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Introduction: While the dental management of patients with haemophilia has changed considerably in the last decade, haemophiliacs in Western Australia have continued to receive pre‐operative factor support for dentistry regardless of the type of dental procedure. Aim: To review the efficacy and safety of established dental protocols that reduce factor use in the dental management of patients with haemophilia and to estimate cost savings. Methods: Records of 11 patients with haemophilia that were seen in the pilot programme period were reviewed. These were cross‐referenced with previous dental and haematology notes that stated the amount and type of pre‐operative factor used. Cost savings were estimated using the Australian National Blood Authority's Product List. Results: All study participants were male, and included those with haemophilia A (n = 9), and B (n = 2). Mean age was 45 years (range 22–80). A variety of dental treatments were undertaken, and no pre‐operative factor was used. Patients on prophylaxis (n = 6) received dental treatment the same day as their regular factor administration. It was estimated AUD$26,314 was saved by not using pre‐operative factor. One patient had bleeding post‐extraction and was seen the following day to achieve haemostasis using local measures. The remaining patients had no complaints of post‐operative bleeding, and did not require any further haemostatic measures. Conclusion: This pilot programme supports data that haemophiliacs can safely receive a variety of dental treatments without the need for pre‐operative factor, and the significant cost savings of doing so. Further data is required to support this protocol for invasive dental procedures. [ABSTRACT FROM AUTHOR]

Introduction Routine outcome assessment of prophylaxis should use validated tools, while balancing comprehensiveness and burden. Collecting overlapping information should be avoided. Aim To assess correlations between different outcome assessment tools in haemophilia. Methods From an international cross-sectional study, data on objective outcome (Haemophilia Joint Health Score ( HJHS 2.1, range 0-124), radiological Pettersson score) and self-reported joint bleeding, Haemophilia Activities List ( HAL, range 100-0), health-related quality of life ( SF-36, including five physical and five mental domain scores, range 100-0), and Utility ( SF6D and EQ-5D, range 1.0-0) were extracted. Spearman's correlations were calculated: ≥0.8 very strong, 0.60-0.79 strong, 0.40-0.59 moderate. Results Ninety patients with severe haemophilia, on prophylaxis since median age 3.4 years, were evaluated at median 25.5 years (range 16.0-37.6). Objective outcome was favourable (median HJHS 2.1 6 points, Pettersson score 9 points). Self-reported outcome showed a median of 7 joint bleeds in 5 years, median HAL sum 96 points, high scores for physical domains of SF-36 (median 80-95) and high Utility values (median SF6D 0.87; EQ-5D 0.84). Physical examination ( HJHS 2.1) showed strong correlation with radiological scores, moderate correlation with physical domains of the SF-36 and Utility, but no correlation with self-reported bleeding or limitations in activities ( HAL). Bleeding was not associated with any other outcome parameter. The HAL was only correlated with the SF36 'Physical functioning' domain. Conclusion For the evaluation of patients on early prophylaxis, information on bleeding should be complemented by objective joint assessment as well as self-reported limitations in activities and quality of life. [ABSTRACT FROM AUTHOR]

Aim This observational study was undertaken with the aim to describe the characteristics and evaluate the outcomes of prophylactic treatment in children with severe haemophilia A ( HA) treated at our centre. Methods Twenty-five patients aged 4-19 years with severe HA, no history of inhibitors and treated with at least two infusions of factor VIII (FVIII) per week were studied. Prophylactic doses and annual joint bleeding rate ( AJBR) were retrospectively evaluated over the last 5 years. Current joint status was assessed using the Haemophilia Joint Health Score ( HJHS) (136 joints of 23 patients) and the Haemophilia Early Arthropathy Detection with Ultrasound ( HEAD- US) procedure (124 joints of 21 patients). Results Median AJBR was 0.2 and median prophylaxis dose 65.4 IU−1 kg−1 week−1. Median total HJHS was 0 (range 0-13) and total HEAD- US 1 (0-8). At the joint level, 85.3% of joints were normal on HJHS and 79.0% on US. The ankle was the joint most commonly affected, considering bleeding and ultrasound results. Correlation was found between HEAD- US scores and bleeding scores but not between HEAD- US and HJHS scores. HJHS and HEAD- US scores were concordant in 91/124 (73.4%) joints (86 joints normal and five abnormal). Ultrasound detected minimal changes in 19.6% of joints with normal physical function, whereas 12.2% of joints considered normal on ultrasound showed changes at HJHS. Conclusion A well-preserved joint status was found in our cohort. High-resolution US detected a higher percentage of abnormalities than the physical evaluation, but the clinical implications of these findings still need to be ascertained. [ABSTRACT FROM AUTHOR]

Treatment adherence in adolescents with chronic diseases is around 50%, and failure is more common in preventive therapy. In haemophilia, contradictory results are reported by the published studies. The objective of this study was to evaluate adherence with factor VIII (FVIII) prophylaxis in Spanish patients with severe haemophilia A between age 6 and 20 years. Data were collected retrosp-ectively in the previous 2 years. The primary endpoint was the absolute adherence index (AAI), and the endpoints were related to clinical status, age, prophylaxis regimen, responsibility for factor administration and quality of life (QoL), assessed by the Haemo-QoL questionnaires. A total of 78 patients from 14 Spanish hospitals were recruited. Adherence ranged between −64.4 and 66.7 (mean −3.08). No differences were observed between children and adolescents (7.11 vs. 6.39; P = 0.809). A statistically significant association ( P < 0.010) between infra adherent group and target joint was found, as was a statistically significant difference ( P < 0.010) between the number of bleeding episodes experienced by the adherent group (mean 1.4) and by infra adherents (mean 4.5). There was no significant difference between AAI and prophylactic regimen (6.35 vs. 6.96, P = 0.848), neither between AAI and the person responsible for factor administration (5.57 vs. 8.79, P = 0.326). The Haemo-QoL scores (8-12 years) were related to adherence level ( P < 0.05). Adherence was approximately ideal and patients perceived a high QoL. Because of the repercussions for compliance, it is essential to work during puberty on emotional and self-acceptance aspects of the disease, as well as coping, and the patient's family, school and health team relationships. [ABSTRACT FROM AUTHOR]

Objective: A cost analysis model was developed to compare annual cost of prophylaxis with activated prothrombin complex concentrate ( aPCC) vs. on-demand therapy with activated recombinant factor VII ( rFVIIa) in severe haemophilia A patients with inhibitors for the Spanish National Health System ( NHS). Methods: Model inputs were drug cost for prophylaxis ( aPCC) and for on-demand treatment ( rFVIIa or aPCC); bleeding episodes management (excluding bypassing agent cost); surgical costs and disease management (excluding bleeding episodes). Annual bleeding episodes treated on-demand was assumed to be 25, whereas breakthrough bleeds on prophylaxis was 8. Dose for prophylaxis was 75.72 U kg−1, three times per week. The total on-demand dose/bleeding episode was 679.66 μg kg−1 ( rFVIIa) and 235.28 U kg−1 ( aPCC). The average bleeding cost (€2998) considered different bleeding sites (62.5% joints, 28.6% muscles and soft tissues, 3.6% mucocutaneous tissues and 5.4% other areas). A 7.5% deduction was applied to ex-factory drug prices. Unitary costs (€2013) derived from local databases. Sensitivity analyses ( SA) were performed. Results: Annual cost of aPCC prophylaxis (€524 358) was 16% lower than on-demand treatment with rFVIIa (€627 876). Yearly drug costs were €497 017 for aPCC (€73 166 for on-demand treatment and €423 850 for prophylaxis), and €548 870 for rFVIIa. Disease management cost (€2645 per year) and surgical procedures (€708 per year) were common for both strategies. In the SA prophylactic treatment led to savings between €26 225 and €-1 008 960. Conclusion: Prophylaxis with aPCC reduces number of bleeding episodes in severe haemophilia A patients with inhibitors. aPCC prophylaxis resulted in savings in excess of €100 000 per-patient per year, being 16% less costly than on-demand treatment with rFVIIa, for the Spanish NHS. [ABSTRACT FROM AUTHOR]

In patients with haemophilia A, factor VIII ( FVIII) prophylaxis reduces bleeding frequency and joint damage compared with on-demand therapy. To assess the effect of prophylaxis initiation age, magnetic resonance imaging ( MRI) was used to evaluate bone and cartilage damage in patients with severe haemophilia A. In this cross-sectional, multinational investigation, patients aged 12-35 years were assigned to 1 of 5 groups: primary prophylaxis started at age <2 years (group 1); secondary prophylaxis started at age 2 to <6 years (group 2), 6 to <12 years (group 3), or 12−18 years (group 4); or on-demand treatment (group 5). Joint status at ankles and knees was assessed using Compatible Additive MRI scoring (maximum and mean ankle; maximum and mean of all 4 joints) and Gilbert scores in the per-protocol population ( n = 118). All prophylaxis groups had better MRI joint scores than the on-demand group. MRI scores generally increased with current patient age and later start of prophylaxis. Ankles were the most affected joints. In group 1 patients currently aged 27−35 years, the median of maximum ankle scores was 0.0; corresponding values in groups 4 and 5 were 17.0 and 18.0, respectively [medians of mean index joint scores: 0.0 (group 1), 8.1 (group 2) and 13.8 (group 4)]. Gilbert scores revealed outcomes less pronounced than MRI scores. MRI scores identified pathologic joint status with high sensitivity. Prophylaxis groups had lower annualized joint bleeds and MRI scores vs. the on-demand group. Primary prophylaxis demonstrated protective effects against joint deterioration compared with secondary prophylaxis. [ABSTRACT FROM AUTHOR]

Swimming is beneficial for persons with haemophilia ( PWH) providing good maintenance of the cardiovascular and musculoskeletal system and improving many psychological characteristics. In the Desafío del Caribe Project, young PWH from Venezuela and Mexico took part in an open water competition in the Gulf of Mexico under a multidisciplinary team supervision. Eight severe haemophilia A, two moderate haemophilia A, one severe haemophilia B and two moderate haemophilia B subjects were included. Haematological, musculoskeletal and psychological evaluations were carried out before and during training for the competition. Training program included physical exercise routines and swimming practices that alternated between pools and open water. Swimmers had coverage with factor concentrates before pool and open water trainings. In physiatric evaluations, the Hemophilia Joint Health Score ( HJHS) was used. The objective of the psychology area was to analyse self-esteem, precompetition anxiety, coping mechanisms and relaxation levels. The need of factor prophylaxis before intense trainings was confirmed. In the musculoskeletal system a decrease of elbow pain as well as an increase of muscle strength in the ankles were observed. In the psychological area significant differences between the first and second test in self-esteem levels, cognitive anxiety and group cohesion were found. PWH must be provided with orientation and encouragement to practice swimming regularly. High competition exercise must be supervised by a multidisciplinary team which must evaluate the pros and cons of the activity to make relevant recommendations. [ABSTRACT FROM AUTHOR]

Congenital factor XIII ( FXIII) deficiency is a rare condition with substantial risk for life-threatening bleeding. Replacement of deficient FXIII with plasma-derived FXIII concentrate is a treatment option. The current 12-week study evaluated the steady-state pharmacokinetic ( PK) and safety profile of prophylactic infusions of FXIII concentrate (human) in patients with congenital FXIII deficiency. Patients received FXIII concentrate (human) 40 IU kg−1 on Days 0, 28, and 56. FXIII levels were assessed before and after each infusion; steady-state PK parameters were assessed up to 28 days after the infusion on Day 56. Treatment effectiveness in maintaining trough FXIII activity levels ≥5% over 28 days and safety parameters were also assessed. Fourteen patients received FXIII concentrate (human) and 13 completed the study. Post-infusion, FXIII activity levels increased to within the range found in patients without congenital FXIII deficiency without reaching supra-therapeutic levels. Non-baseline-adjusted trough FXIII activity levels were maintained at or above 10% at all post-baseline visits in all patients. Steady-state PK parameters were baseline-adjusted; maximum FXIII activity was 87.7% at 1.72 h post-infusion, subsequently declining to a minimum of 5.0%. The half-life was 6.6 days. FXIII concentrate (human) was generally well tolerated. Two patients had possibly treatment-related adverse events. There were no reports of thromboembolism, viral transmission, bleeding events or treatment-related hypersensitivity. These findings support use of FXIII concentrate (human) 40 IU kg−1 every 28 days as an appropriate regimen for routine, long-term prophylaxis in children and adults with congenital FXIII deficiency. Clinical trial registration: . [ABSTRACT FROM AUTHOR]

The HERO (Haemophilia Experiences, Results and Opportunities) quantitative surveys collected information on characteristics and perceptions of adult persons with haemophilia ( PWH) and parents of children with haemophilia. The aim of this article is to describe the perceptions of PWH and parents on psychosocial aspects related to treatment. Two online surveys (one for PWH, one for parents) were conducted in 10 countries. Among 675 PWH respondents, 77% reported having responsibility for their own care; 72% of 561 parent respondents had the main responsibility for their son. PWH were most commonly treated on demand (45% of 648 adults using factor concentrate), with 32% on regular prophylaxis and 23% treated on demand with short-term prophylaxis (e.g. for sports/physiotherapy). Children were most often treated with prophylaxis (65% of 549 children using factor concentrate), with 26% treated on demand and 8% treated on demand with short-term prophylaxis. Factor was generally used as instructed at home. Some respondents (41% PWH; 30% parents) had difficulties/concerns with factor availability/affordability. PWH reported more bleeds in the last 12 months than parents reporting their son's bleeds (mean 17.8 vs. 8.7). Both PWH and parents generally perceived that overall, their (their son's) haemophilia was well controlled. Results differed by country. The HERO study captured new, patient-based data regarding many facets of life relevant to PWH, including treatment. The information conveyed in this article largely represents new insights regarding perceptions of treatment and provides initial benchmark statistics for further research. [ABSTRACT FROM AUTHOR]

Congenital factor XIII ( FXIII) deficiency is an extremely rare, potentially life-threatening bleeding disorder. Routine prophylactic management is recommended for individuals with clinically relevant FXIII deficiency. This prospective, multicentre, open-label study evaluated the long-term efficacy and safety of prophylactic infusions of FXIII concentrate (human) 40 IU kg−1 in patients with congenital FXIII deficiency. FXIII concentrate (human) was administered every 4 weeks for 12 months. Dosing was adjusted to maintain trough FXIII activity levels of 5-20%. Logistical and ethical constraints precluded use of a placebo control group. Annualized incidence of spontaneous bleeding was compared with historical rates; safety was assessed as a secondary objective. Forty-one patients were enrolled and completed the study. The annualized rate for spontaneous bleeding episodes requiring FXIII treatment was 0.000 episodes per patient-year (95% CI: 0.000; 0.097). The study met its primary endpoint: the upper limit of the 95% CI was substantially below the historical rate of 2.5 bleeding episodes per patient-year. Five spontaneous bleeding episodes (involving three patients; none requiring FXIII treatment) and eight trauma-related bleeding episodes (two requiring FXIII treatment) occurred. Five patients had surgery during the study, only one of whom required FXIII treatment for post-surgical bleeding. Most patients (≥85%) had trough FXIII activity levels ≥10%. No patient discontinued treatment due to an adverse event. No adverse events related to thromboembolism or viral transmission were reported. Prophylactic treatment with FXIII concentrate (human) was well tolerated and prevented spontaneous bleeding episodes that were serious enough to require treatment with FXIII-containing product. Clinical trial registration:. [ABSTRACT FROM AUTHOR]

Several risk factors for inhibitors have recently been described for haemophilia A. It has been assumed that similar risk factors are also relevant for haemophilia B, but there is limited data to confirm this notion. The aim of this study was to determine the prevalence of and risk factors associated with inhibitors in haemophilia B. The database of the Universal Data Collection ( UDC) project of the Centers for Disease Control for the years 1998-2011 was queried to determine the prevalence of inhibitors in haemophilia B subjects. In addition, disease severity, race/ethnicity, age, factor exposure and prophylaxis usage were evaluated to determine their impact on inhibitor prevalence. Of the 3785 male subjects with haemophilia B enrolled in the UDC database, 75 (2%) were determined to have an inhibitor at some point during the study period. Severe disease ( OR 13.1, 95% CI 6.2-27.7), black race ( OR 2.2, 95% CI 1.2-4.1), and age <11 years ( OR 2.5, 95% CI 1.5-4.0) were found to be significantly associated with having an inhibitor. There was insufficient data to determine if type of factor used and prophylaxis were associated with inhibitors. Inhibitors in haemophilia B are much less prevalent than haemophilia A, especially in patients with mild disease. Similar factors associated with inhibitors in haemophilia A also seem to be present for haemophilia B. The information collected by this large surveillance project did not permit evaluation of potential risk factors related to treatment approaches and exposures, and additional studies will be required. [ABSTRACT FROM AUTHOR]

There is a paucity of literature on haemophilia treatment in Latin American countries, a region characterized by rapidly improving systems of care, but with substantial disparities in treatment between countries. The aim of this study was to evaluate the musculoskeletal status of haemophilia patients from Latin America and to examine the relationship between musculoskeletal status and treatment practices across countries. The Committee of Latin America on the Therapeutics of Inhibitor Groups conducted a survey of its member country representatives on key aspects of haemophilia treatment in 10 countries. Musculoskeletal status of patients was obtained during routine comprehensive evaluations between March 2009 and March 2011. Eligible patients had severe haemophilia A (factor VIII <1%) without inhibitors (<0.6 BU mL−1) and were ≥5 years of age. Musculoskeletal status was compared between three groups of countries, based primarily on differences in the availability of long-term prophylaxis. Overall, 143 patients (5-66 years of age) were enrolled from nine countries. In countries where long-term prophylaxis had been available for at least 10 years (Group A), patients aged 5-10 years had significantly better mean World Federation of Hemophilia clinical scores, fewer target joints and fewer affected joints than patients from countries where long-term prophylaxis has been available for about 5 years (Group B) or was not available (Group C). In Latin America, the musculoskeletal status of patients with severe haemophilia without inhibitors has improved significantly in association with the provision of long-term prophylaxis. As more countries in Latin America institute this practice, further improvements are anticipated. [ABSTRACT FROM AUTHOR]

Lymphomas or hepatocarcinomas related to blood-borne transmitted diseases are well-known malignancies in persons with haemophilia ( PWH). However, rising life expectancy has increased the number of PWH suffering from other malignancies. This study aimed to collect cancer occurrence data in PWH followed in five European haemophilia treatment centres (Brussels, Geneva, Marseille, Montpellier and Paris-Bicêtre) over the last 10 years and to analyse some particular features of cancer occurring in PWH. In total, 45 malignancies were diagnosed in 1067 PWH. The most common malignancies were hepatocellular carcinoma (12/45) and urogenital tract tumours (9/45). Bleeding at presentation or changes in bleeding pattern was indicative of cancer in four patients. Three patients with mild haemophilia developed anti-factor VIII inhibitors after intensive substitution therapy prior to surgery or invasive procedures. There was no bleeding associated with chemotherapy or radiotherapy. A few bleeding complications occurred following invasive (3/39) or surgical procedures (2/27) as a result of insufficient hemostatic coverage or in spite of adequate substitution. No bleeding was noted after liver or prostate biopsies. Following cancer diagnosis, five patients were switched from on-demand to prolonged prophylaxis substitution. In the majority of cases, the standard cancer treatment protocol was not modified on account of concomitant haemophilia. Thus, oncological treatments are not contraindicated and should not be withheld in PWH assuming that adequate haemostasis correction is undertaken. As shown by our study results, a change in bleeding pattern in adult PWH should raise suspicion of a malignancy. Intensive substitution must be considered a risk factor for inhibitor development. [ABSTRACT FROM AUTHOR]

Patients with severe haemophilia A experience frequent and spontaneous bleeding, causing debilitating damage to joints and decreasing quality of life. Prophylaxis with factor VIII (FVIII) reduces joint damage if initiated early. Circulating FVIII levels may be influenced by endogenous von Willebrand factor ( VWF), a chaperone protein that binds and stabilizes FVIII. The aim of this study was to determine whether endogenous VWF antigen ( VWF:Ag) levels are correlated with FVIII pharmacokinetic ( PK) parameters and clinical outcomes in patients with severe haemophilia A. Previously treated, non-inhibitor patients in a multinational, randomized, double-blind, Ph II study received prophylaxis with once-weekly BAY 79-4980 (35 IU kg−1) or thrice-weekly recombinant sucrose-formulated FVIII (rFVIII- FS; 25 IU kg−1). PK parameters were evaluated at weeks 1 and 26. The number of bleeds per patient during the study was captured as part of the core efficacy endpoint. Spearman rank correlations assessed relationships of VWF:Ag levels with patient age, PK and annualized bleeding rate. Of 131 study patients (aged 13−64 years; BAY 79-4980, n = 63; rFVIII- FS, n = 68), 27 (21%; n = 15 and 12 respectively) were evaluable for PK assessment. Baseline VWF:Ag levels correlated with patient age ( P < 0.0001). There was no significant difference in PK results between treatments; thus, PK parameters and VWF levels of all patients were analysed together. AUCnorm and T 1/2 significantly increased with increased VWF:Ag ( P < 0.001); clearance significantly decreased with increased VWF:Ag ( P = 0.002). Annualized bleeding rate in patients treated with 3× per week rFVIII- FS significantly correlated with VWF:Ag and age ( P = 0.038 and 0.021 respectively). PK parameters as well as the clinical outcome significantly correlated with endogenous VWF:Ag. The improved clinical outcome in subjects with high VWF:Ag levels may be explained by VWF:Ag influence on FVIII PK. [ABSTRACT FROM AUTHOR]

Factor replacement therapy for the treatment of moderate to severe haemophilia A and B can be complicated by the production of inhibitory alloantibodies to factor VIII (FVIII) or factor IX. Treatment with the nanofiltered anti-inhibitor coagulant complex, Factor Eight Inhibitor Bypassing Activity (FEIBA NF), is a key therapeutic option for controlling acute haemorrhages in patients with high-titre inhibitors or low-titre inhibitors refractory to replacement therapy. Given the high risk for morbidity and mortality in haemophilia patients with inhibitors to FVIII or FIX, we conducted this Phase 3 prospective study to evaluate whether prophylaxis with FEIBA NF is a safe and effective treatment option. Over a 1-year period, 17 subjects were treated prophylactically (85 ± 15 U kg−1 every other day) while 19 subjects were treated on demand. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 7.9 (8.1), compared to 28.7 (32.3) during on-demand treatment, which amounts to a 72.5% reduction and a statistically significant difference in ABRs between arms ( P = 0.0003). Three (17.6%) subjects (ITT) on prophylaxis experienced no bleeding episodes, whereas none treated on demand were bleeding episode-free. Total utilization of FEIBA NF for the treatment of bleeding episodes was significantly higher during on-demand therapy than prophylaxis ( P = 0.0067). There were no differences in the rates of related adverse events between arms. This study demonstrates that FEIBA prophylaxis significantly reduces all types of bleeding compared with on-demand treatment, and the safety of prophylaxis is comparable to that of on-demand treatment. [ABSTRACT FROM AUTHOR]

Two distinctly different substitution principles are commonly used in haemophilia: treatment at bleeding episodes only referred to as on-demand treatment, and prophylactic factor administration. The aim of the cross-sectional study which was undertaken in young patients suffering severe haemophilia A was to challenge our hypothesis that on-demand treatment is inferior to prophylactic substitution in prevention of chronic joint disease at young age. The method involved an investigation of 40 patients from Russia ( n = 27) and Denmark ( n = 13) born between 1975 and 1990 with no history of inhibitors; Russian patients had exclusively received factor VIII on demand, while Danish patients were managed with prophylactic treatment during a mean period of 16 years since median age of 5 years. The study endpoints were clinical joint scores, Quality of Life scores and functional independence scores. Matched by identical age (±1 year) 13 Danish and 13 Russian patients were compared, while 14 age similar Russian patients served as controls. Demographic data among all groups were quite comparable. The results are that Russian patients presented with clinical joint scores at 27 ± 8.5 (mean ± SD) while matched Danish counterparts scored 3.8 ± 5.3 (mean ± SD), differences being highly significant. The number of joint bleeds in recent 5 years were 199.5 ± 135 (mean ± SD) vs. 8.1 ± 8.7 (mean ± SD). Likewise, Quality of Life and functional independence scores were significantly higher in patients on prophylaxis as compared to on-demand treatment. In conclusion, the study outcomes confirmed our hypothesis. Longer term prophylactic factor administration during childhood and adolescence prevents joint destruction. [ABSTRACT FROM AUTHOR]

Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder, which in its severe form is associated with a significant bleeding phenotype, requiring regular prophylactic therapy. A recently developed recombinant FXIII ( rFXIII) has demonstrated safety and efficacy in children aged ≥6 years and adults (mentor™1 trial). This article describes the mentor™4 trial, which has assessed the pharmacokinetics (PK) and safety of rFXIII in younger children (1 to <6 years) with congenital FXIII deficiency, and compares extrapolated PK parameters with the mentor™1 trial. Six children with congenital FXIII A-subunit deficiency received a single, 35 IU kg−1 rFXIII dose. PK properties were similar in all the children, with a mean area under the concentration vs. 30-day time curve of 248.6 IU h−1 mL−1, maximal FXIII activity (30 min) of 0.67 IU mL−1, and mean 30-day trough of 0.21 IU mL−1. All patients maintained FXIII activity above the lower target level (0.1 IU mL−1). rFXIII half-life was 15.1 days (range, 10-25). No safety findings of clinical concern were observed. PK properties of rFXIII were similar in patients from both trials. The study demonstrated that a single dose of 35 IU kg−1 rFXIII maintained plasma FXIII levels above 0.1 IU mL−1 over a 30-day period in young children with congenital FXIII deficiency, and is, therefore, likely to provide adequate prophylaxis in this age group. The study extends the previous findings of the mentor™1 trial and confirms that no dose adjustment is required for different age groups with congenital FXIII deficiency. [ABSTRACT FROM AUTHOR]

Severe haemophilia is often managed by prophylactic factor infusions in developed countries. The benefits of secondary prophylaxis in adults are currently being studied and adherence to the prescribed prophylactic factor regimen is vital to decreasing bleeding episodes. The aim of this study was to measure discrepancy between the physicians' prescription for prophylactic factor usage, and the actual factor usage obtained through infusion logs. During this method subjects with severe haemophilia A or B ( FVIII or FIX ≤2%), from a single haemophilia clinic with complete medical and infusion records from July 01, 2009 to June 30, 2011, were evaluated. Continuous prophylaxis ≥4 weeks were included in the analysis. A scoring system for adherence to prescribed dosing and frequency was developed. A global scale of adherence was performed by two independent nurses using visual analogue scale. Thirty-one subjects, all with haemophilia A, with a median age of 26 years (range 18-56) were included. Results showed that the median ( IQR) adherence rate to prescribed frequency and dosage, respectively, was 76% (67;85) and 93% (73;97). In multivariate analysis, only the length of time on prophylaxis during the study period showed a positive correlation with adherence whereas age, number of co-infections, number of bleeds and number of joints with chronic arthropathy did not. Global nursing assessments were in general agreement with the score. In conclusion, we observed a moderately good level of adherence based on score and by the nurse global assessment. Better adherence was found in subjects with longer exposure to prophylaxis. [ABSTRACT FROM AUTHOR]

BAX326 is a recombinant factor IX (rFIX; nonacog gamma) manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps (solvent/detergent treatment and 15 nm nanofiltration). The aim of this prospective trial was to investigate the pharmacokinetics, haemostatic efficacy and safety of BAX326 in previously treated patients aged 12-65 years with severe or moderately severe haemophilia B. BAX326 was safe and well tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7% incidence, all non-serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence ( n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC0-72 h per dose. Twice-weekly prophylaxis [mean duration 6.2 (±0.7) months; 1.8 (±0.1) infusions per week, 49.5 (±4.8) IU kg−1 per infusion] was effective in preventing bleeding episodes, with a significantly lower (79%, P < 0.001) annualized bleed rate (4.2) compared to an on-demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43%) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7%) were controlled with one to two infusions of BAX326. Haemostatic efficacy at resolution of bleed was rated excellent or good in 96.0% of all treated bleeding episodes. The results of this study indicate that BAX326 is safe and efficacious in treating bleeds and routine prophylaxis in patients aged 12 years and older with haemophilia B. [ABSTRACT FROM AUTHOR]

Obtaining a reliable venous access is a limiting factor for early initiation of clotting factor prophylaxis and immune tolerance induction. To circumvent this issue, central venous access devices ( CVADs) are increasingly being used. Catheter-related infections ( CRIs) remain the primary complication of insertion of CVAD. Thus, newer strategies for treatment and prevention of CRI are needed. Ethanol lock therapy ( ELT) has been used to treat and prevent CRI in non-bleeding disorder patients. The aim of this study was to assess the efficacy of ELT in treating and preventing CRI in bleeding disorder patients. The medical charts of patients with bleeding disorders who underwent ELT for antimicrobial resistant CRIs were reviewed and data were analysed. ELT was effective in catheter salvage in 87% of patients with antimicrobial resistant CRI by a wide variety of pathogens. Prophylactic therapy with ethanol lock was associated with catheter dysfunction especially in mediports. ELT should be considered prior to removal of catheters in bleeding disorder patients with resistant CRIs. Further studies are needed for using prophylactic ethanol lock in prevention of CRIs in bleeding disorder patients. [ABSTRACT FROM AUTHOR]

Long-term adherence to prophylactic therapy is the key to successful prevention of bleeds in severe haemophilia. The present study aims to provide a systematic review of the literature on the determinants of adherence to prophylaxis in haemophilia. A literature search in the largest medical databases in Oct 2011 yielded 880 articles, which were reduced to 72 by further selection on title. Twenty-eight articles were excluded due to inclusion criteria. Full paper evaluation of 44 articles yielded five relevant articles that were critically appraised using the STrengthening the Reporting of OBservational studies in Epidemiology ( STROBE) statement and items extracted from the critical appraisal criteria for cohort studies (Dutch Cochrane Centre). After critical appraisal, 2/5 studies were considered as the best evidence available. The results of these two studies were further used in the synthesis for description of the determinants of adherence. This concerned a total of 245 subjects in all age groups. Data were collected using questionnaires and interviews. Motivators for a high adherence were as follows: experience of symptoms, a positive belief of necessity of treatment and a good relationship with the health care provider. Important barriers were defined as: infrequent or absence of symptoms and increasing age. Two high-quality studies were identified. Reported determinants of adherence to prophylaxis were age, symptoms, beliefs, and the relation with the health care provider. This information may provide a first step towards a strategy to promote adherence in haemophilia, with an important focus on age-specific interventions and patient education. [ABSTRACT FROM AUTHOR]

The article presents abstracts of various studies related to hemophilia discussed during the 6th Annual Congress of the European Association for Haemophilia and Allied Disorders which includes "Prophylaxis in Adults," by researcher P. Collins and colleagues, "Is Hemophilia B Less Severe Than Hemophilia A?," by P.M. Mannucci and colleagues and "Current Issues on Pathogen Safety in Coagulation Factor Concentrates," by R. Lassila and colleagues.

We recently showed in a single centre trial that low-dose secondary prophylaxis in severe/moderate haemophilia patients with arthropathy is feasible and beneficial. However, this regimen has not been validated in a multicentre setting and what obstacles are there to prophylaxis remain unclear. (i) Benefit study: to confirm the benefits of similar prophylaxis protocol in severe/moderate haemophilia A ( HA) in a multicentre setting in China. (ii) Follow-up obstacle study: to investigate obstacles in compliance to prophylaxis treatment. (i) Benefit study: severe/moderate HA children with arthropathy from 15 centres were enrolled to undergo an 8-week on-demand treatment, followed by 6 to 12-week low-dose secondary prophylaxis. Outcomes compared in the two periods include joint and severe bleeding, daily activities and factor consumption. (ii) Obstacle study: questionnaires to investigators to collect data on patient and centre factors contributing to inability to comply with prophylaxis. We enrolled 191 patients from 15 centres. Sixty-six (34.6%) from three centres completed the prophylaxis protocol, and they had significantly decreased bleeding (78.8% haemarthrosis and 68.9% severe bleedings) and improved daily activities with no increase in factor consumption over that in the on-demand therapy period. The remaining 125 patients from 12 centres were not compliant to the prophylaxis protocol; questionnaire data indicated that the major obstacles were inability of patients/parents to accept (41.7%) or to adhere (33.3%) to the prophylaxis protocol, mostly because of failure to understand the benefits and to accept the frequent injections. Non-availability of a centre comprehensive care team was another important determinant. Short-term low-dose secondary prophylactic therapy is beneficial without increasing factors consumption for severe/moderate HA with arthropathy in a multi-centre setting in China. Obstacles to overcome must include improvement in comprehensive care and in education to patient/parents and healthcare personnel. [ABSTRACT FROM AUTHOR]

In 2008 the 10 Principles of Haemophilia Care were outlined to provide a benchmark for haemophilia treatment. The EHTSB performed a survey to establish to what extent the Principles of Haemophilia Care were being applied throughout Europe. In total, 21 centres from 14 countries ( France, UK, Germany, Switzerland, Sweden, Norway, the Netherlands, Belgium, Poland, Portugal, Slovakia, Spain, Greece and Italy), were surveyed. A central organization of haemophilia care (principle 1) was present in 79%, and a central patient registry in 57% (principle 2). National haemophilia care decision-making was performed by clinicians, ministries and patient organizations (principle 4). All had designated comprehensive care centres ( CCC - principle 3), responsible the majority of severe patients, but in 36% some patients were treated outside CCC/haemophilia treatment centres ( HTC)s. Clotting factor concentrates were available everywhere, without dosing restraints (principle 5), including recombinant products in 86% of countries. Prophylactic treatment was available for all children but not for all adults (principle 7). Immune tolerance was available in all countries (principle 9). Home treatment was supported and taught by all centres (principle 6). At centre level, 86% had 24-h laboratory facilities and all participated in education and research (principle 10). An experienced haematologist was available at all centres, a paediatrician in 47%, and prompt out of hours review was available in all (principle 8). The Principles of Haemophilia Care were generally applied throughout Europe. Some aspects of centralization, national organization of care, use of registries, formal paediatric care and prophylaxis for adults may be improved. [ABSTRACT FROM AUTHOR]

A number of studies have been published on the benefits of prophylactic treatment in adults with haemophilia. However, in many countries, it is considered as optional due to financial constraints. This survey was carried out to examine the long-term effects of prophylaxis and the continuing benefit of the treatment into adulthood. Self-assessed health-related data and the EQ-5D questionnaire measuring health utility were collected from 124 men (26.9 ± 4.6 years) from Canada ( N = 40), France ( N = 14), Ireland ( N = 17), the Netherlands ( N = 16), Poland ( N = 24) and the UK ( N = 13). The respondents were split into four groups: On-Demand, <50% life on prophylaxis, ≥50% life on prophylaxis, Prophylaxis. Overall, long-term prophylaxis results in lower presence of target joints ( P ≤ 0.001), occurrence of serious bleeding episodes ( P ≤ 0.05), recurring bleeding episodes ( P ≤ 0.01) and requirement for surgical procedures ( P ≤ 0.05). Furthermore, health utility ( P ≤ 0.01) in the On-demand group was significantly lower ( P ≤ 0.01) compared to the ≥50% life on prophylaxis and the Prophylaxis group. No significant differences between countries were found except between the Netherlands and Poland, with Poland showing the lowest health utility ( P ≤ 0.01) and the most problems with mobility ( P ≤ 0.05) and pain/discomfort ( P ≤ 0.001). The Netherlands showed the highest health utility (0.915) followed by Canada (0.791), Ireland (0.786), UK (0.768), France (0.687) and Poland (0.629). The results demonstrate consistently higher quality of life of individuals who are on long-term prophylactic treatment when compared to on-demand treatment or intermittent prophylaxis and on -demand treatment. [ABSTRACT FROM AUTHOR]

The bleeding patterns of severe von Willebrand's disease ( VWD) adversely affect quality of life, and may be life threatening. There is a presumed role for prophylaxis with VWF-containing concentrates, but data are scarce. The von Willebrand Disease Prophylaxis Network ( VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is not responsive to other treatment(s).Using a retrospective design, the effect of prophylaxis was studied. Availability of records to document, or reliably assess, the type and frequency of bleeding episodes prior to, and after, the initiation of prophylaxis was required. Annualized bleeding rates were calculated for the period prior to prophylaxis, during prophylaxis and by primary bleeding indication defined as the site accounting for more than half of all bleeding symptoms. The Wilcoxon signed-rank test of differences in the medians was used. Sixty-one subjects from 20 centres in 10 countries were enrolled. Data for 59 were used in the analysis. The median age at onset of prophylaxis was 22.4 years. Type 3 VWD accounted for the largest number ( N = 34, 57.6%). Differences in bleeding rates within individuals during compared with before prophylaxis were significant for the total group ( P < 0.0001), and for those with primary bleeding indications of epistaxis ( P = 0.0005), joint bleeding ( P = 0.002) and GI bleeding ( P = 0.001). The effect of prophylaxis was similar among those age < 18 years and those ≥18. One person developed an inhibitor during treatment. We conclude that prophylactic treatment of VWD is efficacious. [ABSTRACT FROM AUTHOR]

. Haemophilia, if not properly managed, can lead to chronic disease and lifelong disabilities. The challenges and issues in infants/young children are different from those in older children and adults although episodes of bleeding still predominate as the diagnostic trigger. Awareness of clinical manifestations and treatment complications are crucial in instituting appropriate management and implementing preventive strategies. Currently, inhibitor development is a challenging complication of paediatric haemophilia and prophylaxis is emerging as the optimal preventive care strategy. In this section we will review some important aspects of haemophilia in children including early prophylaxis, current evidence relating to inhibitor development, including the aims of the SIPPET study which is already ongoing and involves boys <6 years, and the potential of immune tolerance therapy for eradicating the inhibitor and permitting a resumption of standard dosing schedules. [ABSTRACT FROM AUTHOR]

. It is well known and often reported that patients with long-term health conditions have problems adhering to treatment regimens. This is often reportedly worst in adolescents who struggle with the physical and psychological impact of adolescence as well as with the limitations that treatment regimens impose on their day-to-day activities. This article presents results from a larger study that aimed to discover what living with haemophilia in the 21st century was like for boys with severe haemophilia. The overall study was a multi-method, cross-sectional interview based study of 30 boys with severe haemophilia, treated with prophylaxis at a single site in the UK. Although not specifically asked in the interview schedule, opinions about treatment (prophylaxis) were given by 66% of the boys. These boys recognized that prophylaxis offered them protection from bleeding, the older and more sporty boys understood the need for tailored prophylaxis around 'risk' activities such as sport or events away from home. For some boys this meant low dose daily prophylaxis, and this further enhanced treatment adherence, as it became firmly embedded in their daily ritual of health care. This study shows that adolescent boys are in fact adherent with treatment, possibly at a schedule decided upon by them rather than one directed by the haemophilia centre. They are able to comprehend complex treatment decisions and make treatment plans that offer them maximum protection with minimal interference in their day-to-day activities. [ABSTRACT FROM AUTHOR]

. The very high cost of haemophilia care, including the increase in use of factor prophylaxis in both children and adults requires that funders of clotting factor concentrates require objective measures of health, such as joint status and quality of life (QOL). Many clinical trials, especially those for licensing of new products, are including QOL instruments in their protocols to evaluate the patients' perspective of wellbeing before and during therapy. This article gives a perspective on QOL the importance of QOL measurement in the field of haemophilia and its impact on patient outcome. [ABSTRACT FROM AUTHOR]

. Severe haemophilia is associated with recurrent joint bleeds, which can lead to haemophilic arthropathy. Subclinical joint bleeds have also been associated with joint damage detected using magnetic resonance imaging (MRI). We investigated the development of early changes in clinically asymptomatic joints using MRI in haemophilia A or B patients receiving prophylactic therapy. In this single-centre retrospective cohort study, patients with clinical evidence of joint damage in one ankle and one clinically asymptomatic ankle, in which we performed an MRI scan of both ankles in one session, were enrolled. MRI findings were graded using a 4-point scoring system (0 = normal findings and III = severe joint damage). Since 2000, 38 MRIs in 26 patients have been performed. Starting at a median age of 4 years, 23 patients received prophylaxis 2-3 times weekly. On-demand treatment was performed in three patients. Eight patients (31%) presented with an MRI score of 0, 12 (46%) had a score of I, four (15%) had a score of II, and two (8%) had a score of III in the clinically unaffected ankle. The six patients with MRI scores of II and III had started regular prophylaxis between the ages of 2 years and 15 years; none had developed an inhibitor or experienced a clinically evident bleed in the asymptomatic ankle. During our study, five of 26 patients had a worsening of MRI findings without experiencing a joint bleed. Early morphological changes in clinically asymptomatic ankles can be detected using MRI, despite adequate prophylaxis. [ABSTRACT FROM AUTHOR]

Summary. Haemophilia A individuals displaying a similar genetic defect have heterogeneous clinical phenotypes. Our objective was to evaluate the underlying effect of exogenous factor (f)VIII on tissue factor (Tf)-initiated blood coagulation in severe haemophilia utilizing both empirical and computational models. We investigated twenty-five clinically severe haemophilia A patients. All individuals were on fVIII prophylaxis and had not received fVIII from 0.25 to 4 days prior to phlebotomy. Coagulation was initiated by the addition of Tf to contact-pathway inhibited whole blood ± an anti-fVIII antibody. Aliquots were quenched over 20 min and analyzed for thrombin generation and fibrin formation. Coagulation factor levels were obtained and used to computationally predict thrombin generation with fVIII set to either zero or its value at the time of the draw. As a result of prophylactic fVIII, at the time of the blood draw, the individuals had fVIII levels that ranged from <1% to 22%. Thrombin generation (maximum level and rate) in both empirical and computational systems increased as the level of fVIII increased. FXIII activation rates also increased as the fVIII level increased. Upon suppression of fVIII, thrombin generation became comparable in both systems. Plasma composition analysis showed a negative correlation between bleeding history and computational thrombin generation in the absence of fVIII. Residual prophylactic fVIII directly causes an increase in thrombin generation and fibrin cross-linking in individuals with clinically severe haemophilia A. The combination of each individual's coagulation factors (outside of fVIII) determine each individual's baseline thrombin potential and may affect bleeding risk. [ABSTRACT FROM AUTHOR]

Summary. We aimed to evaluate the effect of regular prophylaxis with a Factor X (FX) concentrate for patients with severe FXD in Iran and to assess the correlation of the genotype and phenotype in these patients. Ten patients with severe FXD (FX activity <1%) were enrolled and characterized during 2010-2011. Prophylaxis with 20 IU FX P Behring per kg body weight was administered once a week. FX levels, were monitored at baseline, 15 and 30 min, 1, 3, 6, 12, 24, 48, 72 and 96 h after starting prophylaxis. All patients were followed for 1 year. The mean age of the patients was 15 ± 7.8 years (age range of: 6-27 years). One patient had anaphylactic reaction after the first infusion, and the treatment was stopped. During one-year follow-up after starting prophylaxis, no bleeding symptoms occurred in any patient who tolerated and remained on the prophylaxis programme and all of them had a FX level of 1% or above. The maximum level of FX activity has been observed at 15 min after starting prophylaxis. A level of 1.5-3.5% was detected after 96 h. Homozygous mutations p.Arg40Thr (Arg-1Thr), p.Gly51Arg and p.Glu69Lys were detected in patients with intracranial haemorrhage. In our patients, significant decrease in symptoms without any complication after administration of FX, was demonstrated in all except one patient who had an anaphylactic reaction. It seems that the dose of 20 IU kg−1 could be probably the best choice for patients with severe FXD, who require regular prophylaxis. [ABSTRACT FROM AUTHOR]

The article discusses the study that evaluates the effectiveness of Immune tolerance induction with a factor VIII concentrate containing von Willebrand factor in treating patients with haemophilia A. It reveals that all patients achieved immune tolerance and successfully changed to standard prophylaxis after median 17.6 months. It found no difference concerning success rate between the two groups when the one patient who withdrew treatment is not considered.

Summary. Currently, patients with severe haemophilia can expect to lead a relatively normal life including prevention of disabling arthropathy as a result of the development of factor replacement therapy and advances in the understanding of the use of such therapy given prophylactically. Unfortunately, a subset of patients develops neutralizing antibodies termed inhibitors rendering such therapy ineffective. These patients frequently develop recurrent joint bleeding resulting in arthropathy. Until recently, prophylactic therapy was not considered for patients with inhibitors because of the perceived lack of an effective therapeutic agent. However, an accumulation of case reports and a recent prospective study have suggested that prophylaxis with the currently available bypassing agents could be effective and appears to be safe in selected cases. This report will review the current data on prophylaxis with bypassing agents and suggest specific situations in which prophylaxis in inhibitor patients could be considered. [ABSTRACT FROM AUTHOR]

For patients with haemophilia, the development of inhibitors complicates treatment, and inhibitor patients may thus have a range of unmet needs. Although successful inhibitor eradication will render patients responsive to factor replacement therapy, with potentially beneficial effects on long-term outcomes, this may not always be possible. Physicians treating inhibitor patients should aim to achieve reliable control of bleeding episodes, and the prevention of joint disease should also be a priority. Patients with high-titre inhibitors require therapy with bypassing agents – recombinant activated factor VII (rFVIIa) or a plasma-derived activated prothrombin complex concentrate (pd-APCC) – for the treatment of bleeding. When treating joint haemorrhage in inhibitor patients, both aggressive treatment of intercurrent joint bleeds and prophylaxis should be considered, although evidence is needed as to whether prophylaxis with bypassing agents can significantly delay/prevent the development of osteochondral changes in patients with inhibitors. Despite physicians’ best efforts, joint disease may ultimately occur in inhibitor patients, and in such instances optimizing treatment, of both early and late stages, is important. There is no single therapeutic modality for dealing with the various treatment challenges posed by inhibitor patients, but overall goals should be to improve quality of life, with the provision of cost-effective care that aims to maintain physical function. [ABSTRACT FROM AUTHOR]

Prophylaxis is increasingly prescribed in treatment of haemophilia and its benefit is believed to be most significant for the youngest patients as haemophilic arthropathy may be prevented if prophylaxis is initiated prior to recurrent haemarthroses. While clinical prophylaxis data are readily available for haemophilia A, analogous data for haemophilia B are relatively limited. A prospective clinical study of recombinant factor IX (BeneFIX®; rFIX), designed to allow investigator prescribed prophylaxis according to customary practices, was conducted in children <6 years old with severe haemophilia B. Nearly all children were prescribed prophylaxis (22/25; 88%) for all or part of their study participation. Favourable efficacy and safety profiles were reported. Routine prophylaxis with 1 or 2 rFIX infusions per week over an average of greater than 6 months of therapy resulted in near complete prevention of spontaneous breakthrough haemorrhages (<1 per year), with most children (77%) having none, including seven patients (32%) who had no bleeding episodes at all. Haemorrhages in joints were less common than those outside joints (27% vs. 73% of haemorrhages). In a patient population that included children with multiple prior haemarthroses, 68% of children had no joint bleeding. Breakthrough haemorrhages resolved with 1 or 2 infusions in 89% of episodes. The absence of changes in prophylaxis infusion schedules suggests that 1 or 2 rFIX infusion(s) per week were well-tolerated by these young patients, including those with (41%) and without (59%) central venous access devices. Safety was established by the low incidence of treatment-related adverse events. [ABSTRACT FROM AUTHOR]

Physical activity has been considered as an important factor for bone density and as a factor facilitating prevention of osteoporosis. Bone density has been reported to be reduced in haemophilia. To examine the relation between different aspects of physical activity and bone mineral density (BMD) in patients with severe haemophilia on long-term prophylaxis. The study group consisted of 38 patients with severe haemophilia (mean age 30.5 years). All patients received long-term prophylaxis to prevent bleeding. The bone density (BMD g cm−2) of the total body, lumbar spine, total hip, femoral neck and trochanter was measured by dual energy X-ray absorptiometry. Physical activity was assessed using the self-report Modifiable Activity Questionnaire, an instrument which collects information about leisure and occupational activities for the prior 12 months. There was only significant correlation between duration and intensity of vigorous physical activity and bone density at lumber spine L1-L4; for duration ( r = 0.429 and P = 0.020) and for intensity ( r = 0.430 and P = 0.019); whereas no significant correlation between all aspects of physical activity and bone density at any other measured sites. With adequate long-term prophylaxis, adult patients with haemophilia are maintaining bone mass, whereas the level of physical activity in terms of intensity and duration play a minor role. These results may support the proposition that the responsiveness to mechanical strain is probably more important for bone mass development in children and during adolescence than in adults and underscores the importance of early onset prophylaxis. [ABSTRACT FROM AUTHOR]

Prophylaxis with concentrates of factor VIII has become the standard of care for patients with severe haemophilia A because of its ability to prevent joint and other bleeding events. Recent evidence suggests that the prophylactic use of bypassing therapy – activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) – provides similar benefits to haemophilia patients with inhibitors. To assess the efficacy and safety of prophylaxis with the aPCC FEIBA, a meta-analysis was conducted of six studies and a total of 34 inhibitor patients. The mean prophylactic dose was 78.5 U kg−1, typically infused three to four times weekly. A total of 31 of 33 patients (94%) for whom bleeding data were available prior to prophylaxis experienced a decrease in the rate of haemorrhage, albeit minor in some patients, and, regardless of the type of haemorrhage measured, had on average a 63.9% reduction in bleeding episodes during FEIBA prophylaxis. In the three studies that specifically assessed all joint bleeding, the 18 patients evaluated experienced an average reduction in annual joint bleeding of 74% while on prophylactic regimens. Among the four patients in this group who received concurrent immune tolerance induction and the 14 patients treated with prophylaxis only, annual joint bleeding decreased by an average of 79% and 78%, respectively. Anamnesis following FEIBA exposure was observed in some patients but had no impact on prophylactic efficacy. No thrombotic or other complications were reported. These results suggest that the prophylactic administration of FEIBA can be an effective and safe method for reducing bleeding events in patients with haemophilia A and inhibitors. [ABSTRACT FROM AUTHOR]

Congenital factor XIII (FXIII) deficiency is an extremely rare, yet potentially life-threatening, bleeding disorder, with a 30% rate of spontaneous intracranial haemorrhage. Routine prophylactic management is recommended for all individuals with clinically relevant (FXIII) deficiency and for all symptomatic individuals with congenital factor deficiency. Fibrogammin® P is a purified, pasteurized concentrate of FXIII that appears to carry negligible risk of viral transmission, unlike other unprocessed products containing FXIII. An ongoing Phase II/III study of Fibrogammin® P in patients with congenital FXIII deficiency is being conducted to evaluate the prophylactic efficacy and long-term safety of this product. Using retrospective chart review data from subjects enrolled in the Phase II/III study, the current analysis was designed to compare spontaneous bleed-event rates prior to and after the initiation of Fibrogammin® P prophylaxis. Seven subjects were evaluable for comparison, having received no other prophylactic FXIII-containing product during the 24 months prior to study entry. The mean annual number of spontaneous bleeds was 2.5 events per year prior to Fibrogammin® P prophylaxis and 0.2 events per year during Fibrogammin® P prophylaxis ( P = 0.01). Patients reported no severe bleeds during Fibrogammin® P therapy. This small sample supports a consistent and clinically meaningful reduction in spontaneous bleeding with prophylactic use of Fibrogammin® P. [ABSTRACT FROM AUTHOR]

The article presents several case studies to prevent bleeding and joint damage with the help of prophylaxis treatment of severe hemophilia patients. A 19 year old boy started prophylaxis at the age of seven which has reduced his joint bleeding episodes or trauma. A 21year old man diagnosed with hemophilia followed prophylaxis treatment regularly and resulted in effective state. But, the use of FVIII prophylaxis treatment by a 61 year old man with severe hemophilia was ineffective.

This paper reviews current issues regarding short-term (i.e. for surgery and invasive procedures) and long-term (i.e. regular infusions to prevent bleeding on a permanent or temporary basis) prophylaxis treatment using replacement concentrates for patients with von Willebrand disease (VWD) who do not respond satisfactorily to desmopressin. The standard treatment of these patients is with factor concentrates containing von Willebrand factor (VWF) and factor VIII (FVIII). When dosing these concentrates, the broad variations in content and quality of VWF as well as the FVIII content in the products should be considered. Peri-operative management strategies will depend on the VWD subtype, baseline VWF and FVIII levels, and size of procedure. FVIII level and VWF ristocetin cofactor activity may both be used to determine concentrate potency and to monitor treatment. Long-term prophylaxis, which has become a state-of-the-art approach in haemophilia, is not very common in VWD. However, more recent data suggest that a substantial number of VWD patients could benefit from prophylactic treatment with VWF-containing concentrates. For example, 35 Swedish VWD patients who required prophylaxis (mainly because of nose/mouth bleeds and joint bleeds) showed a substantial overall reduction in bleeding episodes and there were no signs of arthropathy in children who began prophylaxis before the age of 5 years since initiation of treatment with Haemate® P/Humate-P®. Studies of prophylaxis in VWD are urgently needed to develop evidence-based guidelines for this approach; the VWD International Prophylaxis study, for example, has commenced by the VWD Prophylaxis Network. [ABSTRACT FROM AUTHOR]

Despite the tremendous benefit offered by primary prophylaxis, recurrent joint bleeding with progression to chronic synovitis and haemophilic arthropathy is still a daily concern for the multidisciplinary health care teams managing patients with severe haemophilia or haemophilia complicated by inhibitor development. Advanced stages of arthropathy could be prevented by regular assessment of musculoskeletal status and thus early detection of symptoms, daily rehabilitation exercises at home, and implementation of appropriate physiotherapy and medical training. Patient’s education and psychological counselling are crucial. New tools such as magnetic resonance imaging are promising for the monitoring of these patients and might promote early detection of arthropathy and thus appropriate preventive measures to avoid further joint deterioration can be implemented. Medical synovectomy such as radionucleide synoviorthesis is a simple and non-invasive procedure that often delays the need for surgery which despite considerable improvement in techniques and postoperative rehabilitation remains a high-risk strategy in patients with severe haemophilia, especially those with inhibitors. In these high risk patients, availability of specific clotting factors such as activated prothrombin complex concentrate (FEIBA®, Baxter, Vienna, Austria) and more recently, recombinant factor VIIa (rFVIIa, NovoSeven®, Bagsvaerd, Denmark) has allowed to perform effective and safe orthopaedic procedures. The on-going EUREKA study will undoubtedly provide additional information about the optimal use of rFVIIa in this context. [ABSTRACT FROM AUTHOR]

Prophylactic substitution treatment and radiosynoviorthosis have a leading role in preventing irreversible haemophilic arthropathy. The aim of the study was to evaluate the effects of prophylaxis treatment and radiosynovectomy on the length of intervals between subsequent haemorrhages in haemophilic patients. Thirty-three joints were treated with radiosynovectomy in 28 patients with bleeding disorders. 90Y colloid was used in knees and 186Re colloid for elbows, shoulders and ankles. Twenty patients were on prophylaxis. Joint X-rays were evaluated on the Pettersson scale between 0 (normal) and 13 (severe joint destruction). During an observation period (range 6–44 months) bleeding episodes were recorded and data statistically analysed. Before radiosynovectomy, increasing intensity of the prophylaxis 10% lengthens intervals between two haemorrhages by 1% ( P < 0.05). In patients with a Pettersson score higher than nine, intervals between bleedings are shorter by 73% ( P < 0.05), in comparison with patients with lower Pettersson scores of 0–5. After radiosynovectomy, the length of the first non-bleeding interval increased by 120% (to 60 days) in comparison with the intervals before the procedure ( P < 0.001). But, in the following year and half, every subsequent non-bleeding interval was 8% shorter ( P < 0.1). In that period, prophylaxis shortened the non-bleeding interval by 1.7% ( P < 0.05) per 10% increase of its intensity. Radiosynovectomy is more efficient in patients with less affected joints and is less efficient in younger patients. Prophylaxis reduced time between the bleedings episodes after isotope application. Before radiosynovectomy, prophylaxis reduces the number of haemorrhages. Our findings support data previously published by Rodriguez-Merchan et al. [ J Thromb Haemost, 5 (2007) P-W-126]. [ABSTRACT FROM AUTHOR]

It has been suggested that more RCTs should be conducted in the evaluation of haemophilia treatment, including prophylaxis. To draw valid conclusions from experimental or observational studies, internal validity should be ensured. In particular, similarity of prognosis between treatment groups compared in a particular study is needed. Because the use of prophylaxis in observational studies is nonrandomized by definition, special efforts should be made to achieve comparability of prognosis, that is, to avoid ‘confounding by indication’; in RCTs this is ensured by randomized allocation of treatment. However, the high costs of an RCT results in a limitation of both patient numbers and length of follow up. Observational studies tend to be more generalizable and cheaper, as they may include a wider spectrum of morbidities, use treatment protocols in agreement with routine care, and use available data. Therefore, observational studies can be much larger and of longer duration than RCTs; and are the preferred design for the evaluation of long term treatment effects. Several valid observational studies comparing prophylaxis and on demand treatment have reported both a short term reduction of 75–90% in bleeding frequency, and significant improvement in arthropathy, quality of life, and socioeconomic parameters after more than 20 years of prophylactic treatment. RCTs provide the most powerful tool for the evaluation of short term effects of any treatment, but are infeasible for the evaluation of long term effects. The definitive assessment of the long-term benefits of prophylaxis requires observational studies that should be performed according to rigorous standards. [ABSTRACT FROM AUTHOR]

Information about several topics discussed at a meeting to identify unsolved issues related to prophylaxis and its affordability is presented. It was agreed that prophylactic therapy which begins at an early age should be considered treatment of choice for severe hemophiliacs. Another issue agreed upon was that there exists considerable inter-patient variability with respect to disease severity even among hemophiliacs with similar baseline factor.

This clinical trial evaluated the safety and efficacy of ReFacto (St Louis-derived active substance) in patients with severe or moderately severe haemophilia A over a period of 6 months or 50 exposure days (EDs), whichever occurred first. Sixty patients, 58 previously treated and two previously untreated, were enrolled into this study. This was an open-label, multicentre, postmarketing surveillance study in which patients received prophylaxis or on-demand treatment as determined by their doctor. Surgical prophylaxis was evaluated in seven patients requiring elective surgery. Thirty-two patients aged <1 to 66 years (median 19.5) received prophylaxis and 28 patients, aged 1–71 years (median 33.5), received on-demand treatment. The majority of patients had severe haemophilia A (FVIII:C < 2%): 84.4% in the prophylaxis group and 85.7% in the on-demand group. Prophylaxis with ReFacto was associated with a median of 6.7 bleeds per year (range: 0–37). The investigator's assessment of final outcome for prophylactic treatment was excellent or effective for 93.1% of patients. ReFacto resolved 92.8% of bleeds with one or two infusions. The investigator's assessment was excellent or good for 98.2% of bleeds treated with ReFacto. Haemostasis was achieved for all seven surgical cases and ReFacto gave an excellent or good response for each. The nature and incidence of adverse events was as expected and no new safety concerns emerged. One previously treated patient (PTP) developed a high-titre inhibitor (maximum 75 BU) and one minimally treated patient (MTP) developed a low-titre inhibitor while on the study but eventually achieved high titres (maximum 30 BU) after immune tolerance therapy was initiated with a plasma-derived FVIII product. One previously untreated patient (PUP) developed a transient low-titre inhibitor (0.4 BU). Other serious adverse events (SAEs) were unrelated to study treatment. There were no allergic events. The results of this study are consistent with the previously published ReFacto pivotal studies. [ABSTRACT FROM AUTHOR]

Summary. Recently reported data suggest the possibility of differences in clinical efficacy between full-length factor VIII (FL-FVIII) and B-domain deleted recombinant factor VIII (BDD-rFVIII). To address this question, we conducted a meta-analysis of studies reporting the incidence of bleeding under prophylaxis, as well as studies of FL-FVIII and BDD-rFVIII half-life. The pooled cumulative weekly prophylactic dose of BDD-rFVIII (81.3 ± 13.8 IU kg-1 week-1 ) was greater by 36% (P = 0.11) than that of FL-FVIII (60.0 ± 5.9 IU kg-1 week-1 ). The pooled incidence of bleeding in BDD-rFVIII recipients [16.8 bleeds per patient year; confidence interval (CI), 9.5–24.2 bleeds per patient year] was more than 2.5-fold larger (P < 0.0005) than that in patients receiving FL-FVIII (6.6 bleeds per patient year; CI, 4.7-8.5 bleeds per patient year). In a multivariate analysis, the incidence rate ratio was 2.10 (CI, 1.98-2.24), indicating that breakthrough bleeding under prophylaxis was more than twice as likely with BDD-rFVIII than FL-FVIII at equivalent doses and ages. The pooled half-life for plasma-derived FL-FVIII (13.7 h; CI, 12.8-14.6 h) was closely similar to that for recombinant FL-FVIII (14.3 h; CI, 13.3-15.4 h). By contrast, the pooled half-life for BDD-rFVIII (11.3 h; CI, 9.9-12.7 h) was shorter by approximately 3 h compared with FL-FVIII. Although the results of the meta-analysis need to be interpreted with caution, the pooled data suggest that breakthrough bleeding under prophylaxis may occur more frequently in patients receiving BDD-rFVIII than FL-FVIII and may at least partly reflect a more abbreviated half-life of BDD-rFVIII. Several biochemical differences between BDD-rFVIII and FL-FVIII may underlie the observed disparities in bleeding incidence and half-life. This meta-analysis should be confirmed by further studies. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the success of prophylactic administration in women with bleeding diatheses.

A letter to the editor is presented regarding a haemophiliac boy with a secondary prophylaxis for three years who receives prothrombin complex concentrate (PCC) and immune tolerance induction (ITI).

A response by the authors to a letter to the editor about their article that discusses the deficiency in coagulation factor XIII (FXIII) and the proper prophylaxis intervals is presented.