The psychosocial impact of haemophilia from patients' and caregivers' point of view: The results of an Italian survey.

BACKGROUD: A huge amount of data about psychosocial issues of people with haemophilia (PwH) are available; however, these materials are fragmentary and largely outdated, failing to reflect the impact of current treatment strategies. AIM: Describing the influence of illness on psychosocial aspects of adult PwH (≥18 years) and caregivers of children with haemophilia (CPwH) without inhibitors, in Italy. METHODS: Surveys (for adult PwH, CPwH and haemophilia specialists) were developed by a multidisciplinary working group and conducted from November 2019 to June 2020. RESULTS: A total of 120 PwH without inhibitors and 79 CPwH completed the survey. Adult patients reported a significant impairment in many psychosocial aspects, including working activities, relations with family members and social relations. Caregivers generally reported better scores in all aspects of the survey. Mobility, Pain and Mental health domains of EQ-5D were the most frequently impaired in both patients and caregivers, reducing the perceived quality of life. Genetic counselling was an important issue, 53% of CPwH declaring unawareness of their carrier status, as well as the psychological support offered by the reference center, 67.0% of respondents reporting that no psychological support was provided at the time of diagnosis communication. CONCLUSION: This study provides information about PwH's and CPwH's point of view in the current scenario of continuous innovations in haemophilia treatment and management furthermore, updated insights on psychosocial problems faced by patients and caregivers are reported.

Managing Relevant Clinical Conditions of Hemophilia A/B Patients.

The Medical Directors of nine Italian Hemophilia Centers reviewed and discussed the key issues concerning the replacement therapy of hemophilia patients during a one-day consensus conference held in Rome one year ago. Particular attention was paid to the replacement therapy needed for surgery using continuous infusion (CI) versus bolus injection (BI) of standard and extended half-life Factor VIII (FVIII) concentrates in severe hemophilia A patients. Among the side effects, the risk of development of neutralizing antibodies (inhibitors) and thromboembolic complications was addressed. The specific needs of mild hemophilia A patients were described, as well as the usage of bypassing agents to treat patients with high-responding inhibitors. Young hemophilia A patients may take significant advantages from primary prophylaxis three times or twice weekly, even with standard half-life (SHL) rFVIII concentrates. Patients affected by severe hemophilia B probably have a less severe clinical phenotype than severe hemophilia A patients, and in about 30% of cases may undergo weekly prophylaxis with an rFIX SHL concentrate. The prevalence of missense mutations in 55% of severe hemophilia B patients allows the synthesis of a partially changed FIX molecule that can play some hemostatic role at the level of endothelial cells or the subendothelial matrix. The flow back of infused rFIX from the extravascular to the plasma compartment allows a very long half-life of about 30 h in some hemophilia B patients. Once weekly, prophylaxis can assure a superior quality of life in a large severe or moderate hemophilia B population. According to the Italian registry of surgery, hemophilia B patients undergo joint replacement by arthroplasty less frequently than hemophilia A patients. Finally, the relationships between FVIII/IX genotypes and the pharmacokinetics of clotting factor concentrates have been investigated.

Bioequivalence of recombinant factor VIII products: a position paper from the Italian Association of Hemophilia Centers.

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.

Acquired haemophilia A: Italian Consensus Recommendations on diagnosis, general management and treatment of bleeding.

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.

Haemophilia management and treatment: An Italian survey on patients', caregivers' and clinicians' point of view.

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.

Diagnosis and treatment of chronic synovitis in patients with haemophilia: consensus statements from the Italian Association of Haemophilia Centres.

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.

Italian experience with rVIII-single chain: a survey of patients with haemophilia A and their physicians.

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.

Promoting physical activity in people with haemophilia: the MEMO (Movement for persons with haEMOphilia) expert consensus project.

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

Predictors of inhibitor eradication by primary immune tolerance induction in severe haemophilia A with high responding inhibitors.

BACKGROUND: Immune tolerance induction (ITI) is the only proven strategy to eradicate factor VIII inhibitors in patients with haemophilia A (HA). AIM: To identify patients and treatment options with the highest chance of inhibitor eradication by primary ITI. PATIENTS AND METHODS: In the frame of the Italian ITI Registry, carried out from 1995 to 2015 (last follow-up 2018), 137 primary ITI courses in severe HA patients (90/137 with poor prognosis) were analysed for predictors of outcome (complete/partial response or failure). Sixty-six of them (48%) were prospectively evaluated. RESULTS: ITI was successful in 91/137 patients (66.4%) and 70 (51.1%) achieved complete response within 11 months (median). Historical peak titres ≤200 BU/ml (P = .033), inhibitor titres ≤5 BU/ml at ITI start (P = .001), peak titres ≤100 BU/ml during ITI (P < .001) and missense mutations and small insertions/deletions of FVIII gene (P = .027) predicted complete inhibitor eradication. A score that considers the cumulative number of these variables predicted complete response with positive predictive values up to .81 at ITI start and .91 during ITI, respectively. Patients who had no bleeding (OR, 3.45, 95% CI: 1.4-8.6) nor other adverse events (OR 2.6, 95%CI: 1.3-5.3) during ITI had higher chances of complete response. During the 120-month follow-up (median), 2/70 patients who had achieved complete response relapsed (2.9%). CONCLUSIONS: This Registry, with a centralized review of outcomes, homogeneous data collection (half of which prospective) and long-term follow-up, provides insights for optimizing ITI, with a rationale for further studies in the currently evolving scenario of inhibitor management in HA patients.

Improving assessment and management of pain in hemophilia: an Italian Delphi consensus statement.

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.

Pain assessment and management in Italian Haemophilia Centres.

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.

Management of patients with severe haemophilia a without inhibitors on prophylaxis with emicizumab: AICE recommendations with focus on emergency in collaboration with SIBioC, SIMEU, SIMEUP, SIPMeL and SISET.

INTRODUCTION: The factor VIII (FVIII)-mimetic bispecific monoclonal antibody, emicizumab, previously approved for prophylaxis in haemophilia A with inhibitors, has been recently licensed in several countries also in patients with severe haemophilia A (PWSHA) without inhibitors. The introduction of this innovative agent requires the development of specific pathways at Haemophilia Treatment Centres (HTC), particularly regarding laboratory testing and treatment of breakthrough bleeds and invasive procedures/surgeries, even more critical when patients are managed by non-specialist professionals. Limited literature data and clinical experience in PWSHA without inhibitors on emicizumab are currently available. AIM: To promote awareness and overcome these challenges, the Italian Association of Haemophilia Centres (AICE) issued a guidance on the management of PWSHA without inhibitors on emicizumab prophylaxis, focused on emergency and shared with other National Scientific Societies in the field. METHODS: The document, drafted by an AICE expert panel and approved through online consultation, was further revised by a multidisciplinary working group, including members of 5 haemostasis, laboratory and emergency scientific societies. The final version was approved by the Council of each society. RESULTS: General recommendations about use of FVIII concentrates for the treatment of bleeding or haemostatic coverage of invasive procedures/surgeries and laboratory monitoring in PWSHA without inhibitors on emicizumab are provided. Specific issues of the management in the emergency room are focused, highlighting the need for direct involvement or formalized supervision by specialist HTC physicians. CONCLUSIONS: This guidance provides a reference pathway to be implemented in the different healthcare organizations, especially for the challenging emergency management in this setting.

Perceived well-being and mental health in haemophilia.

The investigation of mental health among persons with haemophilia is mostly focused on negative and disease-related indicators. Literature however shows that psychosocial resources and optimal daily functioning can co-exist with chronic disease. The Dual Continua Model operationalizes positive mental health as 'flourishing', a condition comprising emotional, psychological, and social well-being dimensions. In the present study physical and mental health were comparatively assessed through positive and negative indicators in adults with haemophilia and a control group. Participants included 84 Italian persons with severe haemophilia (Mage = 43.44; SDage = 13.04) and 164 adults without history of chronic illness (Mage = 40.98; SDage = 12.26), who completed the Short Form Health Survey, the Positive and Negative Affect Schedule, and the Mental Health Continuum Short Form. MANOVA and post-hoc t-tests provided evidence of worse general health, lower negative affect and higher psychological well-being among participants with haemophilia compared with the control group. Moreover, the percentage of flourishing individuals was higher among participants with haemophilia. Results support previous evidence suggesting that a chronic disease does not prevent mental well-being attainment. The identification of assets and strengths allowing people with haemophilia to flourish can be fruitfully used to design resource-centered interventions.

Physical activity improved by adherence to prophylaxis in an Italian population of children, adolescents and adults with severe haemophilia A: the SHAPE Study.

BACKGROUND: Physical activity in people with haemophilia (PWH) reduces the development of severe arthropathy, but it must be performed after regular, proper prophylaxis. Strict adherence to treatment is crucial to achieving effectiveness and established outcomes. The primary aim of this study was to collect prospective data on adherence to prophylaxis for over 36 months. A secondary aim was to verify whether adherence correlates with physical activity. MATERIALS AND METHODS: Italian patients with severe haemophilia A treated on prophylaxis with octocog alfa were included in the study. Physical findings were assessed by the Haemophilia and Exercise Project (HEP)-Test-Q and the Early Prophylaxis Immunologic Challenge (EPIC)-Norfolk Physical Activity Questionnaire; orthopaedic status was assessed by the Hemophilia Joint Health Score (HJHS). Adherence was measured as percentage of empty vials returned with respect to the prescribed amount. RESULTS: Forty-two PWH were enrolled: 31% children, 21.4% adolescents, and 47.6% adults. Type, frequency and impact of physical activities differed among the three groups. The HEP-Test-Q showed the highest impairments in the domains "endurance" and "strength/co-ordination". Eight percent of patients were classified as adherent to prophylaxis. Among them, 50% had at least one bleeding episode in the year before enrolment; this percentage dropped during the three years of the study. While remaining stable in the "non-adherent" group, the HJHS score decreased in the "adherent" patients. The mean number of school/work days lost was lower in adherent patients (from 3.4±6.8 to 0.2±0.9) than in non-adherent ones. DISCUSSION: PWH with better orthopaedic scores reported better physical performance. Adherence to long-term prophylaxis proved to be high and correlated with a reduction in bleeds, target joints, school/work days lost, and with a performance improvement in endurance sports activities over time.

Emergency management in patients with haemophilia A and inhibitors on prophylaxis with emicizumab: AICE practical guidance in collaboration with SIBioC, SIMEU, SIMEUP, SIPMeL and SISET.

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.

Immune tolerance induction with moroctocog-alpha (Refacto/Refacto AF) in a population of Italian haemophilia A patients with high-titre inhibitors: Data from REF.IT Registry.

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