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Background: Gene therapy is designed to provide people with hemophilia B with a steady and elevated factor (F)IX activity, thereby strengthening protection and relieving the burden of frequent replacement therapy infusions. The European Medicines Agency has approved gene therapy for the severe and moderately severe forms of hemophilia B that uses the FIX-Padua variant (etranacogene dezaparvovec)., Objectives: The aim was to provide a document dedicated to hemophilia B gene therapy and give a comprehensive overview of the topic., Methods: An Italian group of experts in hemophilia carried out a narrative review of the literature and discussed during a virtual meeting several key aspects of the delivery of this treatment in Italy. The discussion covered the organizational model, the role of the multidisciplinary team, the laboratory surveillance, and the patient's journey, from the follow-up to the identification of safety issues and outcome measures., Results: This article highlights the need to follow the Hub and Spoke organizational model and sheds light on the role of each professional figure within the multidisciplinary teams to favor patient engagement, management, and retention. Moreover, this article stresses the need to perform laboratory tests for patient screening and follow-up and proposes a checklist to help patient identification. Finally, the needs of Italian hemophilia centers have been considered to ensure an efficient implementation of the care delivery model., Conclusion: It is crucial to ensure that centers are appropriately organized, equipped, and trained to adequately select patients, deliver the gene therapy, and perform follow-up., Competing Interests: Declaration of competing interests G.C. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, BIOVIIIx, CSL Behring, BioMarin, Sanofi, Novo Nordisk, Takeda, Kedrion, LFB, Grifols, Roche, Sobi, and uniQure and reports participation on data safety monitoring board or advisory board for Bayer, CSL Behring, BioMarin, Sanofi, Novo Nordisk, Takeda, Kedrion, LFB, Grifols, Pfizer, Roche, and uniQure. G.D.M. reports being a speaker or a member of a speaker bureau for BioMarin, Bayer, CSL Behring, Roche, Takeda, and Viatris Pharmaceuticals and consultant or ad hoc speaker/consultant for BioMarin, Bayer, Pfizer, Takeda, and Viatris Pharmaceuticals. P.S. reports being a speaker for Bayer, CSL Behring, Stago, uniQure, Werfen, and Pfizer. S.S. has acted as a consultant for CSL Behring, Amgen, Novartis, Novo Nordisk, Sobi, and Bayer. E.B. participated in advisory boards for Amgen, Novartis, CSL Behring, Bayer, Roche, and Sobi. V.L.M. is a member of the advisory board of Pfizer, CSL Behring, and BioMarin; is a speaker for Gore and Alfasigma; and received research grants from Gilead and travel grants from Sobi, Sanofi, and Takeda. A.L. has participated in speaker bureaus for BioMarin and CSL Behring. F.P. reports consulting for and being a member of advisory boards of CSL Behring, BioMarin, Roche, Sanofi, and Sobi and is a member of the speaker’s bureau or educational programs/symposia for Takeda/Spark. E.F.G. has participated in speaker bureaus and advisory boards for BioMarin, Sobi, and Roche e Novo Nordisk. A.C.M. declares that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A prolonged preoperatory aPTT in children is often the cause of a delay of scheduled surgeries and the repetition of multiple blood tests, with the consequent wasting of resources and significant discomfort for children and parents. The aim of this review is to analyze the situations in which an isolated prolongation of aPTT is found during preoperative evaluation in children, especially when it is due to the presence of antiphospholipid antibodies, providing the readers with the keys to interpret this situation and the possibility to correctly evaluate the hemorrhagic risk of a patient.

Introduction: Considering the advances in haemophilia management and treatment observed in the last decades, a new set of value-based outcome indicators is needed to assess the quality of care and the impact of these medical innovations., Aim: The Value-Based Healthcare in Haemophilia project aimed to define a set of clinical outcome indicators (COIs) and patient-reported outcome indicators (PROIs) to assess quality of care in haemophilia in high-income countries with a value-based approach to inform and guide the decision-making process., Methods: A Value-based healthcare approach based on the available literature, current guidelines and the involvement of a multidisciplinary group of experts was applied to generate a set of indicators to assess the quality of care of haemophilia., Results: A final list of three COIs and five PROIs was created and validated. The identified COIs focus on two domains: musculoskeletal health and function, and safety. The identified PROIs cover five domains: bleeding frequency, pain, mobility and physical activities, Health-Related Quality of Life and satisfaction. Finally, two composite outcomes, one based on COIs, and one based on PROIs, were proposed as synthetic outcome indicators of quality of care., Conclusion: The presented standard set of health outcome indicators provides the basis for harmonised longitudinal and cross-sectional monitoring and comparison. The implementation of this value-based approach would enable a more robust assessment of quality of care in haemophilia, within a framework of continuous treatment improvements with potential added value for patients. Moreover, proposed COIs and PROIs should be reviewed and updated routinely., (© 2024 John Wiley & Sons Ltd.)

The number of vascular centers performing endovascular repair of ascending aortic disease is constantly increasing. Accordingly to the guidelines, open surgical repair remains the gold standard for these pathologies. However, approximately one quarter of patients are deemed unfit for open surgery. In this study, we describe three cases of ascending thoracic endovascular aortic repair (TEVAR) performed at our center. All the patients were deemed unfit for open surgery by the aortic team. Two patients had an ascending aortic pseudoaneurysm, and the third had a focal type A aortic dissection. In two cases, we used two abdominal aortic cuffs deployed from zone 0B to zone 0C, with no need for supra-aortic trunk debranching. In one case, we performed a "reverse" extrathoracic debranching, and we deployed a thoracic endograft from zone 0B to zone 2. Complications included one minor stroke and one inguinal hematoma. In one patient with an infected pseudoaneurysm, we performed ascending TEVAR as a bridge strategy for open repair. This patient developed a type Ia endoleak; however, clinical stabilization and infection control were obtained, and he was able to undergo heart surgery successfully. He underwent a second reintervention to treat superior mesenteric embolic occlusion. At 2 years of follow-up, all three patients were alive. Our preliminary experience demonstrates the technical feasibility and clinical appropriateness of ascending TEVAR using standard, commercially available endografts. However, no consensus has been reached regarding some critical aspects, such as the development of a standardized technique or the efficacy of the currently available devices. The improvements in graft design and the adoption of the "aortic team" approach could help in the near future to standardize the procedure, establish appropriate indications, and ensure good clinical outcomes., Competing Interests: None., (© 2024 The Authors.)

Diagnosis of antiphospholipid syndrome (APS) requires the presence of a clinical criterion (thrombosis and/or pregnancy morbidity), combined with persistently circulating antiphospholipid antibodies (aPL). Lupus anticoagulant (LA) is one of the three laboratory parameters (the others being antibodies to either cardiolipin or β2-glycoprotein I) that defines this rare but potentially devastating condition. For the search for aCL and aβ2-GP-I, traditionally measured with immunological solid-phase assays (ELISA), several different assays and detection techniques are currently available, thus making these tests relatively reliable and widespread. On the other hand, LA detection is based on functional coagulation procedures that are characterized by poor standardization, difficulties in interpreting the results, and interference by several drugs commonly used in the clinical settings in which LA search is appropriate. This article aims to review the current state of the art and the challenges that clinicians and laboratories incur in the detection of LA.

Over the last three decades, the continuous evolution of recombinant factor VIII (rFVIII) concentrates for replacement treatment of hemophilia A, including recent extended half-life products, implies that patients may switch from one product to another, technologically more advanced, with the aim of improving treatment efficacy, safety, management and, ultimately, quality of life. In this scenario, the issues of bioequivalence of rFVIII products and the clinical implications of their interchangeability are keenly debated, in particular when economic reasons or purchasing systems influence product availability and choices. Although sharing the same Anatomical Therapeutic Chemical (ATC) level, rFVIII concentrates, as other biological products, show relevant differences in terms of molecular structure, source and manufacturing process, which make them unique products, recognized as new active substances by regulatory agencies. Moreover, data from clinical trials with both standard and extended half-life products clearly document the large inter-patient variability of pharmacokinetic profiles after administering the same dose of the same product; in cross-over evaluations, even when mean values are comparable, some patients show better patterns with one product or with the comparator one. Pharmacokinetic assessment thus reflects the response to a specific product in the individual patient, with his genetic determinants, only partially identified, affecting the behavior of exogenous FVIII. These concepts, consistent with the currently recommended approach of personalization of prophylaxis, are discussed in this position paper endorsed by the Italian Association of Hemophilia Centers (AICE), highlighting that ATC or other available classifications do not completely consider differences between drugs and innovations and that substitutions of rFVIII products will not invariably ensure the previously achieved clinical outcomes or generate benefits for all patients.

Background: Congenital factor XIII (FXIII) deficiency is a rare coagulation disorder characterized by muscular or mucocutaneous bleeding with life-threatening intracranial hemorrhages (ICHs), especially in cases with severe disease. The best treatment is the use of prophylactic plasma-derived or recombinant FXIII (rFXIII). Few data on the use of rFXIII in the real-world scenario are available. The main goal of this study was to assess the efficacy and safety of catridecacog (NovoThirteen ® ) in a population of patients with FXIII deficiency. Other objectives were to compare the different pharmacokinetic (PK) profiles of each patient and to use them to create a tailored prophylaxis regimen., Materials and Methods: We collected and analyzed all pharmacokinetic and clinical data in our registry of the patients with congenital FXIII deficiency treated with rFXIII at eleven Italian hemophilia centers. Data were collected from January 2019 to December 2020., Results: Overall, data on 20 patients with FXIII deficiency were collected, 16 of whom presented with severe disease. Pharmacokinetics was assessed in 18 cases before starting prophylaxis. Prophylaxis was subsequently started in these patients using a wide range of dosages (25.0-80.0 IU/kg; mean 33.8 IU/kg) and infusion intervals (3.0-8.0 weeks). During a mean follow up of 47 months, two minor bleeds and one ICH in a severe patient who had remained under on-demand treatment were reported., Discussion: Efficacy and safety of rFXIII were proven in all patients. The dosage and infusion timing for the treated patients sometimes differed to those reported in the MENTOR pivotal studies, thus underlying the importance of tailored management in a real-world scenario.

Activated partial thromboplastin time (aPTT) is a fundamental screening test for coagulation disturbances. An increased aPTT ratio is quite common in clinical practice. How the detection of prolonged activated aPTT with a normal prothrombin time is interpreted is therefore very important. In daily practice, the detection of this abnormality often leads to delayed surgery and emotional stress for patients and their families and may be associated with increased costs due to re-testing and coagulation factor assessment. An isolated, prolonged aPTT is seen in (a) patients with congenital or acquired deficiencies of specific coagulation factors, (b) patients receiving treatment with anticoagulants, mainly heparin, and (c) individuals/patients with circulating anticoagulants. We summarize here what may cause an isolated prolonged aPTT and evaluate the preanalytical interferences. The identification of the cause of an isolated prolonged aPTT is of the utmost importance in ensuring the correct diagnostic workup and therapeutic choices.

Introduction: Current treatment for haemophilia A involves factor VIII replacement or non-replacement (emicizumab) therapies, neither of which permanently normalise factor VIII levels. Gene therapy using adeno-associated viral (AAV) vectors is an emerging long-term treatment strategy for people with severe haemophilia A (PwSHA) that is likely to be available for clinical use in the near future., Aim: This article proposes practical guidelines for the assessment, treatment, and follow-up of potential PwSHA candidates for AAV-based gene therapy., Method: Using the Delphi method, a working group of Italian stakeholders with expertise in and knowledge of the care of adults with haemophilia A analysed literature for AAV-based gene therapy and drafted a list of statements that were circulated to a panel of Italian peers. During two rounds of voting, panel members voted on their agreement with each statement to reach a consensus., Results: The Delphi process yielded 40 statements regarding haemophilia A gene therapy, across five topics: (1) organisational model; (2) multidisciplinary team; (3) patient engagement; (4) laboratory surveillance; and (5) patient follow-up and gene therapy outcomes. The consensus was reached for all 40 statements, with the second round of voting needed for five statements., Conclusion: Use of the hub-and-spoke organisational model and multidisciplinary teams are expected to optimise patient selection for gene therapy, as well as the management of dosing and patient follow-up, patient engagement, laboratory surveillance, and patient expectations regarding outcomes. This approach should allow the benefits of AAV-based gene therapy for haemophilia A to be maximised., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Factor IX replacement therapy is used for treatment and prophylaxis of bleeding in haemophilia B. rIX-FP is an extended half-life albumin-fusion protein, which, in clinical studies, has demonstrated prolonged dosing intervals up to 21 days for routine prophylaxis, providing therapeutic benefit., Aims: To describe dosing frequency and consumption (primary endpoint), efficacy and safety of rIX-FP treatment during routine clinical practice in Italy., Methods: Patients with moderate/severe haemophilia B on prophylaxis with rIX-FP for ≥6 months, were enrolled in this observational study from October 2017 to February 2019 and followed-up for 2 years. Descriptive analysis included prospective and retrospective data (12 months prior to switching to rIX-FP)., Results: Data were collected from 59 male patients (median age 30.1 years) enrolled by 23 Italian centres. Of them, 50 were on prophylaxis during the entire observation period and completed the study. The infusion frequency changed from 2-3 times/week in 86.0% of patients with previous treatment, to less than once a week in 84.0% of patients treated with rIX-FP at the 2nd-year follow-up. The annual number of infusions decreased by about 70%, whereas the mean FIX activity trough level increased from 3.8% to 14.4% (mean > 10% in all the infusion regimens). Median Annualised Bleeding Rate of .0 was achieved across all prophylaxis regimens. Subjects with zero bleedings increased from 66.0% to 78.0% with rIX-FP., Conclusion: Treatment with rIX-FP reduced infusion frequency, while providing higher FIX trough levels with substantial benefit in terms of annualised bleeding rate and a good safety profile., (© 2022 CSL Behring S.p.A. Haemophilia published by John Wiley & Sons Ltd.)

Recombinant porcine factor VIII (rpFVIII) is indicated for treating bleeding episodes in acquired haemophilia A, but there are few data regarding laboratory methods to adequately monitor treatment. This study involving three Italian laboratories aimed to evaluate the analytical performance of different assays for measuring rpFVIII. Five spiked rpFVIII samples (0.5-1.5 IU/mL) were analysed on three days, in triplicate, with eleven combinations of reagents (Werfen, Boston, MA, USA: SynthasIL and SynthaFax for one-stage assay, Chromogenix Coamatic FVIII for chromogenic assay), FVIII depleted plasmas (with or without von Willebrand factor-VWF) and calibrators (HemosIL human calibrator plasma, porcine calibrator diluted in FVIII deficient plasma with or without VWF). The assays were performed on ACL TOP analysers (Werfen, Boston, MA, USA). Intra- and inter-assay and inter-laboratory Coefficient of Variation (CV%) were calculated together with percentage of recovery (% recovery) on the expected value. The results showed that the reagent combinations reaching satisfactory analytical performance are: SynthasIL/human calibrator/deficient plasma+VWF (total recovery 99.4%, inter-laboratory CV 4.04%), SynthasIL/porcine calibrator/deficient plasma+VWF (total recovery 111%, inter-laboratory CV 2.75%) and Chromogenic/ porcine calibrator/deficient plasma+VWF (total recovery 96.6%, inter-laboratory CV 8.32%). This study highlights that the use of porcine standard (when available) and FVIII deficient plasma with VWF should be recommended.

Objectives: The present review aims to summarize the state-of-the-art von Willebrand disease (VWD) treatment focusing on specific clinical settings (obstetrics, surgery, long-term prophylaxis and comorbidities) as well as on the use of a Von Willebrand factor (VWF) concentrate with low FVIII content., Methods: Literature research and case reports., Results and Conclusions: Considering that patients affected by VWD have an intact ability to synthesize FVIII, in order to avoid excessive levels of FVIII, a highly purified plasma VWF concentrate with low FVIII content could be particularly useful in those patients and clinical circumstances at high thrombotic risk as well as for long-term prophylaxis. When deciding the optimal therapeutic strategy, physicians should take into account both the patient's history and the differences among available concentrates according to the clinical situations requiring treatment., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2021. The Author(s).)

Background: 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., Materials and Methods: 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., Results: 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., Discussion: 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.

Background: Intracranial hemorrhage (ICH) is a highly serious event in patients with haemophilia (PWH) which leads to disability and in some cases to death. ICH occurs among all ages but is particularly frequent in newborns. Aim: The primary aim was to assess the incidence and mortality due to ICH in an Italian population of PWH. Secondary aims were to evaluate the risk factors for ICH, the role of prophylaxis, and the clinical management of patients presenting ICH. Methods: A retrospective-prospective registry was established in the network of the Italian Association of Haemophilia Centers to collect all ICHs in PWH from 2009 to 2019 reporting clinical features, treatments, and outcomes. Results: Forty-six ICHs were collected from 13 Centers. The ICHs occurred in 15 children (10 < 2 years), and in 31 adults, 45.2% of them with mild hemophilia. Overall, 60.9% patients had severe haemophilia (15/15 children). Overall ICH incidence (×1000 person/year) was 0.360 (0.270−0.480 95% CI), higher in children <2 years, 1.995 (1.110−3.442 95% CI). Only 7/46 patients, all with severe haemophilia, had received a prophylactic regimen before the ICH, none with mild. Inhibitors were present in 10.9% of patients. In adult PWHs 17/31 suffered from hypertension; 85.7% of the mild subjects and 29.4% of the moderate/severe ones (p < 0.05). ICH was spontaneous in the 69.6% with lower rate in children (46.7%). Surgery was required in 21/46 patients for cerebral hematoma evacuation. Treatment with coagulation factor concentrates for at least three weeks was needed in 76.7% of cases. ICH was fatal in 30.4% of the cases. Of the survivors, 50.0% became permanently disabled. Only one-third of adult patients received long term prophylaxis after the acute treatment. Conclusion: The results from our Registry confirm the still high incidence of ICH in infants <2 years and in adults, particularly in mild PWHs presenting hypertension and its unfavorable outcomes. The majority of PWHs were treated on-demand before ICH occurred, suggesting the important role of prophylaxis in preventing such life-threatening bleeding.

Background: Central venous catheters (CVCs) represent one of the main risk factors for venous thrombotic events (VTEs) in children., Methods: We studied the Italian Registry of Pediatric Thrombosis (RITI) with regard to systemic radiologically confirmed CVC-related VTEs (CVC-VTEs) occurred during 6.5 years in children aged 29 days to 18 years., Results: A total of 78 CVC-VTEs were included, which occurred in 76 patients (40/76, 53% males). CVC-VTEs comprised 67 non-cardiac VTEs (86%) and 11 intracardiac thrombotic events (ICTEs) (14%); the median age at onset was 19 and 17 months, respectively. The most frequent reason for CVC insertion was supportive therapy. The catheters were placed percutaneously in 85% of cases (56/66) and surgically in the remaining 15% (10/66). Peripherally inserted central catheters (PICCs) were used in 47% (31/66) cases, partially implanted catheters in 42% (28/66), non-implantable catheters in 7% (5/66), and totally implanted catheters (Port) in 2% (1/66). CVC-VTEs were symptomatic in 77% of cases (60/78), while in the remaining 23%, they were incidentally detected on the imaging performed for the underlying condition. The median time between CVC insertion and the onset of symptoms was 10 days in non-cardiac VTEs and 39 days in ICTEs. Doppler ultrasound was the diagnostic technique most frequently used. The venous compartment most frequently affected was the veins of the lower extremities (52%, 43/73). Anti-thrombotic treatment was administered in 96% of CVC-VTEs (75/78). About 2.6% (2/76) of patients experienced a second thrombotic event. At discharge, post-thrombotic syndrome was reported in 13.5% (5/37) events with available data, CVC replacement in 10.8% (4/47), and ischemic necrosis with toe finger amputation in 2.7% (1/37). Three patients died due to an underlying condition; no CVC-VTE-related deaths were reported., Conclusions: We have carried out a registry-based study on CVC-VTEs in the children in Italy, providing the data that may help improve the detection and management of this CVC-related complication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lasagni, Nosadini, Molinari, Saracco, Pelizza, Piersigilli, Putti, Gaffuri, Giordano, Lorenzoni, Francavilla, Trapani, Luciani, Suppiej, Tufano, Tormene, Martinato, Gregori, Sartori, Simioni and The Systemic Thromboses Working Group of the Italian Registry of Pediatric Thrombosis (RITI Registro Italiano Trombosi Infantili).)

Background: Regular factor XIII (FXIII) prophylaxis is standard treatment for congenital FXIII A-subunit deficiency (FXIII-A CD). Recombinant factor XIII-A 2 (rFXIII-A 2 ) was extensively evaluated in the mentor trials., Objective: To assess real-world safety and treatment effectiveness of rFXIII-A 2 prophylaxis from the mentor 6 trial., Patients/methods: mentor 6 was a noninterventional, postauthorization safety study investigating rFXIII-A 2 prophylaxis in FXIII-A CD. rFXIII-A 2 treatment was observed for 2 to 6 years per patient. The primary end point was documentation of adverse drug reactions (including anti-FXIII antibody development). Secondary end points were serious adverse events (SAEs), medical events of special interest (MESIs), and annualized bleeding rate (ABR)., Results: Among 30 patients (mean age, 25.5 years), there were 44 adverse events (AEs) (30 mild, 13 moderate, 1 severe). Eleven AEs were possibly/probably related to rFXIII-A 2 . Of four MESIs, two were unlikely related to rFXIII-A 2 (accidental overdose, deep vein thrombosis), and two were possibly/probably related (nonneutralizing anti-FXIII antibody, decreased therapeutic response). All 10 SAEs were unlikely related to rFXIII-A 2 . Over a follow-up of 75.4 patient-years, there were six treatment-requiring bleeds (all trauma-related with no spontaneous bleeds), giving a treatment-requiring ABR of 0.066; five bleeds were treated successfully with rFXIII-A 2 . Eight of nine minor surgeries performed during rFXIII-A 2 prophylaxis reported successful hemostatic outcomes (one missing evaluation)., Conclusions: These data confirm that rFXIII-A 2 prophylaxis is well tolerated as long-term care. There were no spontaneous bleeds, ABR was low, and rFXIII-A 2 successfully treated bleeds in patients receiving rFXIII-A 2 prophylaxis., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Regular treatment to prevent bleeding and consequent joint deterioration (prophylaxis) is the standard of care for persons with severe hemophilia A, traditionally based on intravenous infusions of the deficient clotting FVIII concentrates (CFCs). In recent years, extended half-life (EHL) CFCs and the non-replacement agent emicizumab, subcutaneously administered, have reduced the treatment burden., Methods: To compare and integrate the opinions on the different therapies available, eight hemophilia specialists were involved in drafting items of interest and relative statements through the Estimate-Talk-Estimate (ETE) method ("mini-Delphi"), in this way reaching consensus., Results: Eighteen items were identified, then harmonized to 10, and a statement was generated for each. These statements highlight the importance of personalized prophylaxis regimens. CFCs, particularly EHL products, seem more suitable for this, despite the challenging intravenous (i.v.) administration. Limited real-world experience, particularly in some clinical settings, and the lack of evidence on long-term safety and efficacy of non-replacement agents, require careful individual risk/benefit assessment and multidisciplinary data collection., Conclusions: The increased treatment options extend the opportunities of personalized prophylaxis, the mainstay of modern management of hemophilia. Close, long-term clinical and laboratory follow-up of patients using newer therapeutic approaches by specialized hemophilia treatment centers is needed.

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., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Circulating dysfunctional factor IX (FIX) might modulate distribution of infused FIX in hemophilia B (HB) patients. Recurrent substitutions at FIX activation sites (R191-R226, >300 patients) are associated with variable FIX activity and antigen (FIXag) levels., Objectives: To investigate the (1) expression of a complete panel of missense mutations at FIX activation sites and (2) contribution of F9 genotypes on the FIX pharmacokinetics (PK)., Methods: We checked FIX activity and antigen and activity assays in plasma and after recombinant expression of FIX variants and performed an analysis of infused FIX PK parameters in patients (n = 30), mostly enrolled in the F9 Genotype and PK HB Italian Study (GePKHIS; EudraCT ID2017-003902-42)., Results: The variable FIXag amounts and good relation between biosynthesis and activity of multiple R191 variants results in graded moderate-to-mild severity of the R191C>L>P>H substitutions. Recombinant expression may predict the absence in the HB mutation database of the benign R191Q/W/K and R226K substitutions. Equivalent changes at R191/R226 produced higher FIXag levels for R226Q/W/P substitutions, as also observed in p.R226W female carrier plasma. Pharmacokinetics analysis in patients suggested that infused FIX Alpha distribution and Beta elimination phases positively correlated with endogenous FIXag levels. Mean residence time was particularly prolonged (79.4 h, 95% confidence interval 44.3-114.5) in patients (n = 7) with the R191/R226 substitutions, which in regression analysis were independent predictors (β coefficient 0.699, P = .004) of Beta half-life, potentially prolonged by the increasing over time ratio between endogenous and infused FIX., Conclusions: FIX activity and antigen levels and specific features of the dysfunctional R191/R226 variants may exert pleiotropic effects both on HB patients' phenotypes and substitutive treatment., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: A shift from a standard to a personalized prophylaxis has been increasingly adopted in patients with severe haemophilia A (SHA). This approach has raised the likelihood of a significant variability in the prophylactic approaches and the relative Factor VIII (FVIII) consumptions. The aim of our study was to assess the treatment variability of SHA patients without inhibitors and on prophylaxis regimen in Italy., Material and Methods: Data reported in the National Registry of Congenital Coagulopathies (NRCC) were analysed to assess treatment distribution within SHA patients without inhibitors, focussing on FVIII consumption in 2017, associated with prophylaxis regimen. The analysis was stratified based on age groups and Italian regions to describe the variability of FVIII consumption in Italy., Results: In 2017, the Registry reported the therapeutic plans of 1068 SHA patients without inhibitors on prophylaxis. The mean (95% CI) individual consumption ranges from 123 127 IU (99 736-146 518) in the age group 0-6 years to 345 000 IU (336 000-354 000) in the age group >20 years. A significant FVIII consumption variability was identified within the adult population. Regions with less than 50 patients reported the higher variability in mean FVIII consumption per patient-year within the different age groups. Similar difference in FVIII consumption variability was reported also in the age groups comparing "low," "middle" and "high" patient volume regions., Discussion: A reliable estimation of FVIII consumption for patients' treatment is necessary to manage and plan the appropriate budget and keep treatment's costs affordable. However, without the implementation of a methodology aiming to assess the overall value produced by these FVIII consumptions, the scenario will keep driven by FVIII consumptions, its costs and the budget available. An effort by haemophilic community, haemophilia treatment centres and institutions is required to develop and share this cultural shift in improving haemophilia management and assessment., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Although the widespread use of factor VIII/IX replacement therapy has significantly reduced the severity of arthropathy in persons with haemophilia (PWH), some develop degenerative joint changes, associated with significant pain. The aim of this survey was to investigate the management and perception of pain among Italian physicians who treat PWH., Materials and Methods: Between September and October 2017, a questionnaire was distributed to 35 Italian haemophilia treatment centres (60 physicians)., Results: Fifty-three haemophilia specialists completed the survey. We found that there was good agreement (98.1%) on the need to investigate pain at each clinical visit, but there was heterogeneity in the opinions of haemophilia specialists with regards to the availability of validated guidelines (35.8%) and whether pain specialists should be a part of the comprehensive care team in daily clinical practice (58.5%). Haemophilia specialists also agreed pain should be evaluated using a rating scale validated in PWH (88.7%). Pain was mainly managed by the haemophilia specialists themselves, supported by a physiatrist and physiotherapist, while a pain specialist was only involved in 26.4% of cases. The combination of paracetamol with tramadol or codeine was the most common first-line treatment, while cyclo-oxygenase-2 inhibitors, non-steroidal anti-inflammatory drugs, and opioids were less commonly used., Discussion: There are some unmet needs in Italy regarding pain management for PWH and the management of pain in these patients by haemophilia specialists. There is a lack of evidence-based guidelines for these specialists to use, as well as a reluctance to involve pain specialists. The lack of spontaneous reporting of pain by PWH, despite using pain relief, highlights the need for clinicians to actively ask patients about any pain they may be experiencing.

Background: In 2016, a new recombinant B-domain deleted porcine FVIII (rpFVIII) was licensed in Italy for the treatment of acquired haemophilia A (AHA), but only a few cases of patients receiving this have been reported in the literature. Here we report the largest registry of the use of rpFVIII for the treatment of AHA. The objective of this retrospective study was to describe the efficacy and the safety of susoctocog-alfa for AHA., Material and Methods: We studied a population of nine patients, recruited in five Italian haemophilia centres presenting AHA, and treated with Obizur ® as first- or second-line therapy., Results: rpFVIII was used as a first-line therapy in one-third of the patients. The median delay between clinical onset and diagnosis was 16 days. Initial bolus of infused susoctocog-alfa was 100 IU/kg, lower than the recommended dose. The treatment was maintained for a median of four days. Only one patient with serious co-morbidities and recurrent infections was treated for 32 days. All patients reached a complete resolution of AHA, and no recurrences were reported. Two patients developed a low-titre inhibitor against rpFVIII, neither experienced any complications., Discussion: In our real world experience, susoctocog-alfa was proven to be an effective and safe therapeutic option for patients with AHA, also at a lower than recommended dosage. In our report, the appearance of low-titre inhibitors against rpFVIII, was not found to be clinically significant.

Emicizumab has been approved in several countries for regular prophylaxis in patients with congenital haemophilia A and FVIII inhibitors because it substantially reduces their bleeding risk and improves quality of life. However, although significantly less frequent, some breakthrough bleeds may still occur while on emicizumab, requiring treatment with bypassing or other haemostatic agents. Thrombotic complications have been reported with the associated use of activated prothrombin complex concentrates. In addition, when surgery/invasive procedures are needed while on emicizumab, their management requires multidisciplinary competences and direct supervision by experts in the use of this agent. Given this, and in order to expand the current knowledge on the use of emicizumab and concomitant haemostatic agents, and reduce the risk of complications in this setting, the Italian Association of Haemophilia Centres (AICE) here provides guidance on the management of breakthrough bleeds and surgery in emergency situations in patients with haemophilia A and inhibitors on emicizumab prophylaxis. This paper has been shared with other National Scientific Societies involved in the field.

Recent evidence demonstrated that weekly prophylaxis with subcutaneous bispecific antibody (emicizumab) has shown higher efficacy in adolescent and adults patients affected by haemophilia A (HA) with inhibitor, compared with patients treated on demand or on prophylaxis with bypassing agents (BPAs). However, no economic evaluations assessing the value and sustainability of emicizumab prophylaxis have been performed in Europe. This study assessed the cost-effectiveness of emicizumab prophylaxis compared with BPA prophylaxis and its possible budget impact from the Italian National Health Service (NHS) perspective. A Markov model and a budget impact model were developed to estimate the cost-effectiveness and budget impact of emicizumab prophylaxis in HA patients with inhibitors. The model was populated using treatment efficacy from clinical trials and key clinical, cost and epidemiological data retrieved through an extensive literature review. Compared with BPAs prophylaxis, emicizumab prophylaxis was found to be more effective (0.94 quality adjusted life-years) and cost saving (-€19.4/-€24.4 million per patient lifetime) in a cohort of 4-year-old patients with HA and inhibitors who failed immune tolerance induction. In the probabilistic sensitivity analysis, emicizumab prophylaxis had always 100% probability of being cost-effective at any threshold. Further, the use of emicizumab prophylaxis was associated to an overall budget reduction of €45.4 million in the next 3 years. In conclusion, the clinically effective emicizumab prophylaxis can be considered a cost-saving treatment for HA with inhibitor patients. Furthermore, emicizumab treatment is also associated to a significant reduction of the health care budget, making this new treatment a sustainable and convenient health care option for Italian NHS., Competing Interests: P.A.C. received a research grant from Shire Plc now part of Takeda and speaking honoraria from Pfizer and Roche; L.G.M. has received grants from MSD and Janssen, for studies not related to the submitted work, and honoraria from Bayer; A.C.M. received honoraria for acting as speaker or consultant from Bayer, CSL Behring, Kedrion, NovoNordisk, Pfizer, Shire-Takeda, SOBI; G.C. participated in Advisory Boards or acted as a speaker for Bayer, Shire/Takeda, CSL Behring, Sobi, Novo Nordisk, Roche, Werfen, Ablynx, Kedrion, Uniqure. He also received research grants directly to his institution from Pfizer, Sobi and CSL Behring. T.G., M.G., I.G. and S.C.S. has no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

: Anticoagulation in a neonate is a challenge and the availability of anticoagulant options is extremely limited. Here we describe the use of a direct thrombin inhibitor, bivalirudin, in a full-term neonate with symptomatic cerebral sinovenous thrombosis complicated by bilateral thalamic hemorrhagic stroke and intraventricular hemorrhage, who could not be effectively treated with sodium heparin due to heparin resistance (HR) and showed thrombosis regression after start of bivalirudin treatment, without worsening of the hemorrhage. While the use of bivalirudin in neonates has been previously described, the indication of cerebral sinovenous thrombosis and the setting of HR are unique.

Background: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents., Methods: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843., Findings: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events., Interpretation: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism., Funding: Bayer AG, Janssen Research and Development., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Data from the literature suggest that in patients with acute, complicated type B aortic dissection (cTBAD), initial successful treatment with thoracic endovascular aneurysm repair (TEVAR) is not necessarily associated with favorable remodeling of the dissected aorta during follow-up, and long-term results indicate that TEVAR failed to completely suppress false lumen patency. Sealing of all relevant distal reentries, infrarenal and/or iliac, seems to be the key issue to induce total false lumen thrombosis in abdominal aorta as well as the iliac arteries, especially in complicated patients presenting with malperfusion or complete true lumen collapse., Materials and Methods: Of the 34 consecutive patients diagnosed with cTBAD at our hospital from January 2015 to April 2018, 30 had complicated dissections receiving endovascular treatment according to the standard Provisional ExTension To Induce COmplete ATtachment (PETTICOAT) technique and were excluded from this study, whereas 4 patients with radiologic evidence of multiple reentry tears at detached lumbar arteries and iliac bifurcation with complete true lumen collapse and clinical evidence of malperfusion were treated with a modified PETTICOAT technique with distal extension of the aortic stent, balloon expansion of the stented true lumen, and use of the AFX bifurcated endograft system to preserve the natural aortic bifurcation and provide complete distal sealing of reentry tears., Results: Primary technical success was achieved in all patients. No postoperative deaths were observed, but 1 patient experienced an hemorrhagic shock on the second postoperative day. No patient suffered postoperative stroke, paraplegia, paraparesis, or acute renal failure., Conclusions: Using an abdominal aortic bifurcated endograft with PETTICOAT to treat acute cTBAD seems to be a feasible approach in high-risk patients to improve aortic remodeling. The AFX bifurcated endograft system meets the requirements of anatomical fixation and sealing of distal tears., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Vaccination against communicable diseases is crucial for disease prevention, but this practice poses challenges to healthcare professionals in patients with haemophilia. Poor knowledge of the vaccination requirements for these patients and safety concerns often result in vaccination delay or avoidance. In order to address this issue, a panel of 11 Italian haemophilia and immunization experts conducted a Delphi consensus process to identify the main concerns regarding the safe use of vaccines in patients with haemophilia. The consensus was based on a literature search of the available evidence, which was used by the experts to design 27 consensus statements. A group of clinicians then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree). The main issues identified by the expert panel included vaccination schedule for haemophilic patients; protocol and optimal route of vaccine administration; vaccination of haemophilic patients with antibodies inhibiting coagulation factor VIII (inhibitors); and vaccination and risk of inhibitor development. This manuscript discusses these controversial areas in detail supported by the available literature evidence and provides evidence- and consensus-based recommendations. Overall, participants agreed on most statements, except those addressing the potential role of vaccination in inhibitor formation. Participants agreed that patients with haemophilia should receive vaccinations according to the institutional schedule for individuals without bleeding disorders; however, vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk. Data also suggest vaccination timing does not need to take into consideration when the patient received factor VIII replacement., (© 2019 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Background: Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20 mg once-daily., Methods: EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20 mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0-18 years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3 months with the option to continue treatment in 3-month increments, up to a total of 12 months. However, based on most common current practice, children younger than 2 years with catheter-related thrombosis will have a main treatment period of 1 month with the option to prolong treatment in 1-month increments, up to a total of 3 months., Conclusions: EINSTEIN-Jr will compare previously established 20 mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials., Trial Registration: Clinicaltrials.gov NCT02234843, registered on 9 September 2014., Competing Interests: Study sponsors and investigators agreed to abide by Good Clinical Practice guidelines and under the guiding principles detailed in the Declaration of Helsinki, and in accordance with any applicable local law(s) and regulation(s). Documented approval from appropriate Independent Ethics Committees/Institutional Review Boards was obtained for all participating centers/countries prior to the start of the study, according to Good Clinical Practice, local laws, regulations and organizations. As a requirement for participation, informed consent will be asked from the parent(s)/legal guardian(s) and, if appropriate as determined by local regulation, age and individual child capability, child assent will be sought, according to country-specific regulations.Not applicable.AWAL, DK, AFP, IA, WTS, AM, and KT are employees of Bayer AG. CM has received consulting fees from Bayer and Bristol-Myers Squibb, and lecture fees from Bayer. GK has received research funding from Pfizer and receives consulting and lecture fees from Daichi Sankyo. MPM has received consulting fees from Bayer. AC has received consulting fees from Bayer, Daiichi Sankyo, and Pfizer/Bristol-Myers Squibb. ACM has received consulting fees from Bayer, CSL Behring, Kedrion, NovoNordisk, Pfizer, Shire, and SOBI. UNG has received consulting fees from Bayer, Boehringer, Octapharma, LFB, and SOBI. MG has received consulting fees from Bayer, Shionogi, Octapharma, Bristol-Myers Squibb Canada, and Daiichi Sankyo, and lecture fees from Pfizer, Alexion, and CSL Behring. SS has received consulting fees from Bayer. MHP has received consulting fees from Bayer, Pfizer, and Daiichi Sankyo. GY, VP, and PM declare no competing financial interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: The Italian Registry of Thrombosis in Children (RITI) was established by a multidisciplinary team with the aims of improving knowledge about neonatal and paediatric thrombotic events in Italy and providing a preliminary source of data for the future development of specific clinical trials and diagnostic-therapeutic protocols., Materials and Methods: We analysed the subset of RITI data concerning paediatric systemic venous thromboembolic events that occurred between January 2007 and June 2013., Results: Eighty-five deep venous thromboses and seven pulmonary emboli were registered in the RITI. A prevalence peak was observed in children aged 10 to 18 years and, unexpectedly, in children aged 1 to 5 years. A central venous line was the main risk factor (55% of venous thromboembolic events); surgery (not cardiac) (25%), concomitant infections (23%) and malignancy (22%) were the clinical conditions most often associated with the onset of venous thromboembolism. There was a diagnostic delay of more than 24 hours in 37% of the venous thromboembolic events. Doppler ultrasound was the most widely used test for the objective diagnosis of deep venous thrombosis (87%). Antithrombotic therapy was administered in 96% of venous thromboembolic events, mainly low molecular weight heparin (60%). In 2% of cases recurrences occurred, while post-thrombotic syndrome developed in 8.5% of cases., Discussion: Although the data from the RITI are largely in agreement with published data, peaks of prevalence of thrombosis, risk factors and objective tests used for the diagnosis showed some peculiarities which may deserve attention.

Thromboembolic disease is a complex disorder with a multifactorial aetiology and a severe outcome. In newborns and children it may be missed or diagnosed late, thus worsening the prognosis. The neonatal disease is different from the disorder affecting older children and adults. However, scant epidemiological data and few randomised clinical trials regarding paediatric patients are available, and treatment recommendations are largely based on adult guidelines. Younger patients then have several decades over which they will suffer from the complications of thrombosis and risk of a new thrombotic episode. Current knowledge about neonatal thromboembolic disease and its prevention is reviewed here along with maternal, foetal, neonatal, pharmacological, environmental, lifestyle and occupational contributing factors. Additional data are urgently needed to improve diagnostic and therapeutic strategies and patient outcomes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

In children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each child's first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0–6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8–28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5–10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors., Competing Interests: Conflict of Interest: All authors declare no competing conflicts of interest with respect to the content of the manuscript.

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on-demand-group, 8% (2/24) children with ICH died and 33% had long-term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non-frequent or no prophylaxis., (© 2017 John Wiley & Sons Ltd.)

Hemophilia is the most common of the severe bleeding disorders and if not properly managed since early infancy can lead to chronic disease and lifelong disabilities. However, it enjoys the most efficacious and safe treatment among the most prevalent monogenic disorders. Hemophilia should be considered in the neonatal period in the case of unusual bleeding or in the case of positive family history. Later, hemophilia should be suspected mainly in males because of abnormal bruising/bleeding or unusual bleeding following invasive procedures-for example, tonsillectomy or circumcision. Prophylactic treatment that is started early with clotting-factor concentrates has been shown to prevent hemophilic arthropathy and is, therefore, the gold standard of care for hemophilia A and B in most countries with adequate resources. Central venous access catheters and arterovenous fistulas play an important role in the management of hemophilia children requiring repeated and/or urgent administration of coagulation factor concentrates. During childhood and adolescence, personalized treatment strategies that suit the patient and his lifestyle are essential to ensure optimal outcomes. Physical activity is important and can contribute to better coordination, endurance, flexibility and strength. The present article focuses also on questions frequently posed to pediatric hematologists like vaccinations, day-care/school access and dental care., Competing Interests: The authors declare no conflict of interest.

Background: Ultrasound-guided (USG) cannulation of the brachiocephalic vein (BCV) is gaining worldwide consensus for central venous access in children. This study reports a 20-month experience with this approach in children., Methods: All patients who underwent percutaneous USG central venous catheter (CVC) positioning in the BCV between August 2013 and March 2015 have been included. Devices inserted during this period were open-ended, either single or double-lumen tunneled CVC. Our series was divided into three consecutive study periods in order to determine the relative incidence of repositioning and complications., Results: During the study period, a total of 95 patients underwent 109 CVC insertions in the BCV. The median length of CVC duration was 230 days for a total of 23,212 catheter days. No major intraoperative complications occurred. Overall rate of CVC-related postoperative complications requiring repositioning or precocious removal was 0.90 per 1,000 catheter days and involved 21 CVC (19%, 95% confidence interval 13-28). These included 18 dislodgments, two infections, and one malfunction. Double-lumen CVCs represented the only significant risk factor for complications (52% complications-three per 1,000 catheter days)., Conclusion: USG supraclavicular cannulation of the BCV represents a safe approach for central line placement in children. It proved to be versatile, as it can be used in premature infants as well as in adolescents. Provided it is adopted by operators experienced in USG cannulation, we strongly suggest to resort to this approach as a first-line choice in children undergoing tunnelled central line placement for long-lasting therapy., (© 2016 Wiley Periodicals, Inc.)

Objective: To evaluate clinical data and associated risk conditions of noncerebral systemic venous thromboembolism (VT), arterial thromboembolism (AT), and intracardiac thromboembolism (ICT) in neonates., Study Design: Data analysis of first systemic thromboembolism occurring in 75 live neonates (0-28 days), enrolled in the Italian Registry of Pediatric Thrombosis from neonatology centers between January 2007 and July 2013., Results: Among 75 events, 41 (55%) were VT, 22 (29%) AT, and 12 (16%) ICT; males represented 65%, and 71% were preterm. In 19 (25%), thromboembolism was diagnosed on the first day of life. In this "early onset" group, prenatal-associated risk conditions (maternal/placental disease) were reported in 70% and inherited thrombophilia in 33%. Postnatal risk factors were present in 73%; infections and central vascular catheters in 56% and 54% VT, respectively, and in 67% ICT vs 27% AT (<.05). Overall mortality rate was 15% and significant thromboembolism-related sequelae were reported in 16% of discharged patients., Conclusions: This report from the Registro Italiano Trombosi Infantili, although limited by representing an uncontrolled case series, can be used to develop future clinical trials on appropriate management and prevention of neonatal thrombosis, focusing on obstetrical surveillance and monitoring of critically ill neonates with vascular access. A thrombosis risk prediction rule specific for the neonatal population should be developed through prospective controlled studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Central venous catheters (CVC), used for the management of children with hemato-oncological disorders, are burdened by a significant incidence of mechanical, infective, or thrombotic complications. These complications favor an increasing risk in prolongation of hospitalization, extra costs of care, and sometimes severe life-threatening events. No guidelines for the management of CVC-related occlusion and CVC-related thrombosis are available for children. To this aim, members of the coagulation defects working group and the supportive therapy working group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) reviewed the pediatric and adult literature to propose the first recommendations for the management of CVC-related occlusion and CVC-related thrombosis in children with hemato-oncological disorders.

Background: 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., Materials and Methods: 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., Results: 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"., Discussion: 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.

Background: The clinical benefits of prophylaxis in patients with hemophilia are well-established and include the following: reduced bleeding episodes, prevention of joint damage, decreased inhibitor development, and improved health-related quality of life. However, the cost-effectiveness of prophylaxis is still not clear., Procedures: We reviewed the published hemophilia prophylaxis economic models focusing on utility assumptions., Results: We found six cost-utility studies that compared prophylaxis and on-demand regimens. These studies reported remarkably different results, using utility values based on different assumptions and data sources., Conclusions: We suggest that cooperation among key stakeholders (clinicians, patient organizations and health-care decision makers) as a means of collecting evidence-based and experiential data to represent both the utility and the quality of life changes for patients with Hemophilia A who are treated with prophylaxis or receive on-demand treatments may represent a winning strategy with which to resolve the outstanding issues related to health technology assessments in the care of patients with hemophilia., (© 2015 Wiley Periodicals, Inc.)