Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment.

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.

Clot lysis phenotype and response to recombinant factor VIIa in plasma of haemophilia A inhibitor patients.

Recombinant activated factor VII (rFVIIa) is a haemostatic agent that is used for the treatment of haemophilia A patients with inhibitors. However, clinical response to rFVIIa is variable and unpredictable with currently available assays. We investigated the anti-fibrinolytic effects of rFVIIa in relation to thrombin generation (TG) and other haemostatic parameters in haemophilia A patients with inhibitors. After addition of rFVIIa to plasma, the clot-lysis assay, TF-dependent TG, TF-independent TG and parameters involved in coagulation, anticoagulation and fibrinolysis were assessed. The clot-lysis test distinguished two groups of patients: a group with a normal and a group with impaired anti-fibrinolytic response to rFVIIa. Our results showed a dose-dependent increase in TF-dependent TG and TF-independent TG in all individuals. There was a significant difference in TF-independent TG parameters between the normal and impaired response groups. In addition, there was a difference between the normal and impaired response group in prothrombin time, which could be explained by significantly higher levels of coagulation factors in the normal response group, and soluble thrombomodulin. In conclusion, we observed different in vitro responses following rFVIIa addition in plasma of patients with haemophilia A and inhibitors, which could be partially attributed to levels of procoagulant proteins and soluble thrombomodulin.

Cost analysis of extended half-life recombinant factor IX products in the treatment of haemophilia B in Italy: an update.

Haemophilia B (HB) is a rare disease which may lead to chronic disabling arthropathy, resulting in a significant clinical, social and economic impact. In recent years, new extended half-life (EHL) factor IX concentrates produced by recombinant technology (rFIX) have been developed. They have shown significantly prolonged half-life as compared to other rFIX products and improved bleeding control when used as prophylaxis. To date, EHL rFIX products reimbursed in Italy are a recombinant coagulation factor IX produced with Fc technology (rFIXFc) and a recombinant fusion protein containing rFIX fused with recombinant albumin (rIX-FP). The results of extension studies with injection intervals with a median of almost every 14 days for the complete individualized interval prophylaxis (IP) group on rFIXFc and 21 days for a selected subgroup of patients on rIX-FP have recently been published. The aim of this analysis was to estimate the cost of prophylactic treatment with rFIXFc and rIX-FP in adult patients, in the light of new clinical evidence and current average prices in Italy. The cost of therapy was estimated on the basis of the results of extension studies, the average prices reported in regional drug tenders and assuming an average patient weight of 70 kg. The analysis estimated a cost per patient/year between €224,407 and €230,355 for rFIXFc and between €242,259 and €368,587 for rIX-FP. The sensitivity analysis confirmed the robustness of the results. The use of rFIXFc over rIX-FP proves to be the least expensive choice for the treatment of HB in Italy.

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.

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.

Budget impact analysis of extended half-life recombinant factor IX (rFIXFc) in the treatment of haemophilia B.

Introduction: Prophylaxis with factor IX (FIX) concentrates, produced by recombinant DNA technology (rFIX) or human plasma-derived concentrates, is the treatment of choice for haemophilia B (HB); rFIX covalently fused to the Fc domain of human immunoglobulin G1 (rFIXFc) allows for prophylaxis/treatment with one infusion every 7-14 days. The purpose of this study is to quantify the financial impact of prophylaxis with rFIXFc vs. other approved rFIX and reimbursed for treatment of HB in Italy. Methods: The number of patients was estimated according to Italian epidemiological data and use of rFIX. Dose and frequency of administration used for weekly prophylaxis were those recommended in the Summary of Product Characteristics (SPC), while clinical trials and literature data were used to calculate bleeding rates and management. Drug costs were calculated using regional ex-factory net prices. In the model, a reference scenario (Reference) vs. an alternative scenario (Alternative) were created to account for introduction of rFIXFc, estimating an increasing trend of the market share of rFIXFc in a 3-year timeframe. The analysis was developed in the perspective of the National Health Service and included healthcare costs related to rFIX for prophylaxis and resolution of bleeding events. Results: The model estimated an overall cumulative expenditure (years 1-3) of €209,453,646 for the Reference and €207,465,568 for Alternative scenarios, with calculated cumulative savings of €1,988,068. Conclusions: The increasing use of rFIXFc as a substitute for other rFIX concentrates in the treatment of HB can represent a financially viable choice for the Italian National Health Service while ensuring effective control of bleeding.

Thrombin activatable fibrinolysis inhibitor pathway alterations correlate with bleeding phenotype in patients with severe hemophilia A.

BACKGROUND: Patients with severe hemophilia A display varied bleeding phenotypes despite similar factor VIII (FVIII) activity levels. OBJECTIVE: We investigated different thrombin activatable fibrinolysis inhibitor (TAFI)-related variables in patients with severe hemophilia A and their possible correlation with bleeding tendency. PATIENTS/METHODS: Sixty-one patients with severe hemophilia A (FVIII:C <1%], treated on demand, were included. Patients were categorized as mild, moderate, and severe bleeders according to number of bleeds per year (≤2, 3-24, ≥25, respectively). Thirty healthy males served as controls. Clot lysis time was assessed by turbidimetric assay, TAFI activation by two-stage functional assay, and response to TAFIa as the prolongation of fibrinolysis time upon addition of purified TAFIa. Circulating levels of activated TAFI (TAFIa/ai) were measured by specific enzyme-linked immunosorbent assay. RESULTS: As compared to controls, hemophilic patients displayed shorter lysis time, less TAFIa generation, and reduced response to TAFIa, but similar TAFIa/ai levels. Clot lysis time was similar in mild, moderate, and severe bleeders, whereas TAFIa generation and response to TAFIa decreased with the increase in bleeding tendency; moreover, circulating TAFIa/ai levels were highest in severe bleeders. Patients with markedly impaired TAFIa generation or TAFIa response (below median) displayed 3-fold to 4-fold higher bleeding rate and factor consumption than patients whose TAFI-related values approached the control ones. CONCLUSION: The TAFI pathway impairment correlates with bleeding phenotype in severe hemophilia and may represent a promising tool to stratify the bleeding risk.

Increased VEGF levels in a case of papillary tumor of the pineal region with intracranial hemorrhage: a potential surrogate indicator of tumor angiogenesis and aggressiveness?

Pineal tumors are rare, about 1% of all intracranial tumors. At variance with pineocytomas, usually characterized by a good prognosis, papillary tumors behave more aggressively. Owing to their rarity, little is known about their biology and clinical behavior, moreover conflicting data on prognosis have been reported. Here we present an unusual case of papillary neuroepithelial tumor of the pineal region in a 40-year-old man who was admitted in a state of unconsciousness due to the presence of intracranial hemorrhage. After 21 days from admission, he underwent third ventriculostomy for hydrocephalus and biopsy of the lesion. Since bleeding manifestations are uncommonly associated with this kind of tumors, we performed some additional non routine laboratory tests in order to identify biological indicators of disease course and abnormal angiogenesis. Coagulation screening tests were performed to rule out the presence of coagulopathy and vascular endothelial growth factor (VEGF ) levels were measured in plasma as marker of tumor angiogenic potential. Histologic evaluation confirmed the diagnosis of a papillary tumor of the pineal region with the presence of tiny vessel lumens that may account for increased angiogenesis Coagulation screening was normal and VEGF levels were extremely high if compared to healthy individuals. After 20 months of follow-up the tumor mass, radiotherapy treated, appeared dramatically reduced at MRI evaluation, and, interestingly, VEGF levels, although still higher than in healthy individuals, resulted significantly decreased as compared to those measured at time of first hospital admission suggesting a role for VEGF as indicator of tumor aggressiveness. In conclusion, measurement of angiogenesis circulating soluble markers could have an additional feedback in the diagnosis, therapy and monitoring the disease in patients with very rare CNS tumors as papillary tumors of pineal region that have non univocal clinical behavior and prognosis.

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.

Factors influencing the long-term outcome of primary total knee replacement in haemophiliacs: a review of 116 procedures at a single institution.

Total knee replacement (TKR) is a safe treatment for alleviating pain and restoring physical function in end-stage arthropathy of the knee. First reports of TKR in haemophiliacs date back to the mid-1970s, however detailed information on long-term outcome is scarce. This study evaluated factors influencing the outcome of 116 primary TKRs performed consecutively over 14 years at a single institution. Haemostatic management is discussed in patients with and without inhibitors. Orthopaedic outcome was measured by using the Hospital for Special Surgery knee-rating scale, knee flexion contracture and range of motion. At the end of follow-up period (median duration: 5.1 years) 96 prostheses (83%) were still in place with a 7-year removal-free survival of 81%, similar between human immunodeficiency virus-positive and -negative patients and lower in inhibitor than non-inhibitor patients (44% vs. 87%; P < 0.05). Sixteen prostheses (14%) were removed for infection (nine) or aseptic loosening (seven) after a median of 4.5 years. Presence of inhibitors, continuous infusion, cementless prostheses and different primary surgeons were associated with an increased risk of infection; however, after adjustment, only primary surgeon was confirmed as an independent risk factor. These results show that TKR represents a safe and effective procedure in haemophiliacs if performed by a highly experienced surgeon.

IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII.

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