Gianna Franca Rivolta

Effects of secondary prophylaxis started in adolescent and adult haemophiliacs

Summary.  While primary prophylaxis is a well‐established and recommended method of care delivery for children with severe haemophilia, fewer studies have documented the benefits of secondary prophylaxis started in adolescence or adulthood. To evaluate the role of secondary prophylaxis started in adolescent and adult severe haemophiliacs, a retrospective observational cohort study was conducted in 10 Italian Centres that investigated 84 haemophiliacs who had bled frequently and had thus switched from on‐demand to prophylactic treatment during adolescence (n = 30) or adulthood (n = 54). The consumption of clotting factor concentrates, the orthopaedic and radiological scores, quality of life and disease‐related morbidity were compared before and after starting secondary prophylaxis. Prophylaxis reduced the mean annual number of total and joint bleeds (35.8 vs. 4.2 and 32.4 vs. 3.3; P < 0.01) and of days lost from work/school (34.6 vs. 3.0, P < 0.01). A statistically significant reduction in the orthopaedic score was observed during prophylaxis in adolescents, but not in the whole cohort. Patients used more factor concentrates with corresponding higher costs on prophylaxis, but experienced a better quality of life. With respect to on‐demand treatment, higher factor consumption and cost of secondary prophylaxis were balanced by marked clinical benefits and greater well‐being in this cohort of adolescent/adult haemophiliacs.

Hemophilia and cancer: A new challenge for hemophilia centers

The improved life expectancy of hemophilia patients due to the advances in hemophilia care and factor replacement therapy has permitted to hemophiliacs to reach an older age. As a consequence, age-related diseases, such as cardiovascular disorders and cancer, have been increasingly recognized in such patients. In particular, the management of cancer in people with inherited hemorrhagic disorders represents a new challenge for physicians working in hemophilia centers. The few published literature data document that there is a close relationship between hemophilia and neoplasia. Indeed, the congenital bleeding tendency may influence the cancer in different ways, by interfering with its clinical presentation, diagnosis and treatment. These aspects, along with the epidemiology of cancer in hemophiliacs will be discussed in this review.

Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study

Rigorous evidence is lacking on long-term outcomes of factor VIII (FVIII) prophylaxis initiated in adolescent or adult patients with severe haemophilia A. The prospective, open-label Prophylaxis versus On-demand Therapy Through Economic Report (POTTER) study (ClinicalTrials.gov NCT01159587) compared long-term late secondary prophylaxis (recombinant FVIII-FS 20-30 IU/kg thrice weekly) with on-demand treatment in patients aged 12 to 55 years with severe haemophilia A. The annual number of joint bleeding episodes (primary endpoint), total bleeding episodes, orthopaedic and radiologic (Pettersson) scores, health-related quality of life (HRQoL), pharmacoeconomic impact, and safety were evaluated over a > 5-year period (2004-2010). Fifty-eight patients were enrolled at 11 centres in Italy; 53 (27 prophylaxis, 26 on demand) were evaluated and stratified into 2 age subgroups (12-25 and 26-55 years). Patients receiving prophylaxis experienced a significantly lower number of joint bleeding episodes vs the on-demand group (annualised bleeding rate, 1.97 vs 16.80 and 2.46 vs 16.71 in younger and older patients, respectively; p=0.0043). Results were similar for total bleeding episodes. Prophylaxis was associated with significantly fewer target joints (p< 0.001), better orthopaedic (p=0.0019) and Pettersson (p=0.0177) scores, better HRQoL, and fewer days of everyday activities lost (p< 0.0001) but required significantly higher FVIII product consumption. The POTTER study is the first prospective, controlled trial documenting long-term benefits of late secondary prophylaxis in adolescents and adults with severe haemophilia A. The benefits of reduced bleeding frequency, improved joint status, and HRQoL may offset the higher FVIII consumption and costs.

The natural history of mild haemophilia: a 30-year single centre experience

Summary.  Although up to 50% of all haemophilic patients followed at haemophilia treatment centres (HTCs) are affected by a mild factor VIII (FVIII) or factor IX (FIX) defect, published data regarding the natural history of these disorders are scarce. To fill this lack of information, a retrospective single centre study was conducted. All cases with mild haemophilia (75 A and 7 B) followed at the regional reference HTC of Parma were evaluated. The patients’ median age at diagnosis was 11.5 years and their median age at first bleeding was 5.5 years; 95% of patients had a history of haemorrhagic problems during their life. Twenty‐three percent of patients were infected by HCV, and none by HIV. Genetic analysis was performed in 80 patients (97% haemophilia A and 100% haemophilia B) and 21 different mutations were characterized. Eleven percent of patients had never received treatment, whereas 67% were treated with plasma‐derived or recombinant FVIII/FIX concentrates (4% developed inhibitors). desmopressin (DDAVP) was used in 80% of the haemophilia A patients. The response to DDAVP was closely related to the patients’ genetic profile, as 60% of non‐responders had a mutation in the F8 promoter region. Patients with mild haemophilia may experience a variety of medical problems, sometimes challenging for the physicians, during their lifetime. The HTCs play an important role in the management of these patients, whose diagnosis is often delayed. The HTCs should improve patients’ knowledge and consideration of their disease and encourage them to maintain regular contact with their haemophilia care provider.

A web-based clinical record ‘xl’Emofilia®’ for outpatients with haemophilia and allied disorders in the Region of Emilia-Romagna: features and pilot use

Summary.  The treatment of haemophilia in developed countries is based on home self‐infusion of concentrates. Improving communication between haemophilia centres (HC) and patients is very important. The Hub Centre (Parma) designed a new outpatient clinical record, ‘xl’Emofilia®’, as part of a project ‘Web Connections of the Region’s HC’ funded by Emilia‐Romagna Health Authority. It is a web‐based application suited to the needs of HC, which shares the databases of the region’s HC, integrated with regional and national registries that can be accessed from anywhere. Data are managed with the ‘https’ protocol. Significant innovations are ‘pathways’ that help with the entry of data and ‘problem list’, which is a summary (updated automatically) of the patient’s clinically significant data that can be consulted at a glance. With a ‘web identity’ (a personal USB key for secure web access), patients can record bleeds and home infusions, consult their own data and allow access to their general practitioners or in emergency departments anywhere in the world (also in English language). In December 2006, the HC started to use ‘xl’Emofilia®’ and 673 clinical records are now active. Since April 2007, 50 pilot patients have been trained and are successfully using the system. A questionnaire administered to these patients on their level of satisfaction with the system and its ease of use gave excellent results. Our web‐based system facilitates communication between patients and HC, improves the quality of care and enables patients to use these information at any time and from anywhere in the world.

Anaphylaxis in patients with congenital bleeding disorders and inhibitors.

Anaphylactic reactions are rare emergencies observed in patients with inherited bleeding disorders. When these adverse events occur in patients with inhibitors, they further complicate the management of an already challenging clinical situation. Anaphylactoid inhibitors have been reported in patients with inhibitors associated with hemophilia A, hemophilia B, and type 3 von Willebrand disease. In this review, we summarize the current literature data on the occurrence of anaphylactoid reactions in patients with inherited bleeding disorders and alloantibodies. In particular, we focus on the pathophysiology of the inhibitor development and its management.

Spectrum of F8 gene mutations in haemophilia A patients from a region of Italy: identification of 23 new mutations

Summary.  Haemophilia A (HA) is an X‐linked recessive bleeding disorder caused by a lack or decrease of coagulation factor VIII activity. The molecular diagnosis of HA is challenging and a variety of different mutations have been identified throughout the F8 gene. Our aim was to detect the causative mutation in 266 HA patients from Emilia‐Romagna region (Italy) and in all suspected carriers. Molecular analysis of F8 in 201 HA patients (152 index cases) was performed with a combination of several indirect and direct molecular approaches, such as long distance polymerase chain reaction, multiplex ligation‐dependent probe amplification, denaturing high performance liquid chromatography and direct sequencing. The analysis revealed 78 different mutations, 23 of which were novel, not having been reported in national or international databases. The detection rate was 100%, 86% and 89% in patients with severe, moderate and mild HA, respectively. The information provided by this registry will be helpful for monitoring the treatment of HA patients in Emilia‐Romagna and also for reliable genetic counselling of affected families in the future.

Characterization of a novel mutation in the F8 promoter region associated with mild hemophilia A and resistance to DDAVP therapy.

We read with interest the recent letter by Dai et al. characterizing a patient with a C>T substitution at position 219 in the F8 promoter region resulting in mild hemophilia A [1]. We report here a novel mutation in the same region occurring in a family group including five patients (Fig. 1A) with factor VIII levels and a clinical phenotype compatible with mild hemophilia A. Four of them (patients IV:1, IV:2, IV:3, and IV:4) were tested with desmopressin (DDAVP; 30 lg/kg given subcutaneously) with no response (FVIII:C levels unchanged 60, 120 and 240 min after DDAVP administration). By contrast, the von Willebrand factor (VWF) response was preserved, with marked increases in VWF antigen and VWF ristocetin cofactor activity levels (Fig. 1B). Mutation screening [2] by denaturing high-performance liquid chromatography analysis, followed by direct sequencing of all 26 exons and exon intron junctions, failed to detect any variation from the normal control. Type 2N von Willebrand disease and a combined FV FVIII deficiency were also ruled out. Patients were then treated with recombinant FVIII products during hemorrhagic episodes, without the development of inhibitors. However, a subsequent analysis of the F8 promoter performed by polymerase chain reaction followed by dideoxy sequencing identified a T>G substitution at position )257 (standardHumanGenomeVariation Society nomenclature [3]) in the four living probands (IV:1, IV:2, IV:3, and IV:4). The lack of this substitution in 100 normal chromosomes enables us to exclude the possibility that this base change is a common, nonpathogenic polymorphism. This mutation was found, in

Assessment of Hemophilic Arthropathy by Ultrasound: Where Do We Stand?

Joint hemorrhages represent the most common type of bleeding episode in persons with hemophilia, and recurrent hemarthrosis triggers chronic arthropathy, which is the most frequent chronic complication in these patients. In recent years, in the frame of a comprehensive care approach, a growing attention has been given to the periodic assessment of the joint status in hemophilia patients with the aim to identify early arthropathic changes and to prevent the development of a clinically overt arthropathy. Besides clinical examination, X-ray and magnetic resonance imaging (MRI) are currently used to evaluate joint status and to monitor the disease progression in hemophilia. Considering the limitations of X-ray and MRI, growing interest has been given to ultrasound (US) as a possible tool to assess joint status and identify early arthropathic changes in hemophilia patients. In the present review, we summarize major literature evidence on the use of joint US for the evaluation of markers of disease activity (joint effusion and synovial hypertrophy) and of degenerative damages (osteochondral changes) in patients with hemophilia. On the whole, being able to identify the presence of intra- or extra-articular fluid, US examination is the fastest and most reliable technique to identify acute conditions, such as hemarthrosis. In addition, the information on joint involvement provided by US in the patient follow-up may influence treatment decisions on a personalized basis. The use of US as part of a routine clinical examination by hemophilia experts may optimize the diagnostic workflow, avoiding additional costs and long waiting lists for patients referred to imaging departments. In the frame of a comprehensive care approach, US might represent a strategy to early detect and monitor synovial hypertrophy and osteochondral changes in hemophilia, thus extending the clinical examination and helping identify joints to be studied with a second-level examination such as MRI.

Hemophilia severity score system: validation from an Italian Regional Hemophilia Reference Center

We read with interest the recent article by Schulman et al. on a composite score for evaluating the phenotypic severity of hemophilia [1]. The conclusions of the authors regarding the need to validate the score system in countries with different levels of care stimulated us to evaluate it in our context. Thus, we applied the hemophilia severity score (HSS) system to hemophiliacs referred to the Hemophilia Centre of Parma, the reference center for the Region of Emilia-Romagna in Italy [2]. The collection of the patients data required for the calculation of the three parameters of the HSS (bleeding score, joint score, and factor concentrate) was facilitated by the availability, since October 2002, of an electronic database developed to collect clinical data for the Registry and Network of Hemophilia Centres of the Emilia-Romagna Region [3]. In addition, since March 2007, data entry has been improved by the implementation of regional web-based clinical records in which patients can promptly record any bleeds and home treatments [4]. Between October 1998 and September 2008, 65 consecutive patients with hemophilia A or B and basal factor levels between 0 and 0.3 IU/mL were evaluated. According to the original protocol by Schulman et al., additional exclusion criteria were a follow-up less than 10 years for each patient, the presence of an inhibitor at any time before or during the study period, and an age less than 18 years at the end of the observation. Informed consent was obtained from the patients. In addition, only patients with reliable and complete data on bleeding score, joint score and factor concentrate utilization were evaluated in the study. Patients with severe/moderate hemophilia were also tested for two of the more common thrombophilic polymorphisms (factor V Leiden and prothrombin G20210A) [1]. The characteristics of the patients enrolled are summarized in Table 1. When our patients were compared with those reported by Schulman et al., hemophilia A and B ratio, age at mid-term, median age at first bleed and hepatitis C virus infection rate were similar, whereas fewer of our patients were on prophylaxis (45% vs. 79%). Furthermore, the median age of patients who started prophylaxis was higher in our series (15 vs. 8). These latter findings were probably due to the fact that prophylaxis became widely used in Italy only recently, and thus later than in northern countries [5,6]. Finally, although orthopedic joint score and factor consumption per year were lower in our patients with severe hemophilia, statistical significance was reached in the three different groups in both studies (Table 1). The higher number of patients on prophylaxis reported by Schulman et al. explains the higher factor consumption recorded in their study. Table 2 shows the HSS and its components according to Schulman s method. It is of note that we did not perform a separate analysis of hemophilia A and B patients, as the HSS was similar according to disease severity. Although ranges of HSS and of its components were wider in our study, especially for patients with severe hemophilia, maximum values were compatible with those tolerated for each score calculation. In addition, in our study, the HSS of patients with moderate hemophilia was lower than that reported by Schulman et al. This difference was probably due to the fact that four of the five patients with a moderate disease (FVIII:C or FIX:C 0.01– 0.05 IU/mL) had a deficient factor level at the upper limits of the range, and thus a milder clinical phenotype. Figure 1 reports HSS according to factor levels in all patients with severe, moderate and mild hemophilia A or B. Among severe hemophiliacs, the HSS was higher for patients on demand therapy than for those on prophylaxis (P = 0.041), and this reflected statistically significant differences in bleeding and joint Correspondence: Annarita Tagliaferri, Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Via Gramsci 14, Parma 43100, Italy. Tel.: +390521703971; fax: +390521704332. E-mail: atagliaferri@ao.pr.it