Major Orthopaedic Surgery in Persons with Haemophilia A with and without Inhibitors Treated by Emicizumab: A Mid-Term, Large, and Successful Series at a Single Center.

Introduction: Patients with Haemophilia (PWH) need orthopaedic treatments and often they undergo surgery. Classically, PWH with inhibitors have to face such procedures earlier than other patients. Major orthopaedic surgery is not easy and complications are frequent. Emicizumab is the first monoclonal antibody introduced for haematological prophylaxis for PWH with inhibitors, achieving an efficacious haemostasis also in patients with severe haemophilia A with inhibitors, later demonstrated for PWH without inhibitors. A few years ago, emicizumab was also proposed for PWH undergoing surgery, as it supports excellent bleeding control. The literature on orthopaedic surgery using an emicizumab protocol is scarce: only isolated case reports with short-term follow-ups are available. Aim: The purpose of this study is the assessment of the mid-term outcomes of major orthopaedic surgery performed in a population of patients with and without inhibitors and an emicizumab regimen. Methods: We reviewed the records of 13 PWH (eight with high-titre inhibitors, five without) with a mean age of 54.6 years, undergoing 15 orthopaedic surgical procedures between 2017 and 2022: primary knee and hip arthroplasty, revision, pseudotumor excision, or amputation. Their prophylaxis consisted of the combination of emicizumab and boluses of rFVIIa (PWH with inhibitors) or rFVIII (PWH without inhibitors). The clinical parameters of evaluation were: VAS, Haemophilic Joint Health Score (HJHS), and standard radiologic studies. Follow-up was conducted at 1, 3, 6 months, and then yearly. The survival rate of all implants was also assessed. Results: The mean follow-up was 38.8 months (range: 12-65). All patients were successfully treated without complications during surgery. During the postoperative period, a patient affected by a septic complication two months after his pseudotumor excision underwent an above-the-knee amputation. All patients were regularly discharged to the rehabilitative ward, reporting satisfaction for pain reduction and improved joint and global function at the VAS and HJHS scores. No revisions or implant failures were recorded. Conclusions: A prophylaxis regimen with emicizumab and factor replacement in PWH with or without inhibitors undergoing major orthopaedic surgery ensures effective bleeding control and good postoperative clinical outcomes at mid-term follow-up, and may be routinely adopted in dedicated high-volume hospitals. This series is the most consistent to date reported at a single Haemophilia centre.

Better Communication for Better Management of Persons with Hemophilia: Results from a Patients'-Clinicians' Project to Address the New Therapeutic Landscape.

Applying the Delphi method, this study aims at characterizing the perceptions and needs of physicians, individuals with hemophilia, and their caregivers in relation to the management of routine visits during regular follow-ups. A single structured questionnaire, prepared by an advisory board, was administered to 139 participants, comprising hemophilia treaters, patients and caregivers, during the period from May to June 2023. Agreement (defined following the Delphi method as developed by RAND Corporation) was reached on several topics. The Principal Component Analysis methods identified the four most relevant areas where consensus was reached among the interviewees, underscoring the necessity for in-depth discussions during routine visits: (1) medical aspects related to symptoms, life-limitations, pain, etc.; (2) non-medical related aspects (ambitions, lifestyle, network, etc.); (3) logistical-organizational aspects (home-hospital distance, alternative modalities of communication); and (4) visit duration and telemedicine integration. The results of both the Delphi and Principal Component Analysis underline that the care of individuals with hemophilia extends beyond merely prescribing drugs or treatment regimens. Instead, it necessitates consideration of numerous variables from both therapeutic and non-therapeutic domains, all of which are deemed important for the holistic management of the individuals. As a result, these aspects are routinely discussed and addressed during visits.

Safe and Successful Surgical Outcome in Persons with Hemophilia A with and without Inhibitors Treated with Emicizumab: A Large, Single Center, Real-World Experience.

Emicizumab is a humanized recombinant bispecific antibody, bridging together activated factor IX (FIXa) and factor X (FX), thus mimicking the activity of FVIII in vivo. Emicizumab is designed for long-term prophylaxis in patients with severe hemophilia A with and without inhibitors. This approach provides constant protection, with significant reduction in bleeding rate and improved quality of life. However, protection provided by emicizumab is not absolute, and clotting factor concentrates (FVIII, rFVIIa, aPCC) may be necessary for post-traumatic bleeding or surgery, with a potential thrombotic risk or difficulty in preventing bleeding. Real world evidence is still scanty, especially for managing major surgery. In this study, 75 surgeries were managed in 28 patients (27 major procedures in 15 patients and 48 minor procedures in 20 patients. In 17 patients without inhibitors, 30 minor surgeries were carried out by using FVIII in 5, with only a bleeding event, which was successfully treated with FVIII concentrate. Six major surgeries were uneventfully performed with FVIII concentrate. Eleven PWHA and high-titer inhibitors underwent 39 surgical procedures (18 minor and 21 major surgeries). Minor surgeries were mostly performed without prophylaxis with rFVIIa, with only a single bleeding complication. All 21 major surgeries were covered with a homogeneous protocol using rFVIIa. In four instances, bleeding complications occurred, treated with rFVIIa. Of them, a single patient only failed to respond and died because of an uncontrollable bleeding from a large ruptured retroperitoneal pseudotumor. Surgery in patients with emicizumab can be safely carried out with the use of appropriate replacement therapy protocols.

Modulation of factor VIII pharmacokinetics by genetic components in factor VIII receptors.

INTRODUCTION: Gene variation in receptors for circulating factor VIII (FVIII) is candidate to explain the large inter-patient variability of infused FVIII pharmacokinetics (PK) in haemophilia A (HA). AIM: To compare in an Italian HA cohort (n = 26) the influence on FVIII PK of genetic components in four von Willebrand factor (VWF)/FVIII receptors. METHODS: Genotypes of low-density lipoprotein receptor (LDLR), asialoglycoprotein receptor minor subunit (ASGR2), family 4 member M (CLEC4M), stabilin2 (STAB2) and ABO blood-group, and VWF:Ag levels were included as independent variables in linear regression analyses of two-compartment model (TCM) - standard half-life (SHL) FVIII PK parameters. RESULTS: In the initial FVIII distribution phase, the STAB2 rs4981022 AA, ASGR2 rs2289645 TT and LDLR rs688 TT genotypes may contribute to increase Cmax , and prolong or shorten AlphaHL. In the elimination phase, a shorter BetaHL was associated with the CLEC4M rs868875 GG (beta-coefficient .366, p = .025) and ASGR2 rs2289645 TC (beta-coefficient .456, p = .006) genotypes, which also showed shorter mean residence time (MRT) than TT genotypes (p = .021). The alpha and beta phase effects were independent of ABO and VWF:Ag levels at baseline. The association of the LDLR rs2228671 genotypes with clearance was independent of ABO (beta-coefficient -.363, p = .035) but not of other receptors or VWF:Ag, which may point out multiple and competing interactions. CONCLUSIONS: With the limitation of the small number of HA patients, these observations highlight multiple genetic components acting in distinct phases of FVIII PK and contributing to explain FVIII PK variability. This analysis provides candidates for genotype-based, individual tailoring of FVIII substitutive treatment.

Hemostatic Abnormalities in Gaucher Disease: Mechanisms and Clinical Implications.

Gaucher disease (GD) is a rare inherited lysosomal metabolism disorder, characterized by an accumulation into lysosomes of reticuloendothelial cells, especially in the bone marrow, spleen, and liver of ß-glucosylceramide and glucosyl sphingosine, which is its deacylated product. Impaired storage is responsible for a chronic inflammatory state at the sites of accumulation and together represents the pathophysiological cause of GD. GD is a progressive, multi-organ chronic disorder. Type 1 GD is the most prevalent form, with heterogeneous multisystem involvement and different severity of symptoms at any age. Hematological involvement is consistent, and a bleeding tendency is frequent, particularly at diagnosis. Several coagulation and primary hemostasis abnormalities are observed in GD. Bleeding manifestations are rarely severe and usually mucocutaneous. Post-operative, delivery, and post-partum hemorrhages are also common. Thrombocytopenia, platelet function defects, and clotting abnormalities, alone or variably associated, contribute to increase the risk of bleeding in GD. Enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) are the two specific available treatments effective in improving typical hematological symptoms and abnormalities, including those of hemostasis. However, the use of medication to potentiate hemostasis may be also useful in defined clinical situations: recent starting of ERT/SRT, surgery, delivery, and life-threatening bleeding.

Orphan Drug Use in Patients With Rare Diseases: A Population-Based Cohort Study.

Background: Orphan drugs are used for the diagnosis, prevention and treatment of rare diseases that, in the European Union, are defined as disorders affecting no more than 5 persons in 10,000. So far, a total of around 800 orphan medicinal products have been approved by the European Medicines Agency, however the utilization profile of orphan drugs has yet to be explored. This study aimed at assessing the utilization profile of orphan drugs authorized for marketing by the Italian Medicines Agency using population-based data. Methods: A total of 21 orphan drugs used in outpatient settings, approved in the European Union before or during the 2008-2018 period and involving 15 rare diseases, were included in the study. The monitored population included patients with one of the conditions surveilled by the population-based Tuscany Registry of Rare Diseases and diagnosed between 2000-2018. A multi-database approach was applied, by linking data from the registry with information collected in drug prescriptions databases. The prevalence and intensity of use were estimated for the selected orphan drugs and other non-orphan medications, used to treat the same rare disease and for which a change in the prevalence of use was hypothesized after authorization of the orphan drug. Results: For some diseases (acquired aplastic anemia, tuberous sclerosis complex, most metabolic diseases) a low prevalence of orphan drugs use was observed (range between 1.1-12.5%). Conversely, orphan drugs were frequently used in hemophilia B, Wilson disease and idiopathic pulmonary fibrosis (maximum of 78.3, 47.6 and 41.8%, respectively). For hemophilia B and Leber's hereditary optic neuropathy, there are currently no other medications used in clinical practice in addition to orphan drugs. Six orphan drugs were used for the treatment of pulmonary arterial hypertension, appearing the elective therapy for this disease, albeit with different utilization profiles (range of prevalence 1.7-55.6%). Conclusion: To the best of our knowledge, this is the first study investigating the utilization profile of orphan drugs prescribed in a defined geographical area, and providing relevant information to monitor over time potential changes in the prevalence of these medications as well as in the health care decision making.

Combination of CLEC4M rs868875 G-Carriership and ABO O Genotypes May Predict Faster Decay of FVIII Infused in Hemophilia A Patients.

The C-type lectin CLEC4M binds and internalizes factor VIII (FVIII). Common CLEC4M variants have been associated with FVIII pharmacokinetic (PK) profiles in hemophilia A (HA) patients. The two-compartment PK analysis of plasma-derived (pd-) and full length recombinant FVIII concentrates was conducted in twenty-six patients (FVIII:C ≤ 2 IU/dL). F8, ABO blood-groups, and the CLEC4M rs868875A/G polymorphism were genotyped. CLEC4M genotype groups differed for the elimination rate constant K 1-0 (p < 0.001), half-life (K 1-0 HL), and the Beta rate constant. Patients treated with pd-FVIII also differed in the Alpha phase. In linear regression models, the contribution of the CLEC4M genotypes to FVIII PK parameters remained significant after correction for ABO, age, and VWF antigen levels at PK. Combined CLEC4M rs868875A/G and ABO genotypes displayed significant interaction (K 1-0, p = 0.014). Compared to other combined genotypes, the G-carriers/O genotypes showed half-reduced K 1-0 HL (p = 0.008), and faster FVIII clearance (mean 7.1 ± 2.2 mL/h/kg SE) than in the G-carriers/non-O (mean 2.4 ± 0.3 mL/h/kg SE), (p = 0.038). Comparison in HA patients recruited in several countries suggests that CLEC4M genotypes coherently influence infused FVIII half-life and clearance. Our analysis supports substantially faster FVIII decay associated with the rs868875 G-carrier/ABO O genotypes, which has potential implications for genetically tailored substitutive HA treatment.

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A.

BACKGROUND: The asialoglycoprotein receptor (ASGPR) binds with high affinity factor VIII (FVIII) through its N-linked oligosaccharides. However, its contribution to the wide inter-individual variation of infused FVIII pharmacokinetics (PK) in hemophilia A (HA) is unknown. OBJECTIVE: To investigate the variability in FVIII PK outcomes in relation to genetic variation in the ASGR2, encoding the ASGPR2 subunit. METHODS: Thirty-two HA patients with FVIII:C ≤2 IU/dL underwent 66 single-dose FVIII PK studies. PK parameters were evaluated in relation to ASGR2 5' untranslated region (5'UTR) polymorphisms, which were investigated by recombinant and white blood cell reverse transcription-polymerase chain reaction approaches. RESULTS: The 5'UTR polymorphisms determine a frequent and conserved haplotype (HT1) in a regulatory region. The HT1 homozygotes may differ in the amounts of alternatively spliced mRNA transcripts and thus ASGPR2 isoforms. Compared with the other ASGR2 genotypes, the c.-95TT homozygotes (n = 9), showed threefold longer Alpha HL (3.60 hours, 95% confidence interval: 1.44-5.76, p = 0.006), and the c.-95TC heterozygotes (n = 17) showed 25% shorter mean residence time (MRT; 18.5 hours, 15.0-22.0, p = 0.038) and 32% shorter Beta HL (13.5 hours, 10.9-16.0, p = 0.016). These differences were confirmed in patients (n = 27) undergoing PK studies (n = 54) with full-length FVIII only. In different linear regression models, the contribution of the ASGR2 genotypes remained significant after adjustment by ABO genotypes and von Willebrand factor (VWF) antigen levels, and explained 14% (MRT), 15 to 18% (Beta HL), and 22% (Alpha HL) of parameter variability. CONCLUSION: Infused FVIII distribution was modulated by frequent ASGR2 genotypes, independently from and together with ABO and VWF antigen levels, which has potential implications for genetically tailored substitutive treatment in HA.

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.

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.

Obstacles to Early Diagnosis and Treatment of Inherited von Willebrand Disease: Current Perspectives.

Von Willebrand disease (VWD), the most common inherited bleeding disorder, is highly heterogeneous, and its early diagnosis may be difficult, especially for mild cases and in qualitative von Willebrand factor (VWF) defects. Appropriate VWD diagnosis requires the combination of personal and/or family history of bleeding and abnormal VWF laboratory testing. The use of bleeding assessment tools has been helpful in standardizing bleeding history collection and quantification of bleeding symptoms to select patients who may benefit of further hemostatic testing. Type 1 and 3 VWD which represent quantitative VWD variants are relatively easy to diagnose. The diagnosis of type 2 VWD requires multiple assessments to evaluate the effects induced by the responsible abnormality on the heterogeneous functions of VWF. Sensitive and reproducible tests are needed to evaluate different VWF activities, starting from measuring VWF-platelet interaction. In the recent years, several increasingly sensitive, rapid and automated assays have been developed, but they are not widely available so far. Genetic testing for VWD diagnosis is not a common practice because VWF gene is very large and highly polymorphic and therefore it is used only in specific cases. It is evident that the early and correct VWD diagnosis allows optimal management of bleeding and situations at risk. Tranexamic acid, desmopressin, replacement therapy with plasma-derived concentrates with a variable content of VWF and FVIII, or the new recombinant VWF are the different therapeutic options available. Careful VWD classification guides treatment because desmopressin is widely used in type 1 while replacement therapy is the cornerstone of treatment for type 2 and 3 variants.

Joint replacement for the management of haemophilic arthropathy in patients with inhibitors: A long-term experience at a single Haemophilia centre.

INTRODUCTION: The association between haemophilia and the so-called 'inhibitors', alloantibodies against the infused factor able to neutralize its clotting activity, is a very rare condition. Those sporadic patients suffer of an even more severe arthropathy and performing primary or revision arthroplasty become truly challenging. Literature about this topic is scarce, consisting in small case series, high rates of complications and mid-term follow-ups. AIM: The purpose of this study is the assessment of the long-term outcomes of primary and revision arthroplasty performed in a population of patients with inhibitors, the more consistent to date reported at a single haemophilia centre. METHODS: We reviewed the records of 18 patients with inhibitors (26 procedures) between 1999 and 2017, divided in two groups. Group A [primary total Knee-Hip arthroplasty (TKA-THA)]: 13 patients underwent 19TKA and 2THA; and B (revision): 5 subjects underwent 3rTKA and 2rTHA. All patients received the same haematological prophylaxis (rFVIIa). Haemophilic Joint Health score and VAS, and X-rays were recorded pre- and postoperatively. The survival rate of all primary implants was assessed. RESULTS: The median follow-up was 12.2 years (3-21) for group A, 8.6 years (4-12) for B. Few complications have been reported; the overall survival rate was 94.7% at 15 years. All patients reported satisfaction, pain reduction and improved functional ability. CONCLUSION: Primary and revision TKA/THA in haemophilic subjects and inhibitors may be nowadays considered safe and effective if performed in dedicated multidisciplinary centres. The use of continuous infusion of rFVIIa showed an adequate haemostatic effect and low rate of complications. As expected, revisions are more prone to complications compared to primary arthroplasty.

Parkinson's disease in Gaucher disease patients: what's changing in the counseling and management of patients and their relatives?

BACKGROUND: How to address the counseling of lifetime risk of developing Parkinson's disease in patients with Gaucher disease and their family members carrying a single variant of the GBA1 gene is not yet clearly defined. In addition, there is no set way of managing Gaucher disease patients, taking into account the possibility that they may show features of Parkinson's disease. METHODS: Starting from an overview on what has recently changed in our knowledge on this issue and grouping the experiences of healthcare providers of Gaucher disease patients, we outline a path of counseling and management of Parkinson's disease risk in Gaucher disease patients and their relatives. CONCLUSION: The approach proposed here will help healthcare providers to communicate Parkinson's disease risk to their patients and will reduce the possibility of patients receiving inaccurate information from inadequate sources. Furthermore, this resource will help to empower healthcare providers to identify early signs and/or symptoms of Parkinson's disease and decide when to refer these patients to the neurologist for appropriate specific therapy and follow-up.

Low bone mass and hypovitaminosis D in haemophilia: A single-centre study in patients with severe and moderate haemophilia A and B.

INTRODUCTION: Haemophilia (H) is frequently associated with a multifactorial reduction in bone mineral density (BDM), but little is known about possible differences between HA and HB according to their severity. AIM: To evaluate the association between low bone mineral density (BMD), 25-hydroxyvitamin D [25(OH)D] concentrations and bone turnover markers in patients with HA and HB younger or older than 50 years. METHODS: In 78 patients <50 years and 33 patients >50 years with severe (S) or moderate (M) HA and HB, BMD was measured by dual-energy X-ray absorptiometry at femoral neck (FN) and lumbar spine and then correlated to annual bleeding rate (ABR), World Federation of Haemophilia orthopaedic joint scale (WFH score), 25(OH)D concentrations, parathyroid hormone (PTH), amino-terminal telopeptide of type 1 collagen (NTx), urinary pyridinolines, osteocalcin and bone-specific alkaline phosphatase. RESULTS: Overall, a high prevalence of hypovitaminosis D was diagnosed. In patients <50 years, low FN-BMD was significantly more frequent in HA than in HB, while PTH, pyridinolines, ABR and WFH score were associated with H type and severity. In patients >50 years, similarly low FN-BMD was observed in HA and HB, while ABR and WFH score were associated with H type and severity, being milder in HB. CONCLUSIONS: Low bone mass is a frequent comorbidity in haemophilic patients of all ages, apart from those with MHB. Clinical and laboratory assessments confirm a higher bone impairment and faster bone resorption in HA compared with HB. Looking at H type and severity, MHB seems to have a normal bone metabolism and a less severe disease.

Concomitant Use of rFVIIa and Emicizumab in People with Hemophilia A with Inhibitors: Current Perspectives and Emerging Clinical Evidence.

Emicizumab, a humanized, bi-specific, monoclonal antibody subcutaneously administered, mimicking the function of FVIIIa, represents a milestone in treatment of patients affected by hemophilia A complicated with inhibitors. The HAVEN 1 and 2 studies have clearly established its superiority compared to bypassing agents for routine prophylaxis in preventing or reducing bleeding episodes in adult and pediatric patients with inhibitors. However, its protection against bleeding is only partial, and concomitant use of a bypassing agent may be required with potential prothrombotic risk. The emicizumab Phase III trials (HAVEN 1, 2 and 4) have shown that the traditional bypassing agents, activated prothrombin complex concentrates or recombinant activated factor VII (rFVIIa), may be necessary for the treatment of breakthrough bleeds or surgery management. A post hoc analysis in particular has shown that the concomitant use of emicizumab and rFVIIa is safe and no thrombotic events have been described. The review describes the state of the art of the concomitant use of emicizumab and rFVIIa for treating acute bleeding and surgeries, its efficacy and safety and the lack of thrombotic events associated with this treatment modality. Data still derive mainly from HAVEN trials; however, the availability of emicizumab in clinical practice is progressively increasing the number of patients treated and no adverse events directly attributed to this agent have occurred. The availability of guidelines for the use and dosing of rFVIIa during emicizumab prophylaxis is useful in clinical practice for managing suspected or ongoing bleeding, emergency situations and elective invasive procedures. In the next years, careful prospective post-licensure surveillance to monitor safety of rFVIIa use during prophylaxis with emicizumab is highly recommended.

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.

High rate of sustained virological response with direct-acting antivirals in haemophiliacs with HCV infection: A multicenter study.

BACKGROUND AND AIMS: Chronic hepatitis C is the main co-morbidity in adult patients with haemophilia (PwH). It causes progressive liver damage leading to end-stage liver disease and/or hepatocellular carcinoma. Eradication of HCV was possible with interferon (IFN)-based regimens in the past and direct-acting antivirals (DAAs) more recently. PwH have been considered "difficult-to-treat" because of several bad predictors of response. The advent of DAAs has provided high rates of sustained virological response (SVR) despite bad prognostic factors. Here, we present the results of antiviral treatment with DAAs in PwH treated in 2 large Italian Hemophilia Treatment Centers. METHODS: PwH and chronic hepatitis C sustained by any HCV genotype were eligible for therapy with DAAs, including those with compensated cirrhosis, HIV infection and/or previous failure to IFN-based antiviral therapy. Patients received DAAs for 8-24 weeks according to existing guidelines. SVR was defined as persistent negative serum HCV-RNA at 12 weeks after treatment completion (SVR12). RESULTS: Between January 2015 and November 2018, 200 patients aged 21-84 years (median: 50.5) received DAAs. HCV genotype 1 was the most prevalent (158, 79%). Forty patients (20%) were HIV positive, 56 (28%) had cirrhosis and 91 (46%) previously failed interferon-based treatment. Ribavirin was used in 70 (35%). HCV-RNA was undetectable at week 4 in 124/192 (65%) and SVR12 was achieved in 193/195 (99%). No patient had serious side effects related to DAAs. CONCLUSIONS: DAAs were safe and highly effective in PwH irrespective of HIV status, stage of liver disease severity and/or previous failure to IFN-based therapy.

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.