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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issues of people with haemophilia (PwH) are available; however, these materials are fragmentary and largely outdated, failing to reflect the impact of current treatment strategies., Aim: Describing the influence of illness on psychosocial aspects of adult PwH (≥18 years) and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., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

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., (© 2022 John Wiley & Sons Ltd.)

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., (© 2021 John Wiley & Sons Ltd.)

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., (© 2020 John Wiley & Sons Ltd.)

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., (© 2019 John Wiley & Sons Ltd.)

Introduction: Although immune tolerance induction (ITI) is considered the first choice treatment to eradicate inhibitors in haemophilia A patients, little is known about outcomes determinants and cost magnitude., Aim and Methods: A retrospective, multicentre study was conducted to assess the relationship between ITI outcome, clinical and treatment characteristics and cost of ITI treatment in haemophilia A patients. Data from 12 months before inhibitor diagnosis to 12 months after ITI completion were collected. Treatment cost was calculated in the third-party perspective and expressed as mean € per patient-month. Cox regression models were used to identify predictors of better outcome and the time taken to achieve tolerance., Results: Seventy-one patients, aged 0.4-41 years (median: 3.8 years) at ITI start, were enrolled. Undetectable inhibitor was achieved in 84.5% of patients and inhibitor eradication with normal factor VIII (FVIII) pharmacokinetics in 74.2%. Median time to successful tolerance was 10.7 months (range 2.0-90.0 months). Peak inhibitor level on ITI was a significant predictor of ITI success. Breakthrough bleeding event incidence during ITI was associated with time to success. The mean cost of treatment for the time period between inhibitor diagnosis and ITI start was €3188 per patient-month (92.1% for bypassing agents), and €60 078 during ITI (76.8% for FVIII use in ITI)., Conclusion: Immune tolerance induction in this patient cohort was successful in 84.5% of patients with a mean cost of €60 000 per patient-month. This high cost is dwarfed by comparison with the prospect of lifelong care of an inhibitor patient, in addition to gains in life expectancy and health-related quality of life., (© 2015 John Wiley & Sons Ltd.)

Despite great advances in haemophilia care in the last 20 years, a number of questions on haemophilia therapy remain unanswered. These debated issues primarily involve the choice of the product type (plasma-derived vs. recombinant) for patients with different characteristics: specifically, if they were infected by blood-borne virus infections, and if they bear high or low risk of inhibitor development. In addition, the most appropriate treatment regimen in non-inhibitor and inhibitor patients compel physicians operating at the haemophilia treatment centres (HTCs) to take important therapeutic decisions, which are often based on their personal clinical experience rather than on evidence-based recommendations from published literature data. To know the opinion on the most controversial aspects in haemophilia care of Italian expert physicians, who are responsible for common clinical practice and therapeutic decisions, we have conducted a survey among the Directors of HTCs affiliated to the Italian Association of Haemophilia Centres (AICE). A questionnaire, consisting of 19 questions covering the most important topics related to haemophilia treatment, was sent to the Directors of all 52 Italian HTCs. Forty Directors out of 52 (76.9%) responded, accounting for the large majority of HTCs affiliated to the AICE throughout Italy. The results of this survey provide for the first time a picture of the attitudes towards clotting factor concentrate use and product selection of clinicians working at Italian HTCs., (© 2014 John Wiley & Sons Ltd.)

This article describes prenatal diagnosis (PND) of haemophilia B (HB) within the framework of Italian haemophilia centres and genetics laboratories. The study details the experience from six haemophilia genetic centres (three in the North, one in the Centre and two in the South of Italy) and summarizes the different techniques used to perform PND of HB during the last 15 years. To date, the Italian HB database includes 373 characterized unrelated patients and their genetic information has permitted the identification of 274 carriers of childbearing age. This database represents the main instrument for timely and precise PND. Sixty-six prenatal diagnoses were performed on 52 HB carriers whose average age at the time was 34 (ranging from 24 to 44 years). In 44 cases, genetic counselling for carrier status determination was performed before pregnancy, while eight were not studied prior to pregnancy. Foetal samples were obtained by chorionic villus sampling in 52 cases, by amniocentesis in 12 while two were diagnosed by analysis of free foetal DNA obtained from maternal peripheral blood. In 35 (53%) pregnancies the foetus was female. For 31 men (47%), haemophilia status was determined by analysis of previously determined informative markers or familial mutations (12 affected and 19 unaffected). There may be more than one laboratory involved in the PND diagnostic pathway (providing DNA extraction, karyotype analysis, gender determination, maternal contamination detection, molecular diagnosis and sequencing). Good communication between all the parties, coordinated by the haemophilia centre, is essential for a successful and rapid process., (© 2013 John Wiley & Sons Ltd.)

The prevalence of inhibitors in haemophilia B is significantly lower than that of patients with haemophilia A. However, the peculiar occurrence of allergic reactions associated with the onset of inhibitor in haemophilia B (HB) may render immune tolerance a risky procedure. We have carried out a detailed survey among all the Italian Hemophilia Centers to analyse all the patients with HB and inhibitors. A total of eight patients were reported among 282 living patients (2.8%) with severe factor IX (FIX) deficiency (FIX < 1 U dL(-1)). In addition, two deceased patients were also identified. Six patients carried nonsense mutations while in four partial or complete gene deletions were detected. Three patients (one deceased) had history of allergic/anaphylactic reaction upon substitutive treatment, which in one case was recurrent and resolved after switching to plasma derived FIX. Immune tolerance was adopted in five patients and in four complete response was achieved while in the remaining it was partial. No nephrotic syndrome was observed. Our data confirm that inhibitors in HB occur in patients with null mutations or complete/partial gene deletion. Immune tolerance can be achieved also in HB patients, without allergic reactions or nephrotic syndrome upon replacement therapy., (© 2013 John Wiley & Sons Ltd.)

Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health-related quality of life (HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate (aPCC) on HRQoL, HRQoL was assessed using the Short-Form (SF)-36 Health Survey and the EQ-5D questionnaire in subjects ≥ 14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on-demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on-demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF-36 dimensions except for vitality/energy and physical functioning. After prophylaxis, 'good responders,' defined as patients experiencing ≥ 50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score (P = 0.021), role - physical (P = 0.042), bodily pain (P = 0.015), and social functioning (P = 0.036). Similarly, the EQ-5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on-demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ-5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on-demand treatment (P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on-demand treatment., (© 2013 John Wiley & Sons Ltd.)

Over the last few decades, clinical follow-up of patients with haemophilia has become more complex as a result of the introduction of new treatment strategies, the presence of comorbidities related to haemophilia or ageing, as well as the emergence of new tools to evaluate the medical and social consequences of haemophilia. This publication describes the parameters and information that should be documented and the tests, examinations and interventions required for optimal follow-up of a patient with haemophilia. In the absence of formal studies, the present recommendations have been established as result of a series of consensus meetings in the frame of the European Haemophilia Therapy Standardization Board (EHTSB). The following 11 domains were identified: Baseline information, Current status, Treatment, Inhibitor status, Bleeding, Joint status and pain, Comorbidities, Dental care, Physical activities, Social participation and Quality of life. For each domain, details are proposed for the relevant parameters to be captured and monitored as well as the relevant tools that facilitate data collection. Adopting these recommendations should help the individual care of patients and, even though this is not the primary objective of this article, it should also help at national and international level to shape a new approach to haemophilia by working towards a more standardized outcome assessment. Greater standardization should have implications for data collection, improvements in treatment evaluation and optimizing resources., (© 2011 Blackwell Publishing Ltd.)

Intracranial haemorrhage (ICH) is the most serious bleeding symptom in haemophiliacs, resulting in high rates of mortality and disabling sequelae. The Association of Italian Haemophilia Centres carried out a retrospective survey (1987-2008) of ICH occurring in haemophiliacs with the goals to establish: (i) incidence, location of bleeding, death rate and disabling sequels; (ii) risk factors for ICH; and (iii) treatment used during the acute phase of ICH and for recurrence prevention. A total of 112 ICH episodes had occurred in 88 patients (78 haemophilia A, 10 haemophilia B), 24 of whom experienced recurrences. The cumulative hazard of ICH for the whole cohort over the entire follow-up period was 26.7 per 1000 patients, and the annualized rate of ICH was 2.50 events per 1000 patients (95% CI 1.90-3.31). The risk of ICH was higher in the youngest children (24.4 per 1000, 95% CI 12.7-47.0 in the first year of age and 14.9, 95% CI 7.1-31.4 in the second year of age) and then progressively rose again after the age of 40. Univariate, bivariate (age-adjusted) and multivariate analysis investigating the effects of patient characteristics on ICH occurrence showed that haemophilia severity and inhibitor status were strongly associated with ICH [severe vs. mild, HR 3.96 (2.39-6.57); inhibitor vs. non-inhibitor 2.52 (1.46-4.35)]. HCV infection was also associated with the risk of ICH [HR 1.83 (1.25-2.69)]. Therapeutic suggestions based upon our experience to control ICH recurrence are provided., (© 2011 Blackwell Publishing Ltd.)

Summary: The development of inhibitors to the infused factor in patients with haemophilia is a serious clinical problem. Recent evidence suggests that alongside the strong genetic contribution to inhibitor formation, there are a number of non-genetic factors--perceived by the immune system as danger signals--which promote formation of inhibitors. This study provides a comprehensive review of clinical studies relating to these factors and also presents a survey of opinion concerning their importance and clinical influence, conducted among the members of the European Haemophilia Treatment Standardisation Board (EHTSB). Taken together, this information highlights the lack of robust data concerning the influence of several non-genetic risk factors on inhibitor development, and an urgent need for prospective, well-conducted studies that adhere to recommendations made by the European Medicines Agency (EMEA) for studying inhibitors. Based on current literature, the EHTSB formulated consensus recommendations. It is desirable to minimize intensive treatment wherever possible, given the clinical situation. Prophylaxis should be offered to all children, although we still need to determine optimal dosing with respect to inhibitor development, and age for starting treatment. Vaccinations should be given subcutaneously and concomitant factor concentrate infusions avoided. According to the board, there is no evidence in the literature supporting suggestions that the type of concentrate influences inhibitor risk; but all patients should be monitored during their first exposures. Furthermore, there is no evidence to support an association between pregnancy-related issues, breast feeding and treatment-related factors (e.g. route of administration, or use of blood components) and inhibitor development.

Although a number of studies have analysed so far the causes of death and the life expectancy in haemophilic populations, no investigations have been conducted among Italian haemophilia centres. Thus, the aim of this study was to investigate mortality, causes of deaths, life expectancy and co-morbidities in Italian persons with haemophilia (PWH). Data pertaining to a total of 443 PWH who died between 1980 and 2007 were retrospectively collected in the 30 centres who are members of the Italian Association of Haemophilia Centres that chose to participate. The mortality rate ratio standardized to the male Italian population (SMR) was reduced during the periods 1990-1999 and 2000-2007 such that during the latter, death rate overlapped that of the general population (SMR 1990-1999: 1.98 95% CI 1.54-2.51; SMR 2000-2007: 1.08 95% CI 0.83-1.40). Similarly, life expectancy in the whole haemophilic population increased in the same period (71.2 years in 2000-2007 vs. 64.0 in 1990-1999), approaching that of the general male population. While human immunodeficiency virus infection was the main cause of death (45%), 13% of deaths were caused by hepatitis C-associated complications. The results of this retrospective study show that in Italian PWH improvements in the quality of treatment and global medical care provided by specialized haemophilia centres resulted in a significantly increased life expectancy.

Haemophilia A (HA) is an X-linked recessive haemorrhagic disorder caused by a deficiency of coagulation factor VIII. Disease causative mutations are heterogeneous and spread all over the F8 gene sequence, with the exception of intron 22 inversion occurring in about 50% of severe patients. To define the specific mutational repertoire and mutation detection rate, we analysed F8 gene, by polymerase chain reaction and direct sequencing, in 128 unrelated patients from Southern Italy with severe (n = 108), moderate (n = 9) or mild (n = 11) HA. We identified 120 mutations, including 64 cases of intron 22 inversion (53.3%), three of intron 1 inversion (2.5%), one large deletion (0,8%) and 52 point mutations (43.3%). In particular, 19/120 were novel and 7/52 point mutations (13.5%) occurred at CpG sites. We also investigated eight prothrombotic genetic variants in a subgroup of 74 severe HA patients to evaluate their possible protective effect on the severity of clinical expression. Methylenetetrahydrofolate reductase A1298C and plasminogen activator inhibitor-1 4G variants recurred more frequently in HA patients with a less-severe phenotype. Clinical impact of these findings needs large-scale studies to further define the role of these prothrombotic variants as possible modifier factors of HA phenotype.

The ultimate goal of treatment for patients with inhibitory antibodies should be to permanently eradicate the inhibitor by immune tolerance induction therapy (ITI). However, ITI procedures fail in a substantial number of patients and in many countries ITI is not even offered owing to its high cost. How patients with inhibitors are managed in different European countries is evaluated with a special focus on the use of by-passing agents, i.e. recombinant FVIIa (rFVIIa) and activated prothrombin complex concentrates (aPCC), as well as the type of monitoring performed. Investigators from 22 large haemophilia centres participating within the network of the European Haemophilia Therapy Standardisation Board (EHTSB) were asked to complete a questionnaire. rFVIIa was routinely used in all centres for both children and adults at dosages ranging from 90 to 250 mug kg(-1) at an interval of 2-4 h. aPCC was used in 85% of the centres in adults and in 25% of the centres in children with haemophilia A at dosages of 50-100 IU kg(-1) every 6-12 h. The corresponding figures for children and adults with haemophilia B were 40% and 15% of the centres, respectively. Higher dosages of both agents were considered in the case of life-threatening bleeds. General recommendations were developed, based on the information provided by the survey. The results clearly indicate the need for well-designed comparative studies to optimize the use of by-passing agents.

The management of patients with inhibitors is an important challenge in haemophilia care. The lack of randomized controlled trials means that clinical decisions are generally based on subjective opinions, and purchasers' attention is likely to focus on the costs of treatment. In order to assess the current management of inhibitor patients and use of immune tolerance induction therapy (ITI) in Europe, we performed a survey within a European network of 21 comprehensive care centres from 14 countries (the European Haemophilia Therapy Standardisation Board). The survey identified a total of 381 patients with inhibitors attending the centres, 211 (55.4%) of whom had never been exposed to ITI. Between 1998 and 2003, the centres performed 233 procedures and 114 (48.9%) were successful. The survey demonstrated that dosing, which is the time to start and stop the ITI, the type of concentrate to use and the definition of success varied among the centres. Well-designed trials are warranted to guide decision-making, but in the absence of these studies we have developed consensus guidance for the management of inhibitor patients based on current clinical practice, as identified by the survey, and review of the literature.

A careful review of the available literature has shown with a moderate degree of evidence that surgery can be safely performed in haemophilic patients with either low-responding or high-responding inhibitors. Until recently, it was generally advised that surgery should be carried out in high responding haemophilic patients only if absolutely necessary, i.e. in emergency situations. Elective surgery was usually discouraged, with the exception of the placing of an indwelling catheter to carry out immune tolerance protocols. However, in reality elective surgery is often advisable in haemophilic patients with inhibitors because it may lead to an improved quality of life. At the present time, several options of treatment exist which appear to be sufficiently safe to assure haemostasis in different surgical procedures However, a more informed choice between different treatment options, based on estimation of advantages and risks linked to each treatment modality is desirable. Furthermore, the choice between different options has to be made taking into consideration costs of treatment. Ideally, randomised prospective studies are needed in order to provide a higher level of evidence of safety and efficacy of different treatment options and specifically comparing the two main bypassing options:activated prothrombin complex concentrates (aPCCs) and recombinant factor (rF)VIIa. In addition, such studies should be done with an adequate protocol, providing sufficient haematological data and an appropriate prolonged postoperative assessment.

Summary. Participants in an international workshop on surgery in haemophilia patients with inhibitors developed a consensus summary of the findings and conclusions of the meeting. In the consensus, participants agreed upon revised definitions for minor and major surgery, including an intermediate degree of surgery. An evaluation system of intraoperative and postoperative bleeding was developed. Recommended doses of FEIBA((R)) and rFVIIa (both in bolus injections and in continuous infusion) for surgery were agreed. Participants also agreed on the main blood tests to be performed peri-operatively. They also suggested the need of a prospective evaluation in the future. Finally, the approximate number of surgical procedures and costs performed on haemophilia patients with inhibitors were analysed.

In a multinational working group, an instrument (Haemo-QoL) to assess quality of life in children/adolescents with haemophilia and their parents has been developed. In co-operation with haemophilia treatment centres in six European countries, approximately 10 children/adolescents with haemophilia per country and their parents were asked to participate in the pilot-testing. Both self-reported and parent-reported questionnaires were provided for two age-groups of children (4-16 years). Medical data was collected from physicians from patient files. Answers to open questions from participants (58 children and 57 parents) confirmed the content of 116 of the preliminary items. Cognitive debriefing revealed that the majority of the Haemo-QoL was rated favourably, but 29 questions were recommended to be omitted and several items to be reformulated. Preliminary psychometric testing of the revised 77 item questionnaire in the same sample showed acceptable reliability and validity, which will be examined in a subsequent study with a larger patient sample.

Inhibitor antibodies to transfused factor VIII pose significant challenges in the management of haemophilia A patients. The main concern is the inefficacy of replacement therapy in patients with high-titre antibodies, who have a shorter life-span and a greater morbidity compared to subjects without inhibitors. The ultimate goal in treating these patients is to eliminate the inhibitor antibody entirely, allowing the recommencement of specific replacement therapy. The results of an immune tolerance regimen based on pharmacokinetic parameters are reported here. In 12 high-responder haemophilia A patients immune tolerance induction (ITI) was attempted with daily administration of factor VIII concentrates of very high purity, either plasma-derived or produced by recombinant-DNA technology. Patients were given 100 IU kg(-1) day(-1) until the inhibitor was shown to be absent by at least two negative assays 1 month apart, with normal recovery of infused factor VIII and normal half-life (> 6 h), as assessed after a 3-day washout period. After the patient was judged to be inhibitor-free, immune tolerance treatment was continued with unmodified factor VIII doses for 2 months. Doses were thereafter gradually reduced and finally, regular prophylaxis by administration of 25 IU kg(-1) three times weekly was instituted. Immune tolerance was achieved in 10 of the 12 patients (including six of seven with long-standing inhibitors) within a median time of 8 months. Outcome of immune tolerance was not influenced by age at start of ITI nor by the interval between inhibitor development and ITI. The success rate and the inhibitor disappearance time of our immune tolerance regimen, utilizing high-purity factor VIII, agrees with those reported by other investigators.

A total gastrectomy with omentectomy and resection of the distal oesophagus in a 69-year-old haemophilia A patient with high inhibitor of 128 Bethesda units is described. Surgery was successfully performed after infusion of 112 microg kg-1 bw of recombinant FVIIa. Ninety-two microg kg-1 were given thereafter at time intervals of 2 h until 12 h, then every 3 h until 24 h, and every 4 h until 48 h after surgery. Doses were gradually reduced in the following days and finally discontinued on day 28 after surgery. The complete treatment schedule required the administration of a total of 708 mg of recombinant FVIIa. Using this approach, we observed normal haemostasis, and there were no signs of excessive postoperative bleeding or wound haematoma. No clinical side-effects or evidence of systemic activation of coagulation occurred during the treatment. As judged from the clinical course of this major surgery, recombinant FVIIa appears to be highly efficacious and safe and should be used as first line treatment in high titre inhibitor patients with cross-reactivity to porcine factor VIII, undergoing surgery.

This study presents the final report of a long-term psychological assessment of men with haemophilia and HIV infection. The knowledge, emotional impact regarding HIV infection and prospective changes over time and the need for psychological support were evaluated. The study group comprised 118 men with haemophilia, 66 HIV seropositive and 52 seronegative, from the Haemophilia Centres in Bari, Florence, Milan and Naples. All subjects performed psychological tests (STAI: state and trait anxiety inventory; SDS: self-rating depression scale) and completed questionnaires to ascertain their knowledge and the emotional impact of AIDS. After enrollment (1992-93) the assessment was repeated twice over a 2-year period. A high percentage of subjects in both groups answered the questionnaire on knowledge correctly and, more specifically, all (100%) admitted knowing that sexual intercourse was a risk factor for HIV infection, adding that sexual partners of haemophiliacs with HIV should be regularly tested. The percentage, however, decreased for seropositives who admitted to always using a condom during sexual intercourse (86%) and for those who declared that partners were periodically tested for HIV (60%). The most important feature of the study is that, contrary to predicted expectations, seropositive and seronegative subjects presented the same degree of emotional involvement: there are no statistically significant differences in average scores between groups either on the anxiety or depression scales. Moreover, for certain aspects, seronegatives revealed greater emotional involvement: at baseline evaluation, they felt more fear and unhappiness with statistically significant differences compared to asymptomatics. Furthermore, seronegatives more than seropositives continue to feel reluctance towards infusion and avoid blood products after learning of AIDS. These results emphasize the importance of paying due attention to the emotional status of seronegatives. Their reluctance towards the use of blood products (despite present safety) is a very important issue for the possible consequences of treatment with the risk of worsening the clinical condition. In conclusion, we believe that counselling on HIV infection/AIDS needs to address every person with haemophilia regardless of HIV status.

Randomized and cohort studies have provided evidence confirming the hypothesis, based on in-vitro observations, that the use of very high-purity factor VIII (FVIII) concentrates, either immuoaffinity chromatography purified or produced by recombinant DNA technology, may slow immunological deterioration in human immunodeficiency virus (HIV)-infected haemophiliacs, while high-purity concentrates, produced by ion-exchange chromatography, did not produce a benefit. Even though these data clearly indicate that very high-purity concentrates should be preferred for the replacement therapy of HIV-positive haemophiliacs, there are little data, based on direct comparison, supporting the use of very high-purity concentrates rather than high-purity preparations, which are less expensive. In an attempt to address this issue, we prospectively compared CD4 cell counts and changes of clinical status in 18 HIV-positive haemophiliacs, randomly assigned either to receive the treatment with a very high-purity FVIII concentrate, purified by immunoaffinity chromatography, or a high-purity product, produced by ion-exchange chromatography. All patients had CD4 lymphocyte counts below 300 μL(-1) , were negative for the hepatitis B surface antigen and the HIV p24 antigen, and were receiving antiretroviral treatment with Zidovudine for at least 6 months. There were no significant changes of CD4 cell counts over the 96-week follow-up period or between the two groups. No signficant differences between the two groups were detected in the occurrence of AIDS-defining diagnoses (one in each group). On the whole, no striking benefit is conferred to the immune status of asymptomatic HIV-positive haemophiliacs by using either of these high-purity and very high-purity FVIII concentrates for 96 weeks. Larger prospective randomized trials are needed to establish definitely whether it is necessary to resort to very high-purity concentrates or it is sufficient to use high-purity concentrates to slow the fall of CD4 cell counts that occurs in HIV-positive haemophiliacs. Randomized trials, based on clinical end-points, are also needed to demonstrate whether slowing the fall in CD4 cells results in clinical benefits, delaying the occurrence of AIDS.