gene. A total of 1234 of 1529 (81%) cases satisfied the inclusion criteria and could be classified as VWD1 (63%), VWD2A (7%), VWD2B (6%), VWD2M (18%), VWD2N (1%), and VWD3 (5%). VWD types were also confirmed by DNA analyses and occur in young adults (83%), mainly in women (58%). Mucosal bleedings (32 to 57%) are more frequent than hematomas (13%) or hemarthrosis (6%). Most patients were exposed to an infusion trial with desmopressin (DDAVP) and found responsive with the following rates: VWD1 (69%), VWD2A (26%), VWD2M (29%), and VWD2N (71%). However, DDAVP was not always used to manage bleeding in all responsive patients and VWF/FVIII concentrates were given instead of or together with DDAVP in VWD1 (30%), VWD2A (84%), VWD2B (62%), VWD2M (63%), VWD2N (30%), and VWD3 (91%). Data of the RENAWI showed that correct VWD identification and classification might be difficult in many Italian centers. Therefore, evidence-based studies should be organized only in well-characterized patients tested by laboratories that are expert in the clinical, laboratory, and molecular markers of VWD.

Abstract 3494 Poster Board III-431 Background von Willebrand disease type 3 (VWD3) is due to virtually complete deficiency of the von Willebrand factor (VWF) and, for this reason, has been also described as “severe VWD”. Although rare (1-5 cases per million population), VWD3 is of major interest because of its severe clinical presentation, the need for replacement therapy with VWF/FVIII concentrates and the risk of occurrence of anti-VWF inhibitors after the infusion of VWF/FVIII concentrates. Aims and design of the study to determine the prevalence and determinants of bleedings requiring therapy with VWF/FVIII concentrates in VWD3 patients, data were collected from the Italian registry on Hemophilia and Allied Disorders organized on behalf of the Italian Association of Hemophilia Centers (AICE). The VWD3 patients included in the registry were then followed up for one year by six Italian Centers and prospective data on number, type and management of bleeding episodes were analyzed. Methods VWD3 patients were diagnosed when VWF antigen was undetectable and factor VIII (FVIII) levels were reduced in plasma. Bleeding severity score (BSS) was calculated at enrollment. Gene deletions and mutations were searched for in all available DNA. Bleeding-free survival was computed with the Kaplan-Meier method and a Cox's proportional hazard model was used to calculate the risk of bleeding (hazard ratio = HR) Results In the Italian registry, 105 VWD3 patients (5.7%) were identified among the 1850 VWD (Italian prevalence=1.75 per million). The entire cohort of VWD3 was characterized by the following demographic, clinical and laboratory parameters (median, range): gender (M/F)= 50/55; age=37 (3-65); BSS=18 (3-35); FVIII= 4 (2-18); anti-VWF inhibitors= 7 cases (6.7%) from 3 families. Molecular diagnosis was available in 65/105 cases with the following gene defects (pt-n): large deletion (7); small deletions and insertions (23); nonsense (9); splice site (8) and missense mutations (17). Mucosal bleedings (64%) were more frequent than hematomas and hemarthrosis (24%). At the time of the enrollment in the registry 95/105 (91%) VWD3 had been already exposed to VWF/FVIII concentrates because of bleeding and/or minor or major surgeries. In the prospective study, 52 VWD3 patients could be enrolled and 46 (88%) were treated in a year for 118 bleeding episodes and 27 minor or major surgeries. BSS>10 (6.8, 3.8-12.3) and FVIII 89% (BSS=5-10&FVIII>10U/dL); 64%(BSS>10&FVIII=5-10U/dL); 59% (BSS=5-10&FVIII10&FVIII Conclusions these retro/prospective studies performed for the first time in a relative large cohort of patients show that also VWD3 can be very heterogeneous. BSS & FVIII levels are good predictors of bleeding. Larger multicenter studies should be organized to identify possible additional modifiers influencing the risk of bleeding in VWD3. Disclosures: No relevant conflicts of interest to declare.

Pathophysiologic considerations as well as non-comparative clinical results suggest that very high purity concentrates may slow immunologic deterioration in human immunodeficiency virus (HIV)-infected hemophiliacs. In an attempt to evaluate this hypothesis, we prospectively compared CD4 cell counts, skin testing responses, and changes of the clinical status in 20 asymptomatic HIV-positive hemophiliacs, randomly assigned to continue the treatment with an intermediate purity concentrate or to receive a very high purity product, purified by immunoaffinity chromatography with monoclonal antibodies. In the group switched to the very high purity concentrate there was no significant change of the CD4 cell counts over the 96-week follow-up period, whereas in the group continued on the intermediate purity concentrate, a highly significant decline was detected (P less than .013). Furthermore, in the very high purity group, four of six anergic patients at entry acquired reactivity to skin testing. The results of this study clearly support the use of very high purity concentrates for the replacement therapy of HIV-infected hemophiliacs.

Immune tolerance induction (ITI) eradicates inhibitors in patients with hemophilia A. This study was designed to investigate the success rate of ITI in high-responding inhibitor patients with severe hemophilia A using recombinant factor VIII (rFVIII). Twenty-six patients received different ITI regimens until a normal recovery (66%) and half-life (6 h) of infused FVIII was achieved. In order to maximize the chance of success, the initiation of ITI was deferred in the majority of patients until the inhibitor declined to10 BU. Twenty-two patients (85%) had baseline inhibitor levels10 BU (median 2.3 BU) when ITI began. Within a median of 6 months, immune tolerance was achieved in 19 of 26 patients (73%) including 12/17 (70%) with intron 22 inversion, 5/7 (71%) with other null mutations and two with small deletion/insertions in the F8 gene. In conclusion, recombinant FVIII induces a high rate of immune tolerance even in carriers of null F8 mutations.

Summary. Aim: A multicenter randomized open-label crossover prospective trial was designed to compare the efficacy, safety, and cost of standard and high dosages of recombinant factor VIIa (rFVIIa) for home treatment of hemarthroses in hemophiliacs with inhibitors. Methods: Patients were instructed to treat, within 6 h from the onset of bleeding, four consecutive hemarthroses of ankles, knees, or elbows, either with the rFVIIa standard dose of 90 μg kg−1 (repeated as necessary every 3 h) or with a single high dose of 270 μg kg−1. Patients who did not achieve a clinical success within 9 h continued rFVIIa treatment with repeated standard doses. Response to treatment was assessed for up to 48 h by patients/caregivers, who reported on a Visual Analogue Scale (VAS) graded from 0 to 100 the improvement in symptoms and also rated the responses as effective, partially effective or ineffective. Success was defined a treatment course rated as effective and with a VAS score ≥70 and failure a treatment course rated as ineffective and VAS score ≤30, whereas treatment courses that did not fulfill these criteria were considered partial responses. Results: Twenty hemophiliacs with inhibitors were originally enrolled (median age: 27 years), 18 of them treated 32 hemarthroses assigned to the standard-dosage and 36 to the high-dosage regimen, during the study period of 18 months. Forty-eight hemarthroses (71%) occurred in target joints. Success rates for standard- and high-dosage regimens were similar: 31% and 25% at 9 h, 53% and 50% at 24 h, 66% and 64% at 48 h, the end point for outcome assessment. The median number of rFVIIa infusions needed to achieve a successful course was significantly greater for the standard-dosage (n = 3) than for the high-dosage regimen (n = 1), and the median amount of rFVIIa ultimately used per successful course was identical (270 μg kg−1). Conclusion: Our results indicate that a high-dosage regimen with rFVIIa for home treatment of hemarthroses is effective, safe, does not imply an increased consumption of rFVIIa and requires the infusion of a smaller number of rFVIIa doses. Its convenience is particularly relevant in cases with difficult venous access and in hemorrhages into target joints.

This case-control study investigated the interactions between genetic and environmental factors and inhibitor development in 108 children with haemophilia A exclusively treated with recombinant factor VIII (FVIII). Sixty patients with inhibitors were compared with 48 inhibitor-free controls. Family history of inhibitors and null mutations in the FVIII gene were more prevalent in cases than in controls (20% vs. 2%, P = 0.001 and 83% vs. 64%, P = 0.04, respectively). On the other hand, there was no difference between cases and controls for such putative risk factors of inhibitor development as amniocentesis/villocentesis, premature/caesarean birth, breast-feeding, treatment during infections/vaccinations, surgical procedures and central nervous system bleeding. A trend was found for an increased risk of inhibitor development in children first treated at a young age (

Background— The results of a number of studies in pigs and mice suggest that absence of von Willebrand factor (vWF) protects against the development of atherosclerosis. We studied whether patients with a complete deficiency of vWF (type 3 von Willebrand disease [vWD]) develop fewer atherosclerotic vessel wall changes than healthy controls. Methods and Results— This study included 47 individuals with type 3 vWD and 84 healthy controls. Early atherosclerotic changes were assessed by measuring the thickness of the intima-media in the carotid and femoral arteries by B-mode ultrasonography. Advanced atherosclerotic changes were quantified by summing the maximal thickness of atherosclerotic plaques in the carotid and femoral arteries and were expressed as a plaque score. Established risk factors were determined to adjust for possible differences between the groups. We found no substantial difference in intima-media thickness between vWD patients and controls (adjusted difference for carotid artery 0.007 mm, 95% CI −0.022 to 0.036 mm; femoral artery 0.069 mm, 95% CI −0.056 to 0.19 mm). Similar proportions of patients and controls had atherosclerotic plaques (19% and 17%, respectively). No difference was found in the plaque score between groups (adjusted difference −0.22 mm, 95% CI −0.69 to 0.26). Among vWD patients, we found no effect of treatment with vWF concentrates on intima-media thickness or plaque score. Conclusions— The results of this study indicate that vWF does not play a substantial role in human atherogenesis.

Hemophilia B (HB) is an X-linked recessive bleeding disorder caused by mutations that produce factor IX (FIX) deficiency. The incidence of HB is ∼1:30 000 live male births. The FIX gene spans ∼34 kb and contains eight exons. The disease results from a myriad of mutations, and because of the rapid turnover of FIX mutations, there is no common mutation pattern in any ethnic group (1). Carrier and prenatal diagnosis can be made by linkage analysis (1)(2), which is rapid and inexpensive but limited by noninformative families, recombinant events, and the high incidence of germline mutations (1). Denaturing gradient gel electrophoresis (3)(4) and direct gene sequencing (5)(6)(7)(8) have been used for the direct identification of FIX mutations. Denaturing reversed-phase HPLC (D-HPLC), which has been used to scan several disease genes, is more sensitive than other scanning procedures and less expensive than direct sequencing (9)(10)(11)(12)(13). In addition, the post-PCR analysis can be automated. We developed an original D-HPLC screening procedure for the whole FIX gene and analyzed a cohort of 18 unrelated HB patients from Southern Italy previously typed by direct sequencing. In all patients, diagnosis was confirmed by FIX assay (Table 1⇓ ). The study was approved by the institutional ethics committee. After obtaining informed consent, we collected blood samples by venipuncture at the time of sampling for routine molecular analyses and extracted the DNA with the “Nucleon” procedure (Amersham). Each DNA sample was amplified by PCR for all FIX exons and for the promoter region and then was analyzed by sequencing and by D-HPLC. FIX exons 2 to 7 were amplified using primers described elsewhere (5). Exon 1 and the upstream region of FIX (i.e., from the nucleotide −482), which …

Two cross-reacting material–positive (CRM+) factor VII (FVII) mutations, associated with similar reductions in coagulant activity (2.5%) but with mild to asymptomatic (Gly331Ser, c184 [in chymotrypsin numbering]) or severe (Gly283Ser, c140) hemorrhagic phenotypes, were investigated. The affected glycines belong to structurally conserved regions in the c184 through c193 and c140s activation domain loops, respectively. The natural mutants 331Ser-FVII and 283Ser-FVII were expressed, and in addition 331Ala-FVII and 283Ala-FVII were expressed because 3 functional serine-proteases bear alanine at these positions. The 331Ser-FVII, present in several asymptomatic subjects, showed detectable factor Xa generation activity in patient plasma (0.7% ± 0.2%) and in reconstituted system with the recombinant molecules (2.7% ± 1.1%). The reduced activity of recombinant 283Ala-FVII (7.2% ± 2.2%) indicates that the full function of FVII requires glycine at this position, and the undetectable activity of 283Ser-FVII suggests that the oxydrile group of Ser283 participates in causing severe CRM+ deficiency. Furthermore, in a plasma system with limiting thromboplastin concentration, 283Ser-FVII inhibited wild-type FVIIa activity in a dose-dependent manner.

Abstract 25 Background: Inhibitor development is influenced by several genetic and environmental factors and the type of factor VIII (FVIII) products may play a role. Methods: We designed a cohort study whose novelty resides in the classification of products not only according to the plasmatic (pdFVIII) or recombinant (rFVIII) source of FVIII but also to the degree of purity expressed as FVIII specific activity per mg of protein. The role of FVIII product as risk factor for inhibitor development was evaluated in a multivariate model adjusting for potential confounders (i.e. age at first FVIII exposure, intensive treatment and prophylaxis). Cumulative incidences of all and high-responding inhibitors were calculated for the whole cohort of 721 patients with severe and moderate hemophilia A followed-up in 3 Italian Hemophilia Centers. Detailed treatment data from the first FVIII infusion up to inhibitor development or 150 exposure days were available for 377 patients and in this group of patients risk factors for inhibitor development including the type of FVIII product and its degree of purity (i.e. low/intermediate-, high-purity pdFVIII and rFVIII) were analysed. Results: The overall cumulative incidence of inhibitors was 22% (n=160; 130 high-responders, 18%) and it was lower in patients first treated with pdFVIII (107/586, 18%) than in those treated with rFVIII (53/135, 39%). Similar results were obtained by evaluating only high-responding inhibitors and patients with severe hemophilia. 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 in patients first treated with rFVIII or high-purity pdFVIII than in those treated with low/intermediate-purity pdFVIII. In fact, in all the aforementioned subgroups by multivariate analysis the risk of inhibitor development was invariably 3- to 6-fold higher in patients first treated with rFVIII than in those first treated with pdFVIII, and similar results were obtained for both all inhibitors and high-responding inhibitors. 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 also within pdFVIII products. Disclosures: No relevant conflicts of interest to declare.

Abstract 720 Patients with congenital hemophilia and inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Anecdotal reports and small case series suggest that regular doses of anti-inhibitor coagulant complex (AICC; FEIBA VH) may be effective in preventing bleeding episodes in patients with hemophilia A and inhibitors. The Pro-FEIBA study is the first prospective controlled clinical trial to study the efficacy of AICC in bleed prevention. Study Population and Design: The study was conducted in hemophilia A patients >2 years with a history of high-titer inhibitors who were using bypassing therapy for the treatment of bleeding episodes. Subjects on or planning immune tolerance therapy were excluded as were patients with thrombocytopenia or other bleeding disorders. This randomized, crossover study compared 6 months of AICC prophylactically dosed at 85 U/kg ± 15% on 3 nonconsecutive days per week (Prophy period) to 6 months of on-demand therapy (OD period) (target dose for the treatment of bleeds: 85 U/kg ± 15%). The 2 study periods were separated by a 3-month washout, during which time patients used on-demand therapy for bleeding. Patients were randomized to initially enter either the 6-month Prophy period or the 6-month OD period. Each patient then crossed-over to the alternate study period after a 3-month wash-out. Results: Thirty-four subjects were randomized; 26 subjects completed both study periods and were deemed evaluable per protocol (PP) for efficacy analysis of the primary outcome to compare bleeds in each 6-month treatment period. Eight subjects did not complete the study (1 patient in the Prophy treatment arm and 1 patient in the post-prophylaxis washout period died of complications associated with underlying illness and bleeding, 1 patient experienced an allergic reaction to study drug, 1 patient was lost to follow-up, and 4 patients withdrew from study). All randomized subjects were evaluated for safety. In the PP group, mean patient age was 26.9 years (median: 24.7; range: 2.8–67.9). In the total randomized group, mean patient age was 27.1 years (median: 28.7; range: 2.8–67.9). Of the 26 subjects who completed the study PP, 14 were randomized to enter the Prophy period first and then crossed-over to the OD period, while 12 subjects were initially randomized to enter the OD period and then crossed-over to the Prophy period. For the PP analysis, total bleeds and joint bleeds requiring treatment during the 2 study periods were compared (p-value is for the Wilcoxon signed-rank test of difference between OD and Prophy periods). In addition, bleeds for the 6-month period prior to enrollment were recorded retrospectively on study entry. Efficacy: Both total bleeds and joint bleeds were significantly reduced during the Prophy period as compared with the OD period (p < .0001) Table 1. There was no difference in bleed event rates based on randomization sequence (ie, no carry-over effect was detected when the Prophy period preceded the OD period). Safety: A total of 38 serious adverse events (SAEs) occurred, none of which was thrombotic in nature. One SAE was deemed by the study safety monitor to be related to the study drug (an allergic reaction). Otherwise, treatment was safe and well tolerated. Conclusion: These results in patients with hemophilia A and inhibitors show that AICC, dosed at 85 IU/kg +/− 15% given on 3 non-consecutive days each week was associated with a 62% reduction in all bleeds and a 61% reduction in joint bleeds as compared with on-demand therapy. Disclosures: Leissinger: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: This is a report of a clinical trial using the Anti-Inhibitor Coagulant Complex, FEIBA, as prophylactic therapy to prevent bleeding in hemophilia patients with inhibitors. FEIBA is not currently licensed for use in prophylaxis in the US. Berntorp:Baxter: Consultancy, Honoraria, Research Funding. Negrier:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rocino:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Windyga:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gringeri:Baxter: Consultancy, Honoraria, Research Funding; NovoNordisk: Honoraria.

3500 Poster Board III-437 Aim This retrospective study evaluates the interactions of known determinants of the inhibitor risk in severe and moderate hemophiliacs followed-up at 3 Italian Hemophilia Centers. Methods clinical data up to inhibitor development or 150 exposure days (EDs) were collected in 393 patients with Factor VIII 3yrs | 16 | 31 | 1 | 1 | | rFVIII at 1st exposure | 46 | 23 | 2.4 (1.7-3.5) | 4.0 (1.8-9.1) | | Intensive treatment (≥ 150 IU/kg) | 22 | 9 | 2.3 (1.5-3.8) | 4.9 (1.7-14.1) | | Prophylaxis | 9 | 25 | 0.3 (0.2-0.6) | 0.05 (0.01-0.2) | | Switch of product class | 38 | 72 | 0.3 (0.2-0.5) | 1.0 (0.3-3.4) | | Surgery | 19 | 27 | 0.6 (0.4-1.0) | Not included | Disclosures: No relevant conflicts of interest to declare.

Backgrounds. Not pegilated liposomal doxorubicin (Myocet®) has a better pharmacokinetic profile with less myelosuppression, much lower gastroenterological and cardiological toxicity than conventional doxorubicin. In order to reduce toxicity of conventional doxorubicin, in our department from 2002 to 2007 we have treated patients with Multiple Myeloma (MM) and Non-Hodgkin’s Lymphoma (NHL) with therapeutical regimens replacing conventional anthracyclines with not pegilated liposomal doxorubicin. Methods. In our department, from 2002 to 2007, 35 patients (17M,18F) with a median age of 68.8±9.6(range 82–33) affected by Multiple Myeloma (MM) received one or more cycles according to chemiotherapic scheme: VCR 1mg iv at day 1 + Myocet® 25mg/sm iv at day 2 + CTX 100mg/sm os days 1–4 + PDN 60mg/sm os days 1–4. Diagnosis concerned patients with IgG Myeloma (n=26), IgA Myeloma (n=7), micromolecular Myeloma (n=1) and PL (n=1). 22 patients (16M,6F) with a median age of 63.6±9.6 (range 45–79) affected by NHL received chemoimmunotherapy COMP21-R (CTX, Myocet®, VCR and PDN plus Rituximab). Four patients were stage I, 7 stage II, 6 stage III and 5 stage IV. According to IPI score: 2 patients were low risk, 6 low-intermediate, 8 intermediate-high and 6 high risk. In all patients, chemoimmunotherapy induced cardiologic evaluation was made considering Left Ventricular Ejection Fraction (LVEF): cardiotoxicity was evaluated testing the null hypothesis that the LVEF delta is more negative than −4% of the baseline value before chemotherapy (which was felt to be a reasonable clinical threshold separating non-clinically-significant cardiac toxicity from clinically significant damage due to chemotherapy). Results. In MM patients evaluation of treatment was made for 31 patients: mean Monoclonal Component (MC) has been reduced from 3048.2±2296.9 to 2353,7±1912.4 and the one sided t-test on the variable delta resulted statistically significant (P = 0.038). Response of treatment was CR 43,3%, PR 23,3%, DP 16,7%, NR 16,7% but no statistically significant correlations were present with both the line of treatment and the diagnosis. For NHL evaluation was made in 20 patients: 17 (77.3%) obtained a Complete Remission (CR), 1 (4.5%) a Partial Remission (PR) and 2 (9.1%) Not Respond (NR) to therapy: no statistically significant correlations were present with both the line of treatment and the diagnosis. In all patients (21 NHL and 30MM, totally 51 subjects), Myocet® cardiotoxicity has been evaluated by LVEF assessment at baseline and monitored along the course of the treatment: baseline mean was 57.8±5.4% and slightly lowered to 55.6±5.2% at the end of treatment. For each sub-population and for the entire population a one-sided t-test was performed in order to determine whether therapy with not pegilated liposomal doxorubicin determines relatively low cardiotoxicity: the tests resulted significant (NHL: P = 0.022, MM: P = 0.0021, All: P = 0.00020), leading to reject the null hypothesis in favour of the alternative hypothesis that cardiotoxicity is actually less severe and that the decrement of LVEF is not as negative as −4%. Conclusion. Myocet® reduce cardiotoxicity and is effective in the treatment of MM and NHL patients.

Pegylated interferon (Peg-IFN) plus ribavirin is the standard treatment for patients with chronic hepatitis C. In a multicenter open trial, we assessed the efficacy and tolerability of this treatment in 78 HIV negative hemophiliacs (age: 20–64 years) with persistently high transaminase values. Sixty-four were naïve and 14 were relapsers to IFN monotherapy. Cirrhosis was clinically detected in 12 patients (15%). HCV genotype was 1 in 69%, 2a/c in 14%, 3a in 14% and 4 in 3%. Peg-IFN alpha-2b was given subcutaneously at doses of 1.5 mcg/Kg/week for 48 weeks in genotypes 1 and 4 and for 24 weeks in genotypes 2 and 3; oral ribavirin at 800–1200 mg/day based on body weight. Treatment was stopped in patients with polymerase chain reaction positive HCV-RNA at month 6. Results: 11 patients (14%) withdrew for side effects (4) or non-compliance (7). Neutropenia ( Conclusions: combination therapy with Peg-IFN plus ribavirin is the recommended therapeutic option for hemophiliacs with hepatitis C chronic infection. Relapsers to IFN monotherapy may benefit of re-treatment with Peg-IFN plus ribavirin achieving at least 20% SVR. Genotype 2 and 3 infection is the most significant predictor of SVR.

A multicenter randomized crossover trial was designed to compare efficacy, safety, feasibility and cost associated with standard- and high-dosages of rFVIIa for home treatment of hemarthroses in hemophiliacs with inhibitors. Enrolled patients were instructed to treat within 6 hours from the onset of bleeding 4 consecutive haemarthroses of ankles, knees or elbows either with the rFVIIa standard dose of 90 mcg/kg (repeated as necessary every 3 hours) or with a single high dose of 270 mcg/kg. Patients who did not achieve a success within 9 hours continued rFVIIa treatment with repeated standard doses. The response to treatment was assessed for up to 48 hours by patients/caregivers who reported on a visual analogic scale (VAS) graded from 0 to 100 the improvement in symptoms and also rated the response as effective, partially effective or ineffective. Success was defined a treatment rated as effective and VAS score ≥70 and failure a treatment rated as ineffective and VAS score ≤30, responses that did not fulfil these criteria being considered a partial response. Of 20 hemophiliacs with inhibitors enrolled (median age: 27 years), 18 treated 32 hemarthroses assigned to the standard- and 36 to the high-dose regimen during the study period of 18 months. Forty-eight hemarthroses (71%) occurred in target joints. Success rates for standard- and high-dose regimens were similar: 31% and 25% at 9 hours, 53% and 50% at 24 hours, 66% and 64% at 48 hours. Recurrence rates were identical (3%). The median number of rFVIIa boluses needed to achieve a successful course was 3 for the standard-dose and 1 for the high-dose regimen, and the median amount of rFVIIa used per successful course was identical (270 mcg/kg). Our results indicate that the use of a high-dose regimen with rFVIIa for home treatment of hemarthroses is effective, safe, does not imply an increased consumption of rFVIIa and requires the infusion of a smaller number of boluses. Its convenience is particularly relevant in cases with difficult venous access and in hemorrhages into target joints.

In a multicenter case-control study we investigated the impact of prenatal/perinatal events and early FVIII exposure on the inhibitor risk in hemophiliacs. Patients: 102 children (age:13–196 months) with hemophilia A (FVIII≤2%) exclusively treated with recombinant FVIII and evaluated for inhibitors every 3 months were included. Forty-seven patients who developed inhibitors at the median age of 26 months (4–80) after a median of 16 exposure days (ED, 5–150), 37 high-responders (6–500 BU/mL) and 10 low-responders (200 ED). Results: by univariate analysis, family history of inhibitors, intron 22 inversion and prophylaxis started after the first 20 ED were significantly associated with an increased risk of inhibitor development (OR 9.5, 95%CI 1.1–79.9; OR 2.7, 95%CI 1.1–6.6; OR 3.7, 95%CI 1.1–12.1, respectively). No statistically significant differences were found for variables such as villocentesis/amniocentesis, premature/caesarian birth, breast-feeding, surgery, central venous devices and FVIII infusions associated with infections/vaccinations. By multivariate analysis, the inhibitor risk was 2.8-folds (95%CI 1.1–7.3) in children with intron 22 inversion and 4.5-folds (95%CI 1.1–17.5) in patients who started prophylaxis after the first 20 ED. By univariate and multivariate analysis, there was not a linear trend in the inhibitor development according to the age at first FVIII exposure (≤6, 7–12, 13–18, 19–24, >24 months). Conclusions: this study showed that starting prophylaxis within the first 20 ED had a favourable impact on the inhibitor risk independently from the age at first FVIII exposure.

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.