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Layered optoelectronic devices are manufactured using multistep procedures that require high precision in the spatial positioning of individual materials. Current technology uses costly and tedious procedures and instrumentation. In this work instead, we propose an approach which exploits the fundamental properties of the substrate to direct the growth of the next layer, here controlled by an electrochemical potential. We have electrochemically synthesized and characterized a series of polymeric materials that are most commonly used in the field. The films produced show gradient monomer ratios embedded in the polymeric film as a function of the distance from the working electrode. Under the optimized conditions, reproducible construction of simple electronic elements, e. g., rectifying diodes, is achieved. We argue that the sequential in situ method leads to gradient composition of polymer chains and the film resulting in the rectification of electric current. We discuss how this system can open new avenues in advanced optoelectronic applications, such as organic light‐emitting diodes (OLEDs) or field‐effect transistors (OFETs). [ABSTRACT FROM AUTHOR]

Porous graphene with catalytically active ceria nanometre‐size particles were prepared using pulsed laser deposition (PLD) on graphene produced through chemical vapour deposition (CVD). The reported process provided porous graphene containing ceria nanoparticles as confirmed by HR TEM and XPS. Isotopically labelled 13C graphene was employed to study desorption of the species containing carbon. Methanol adsorption was utilised to probe the nature of the catalytic activity of prepared ceria decorated graphene. The important role of graphene support for the stabilization of reduced ceria nanoparticles was finally confirmed. Increased dehydrogenation activity of graphene with ceria nanoparticles leading to CO and H2 formation was demonstrated. [ABSTRACT FROM AUTHOR]

Introduction: Contemporary haemophilia management recommends sport and physical activity in children with haemophilia. Assessment of subjective physical functioning requires standardized and validated instruments. Aims: To adapt and psychometrically test the adult Haemophilia & Exercise Project‐Test‐Questionnaire (HEP‐Test‐Q) for children (aged 6‐17 years). Methods: In discussion rounds with children, single items of the adult HEP‐Test‐Q were reformulated to make them understandable without changing the item concept. The validation of the child‐adapted version in children with haemophilia (n = 228) included pre‐testing with feasibility testing, cognitive interviewing (n = 34), pilot‐testing of the revised version in the EIS Study (n = 67) and field‐testing in the SO‐FIT Study (n = 127). Results: Pre‐testing revealed a completion time of 8.2 ± 4.1 minutes and children liked the instrument. Cognitive interviews demonstrated that most items were easy to understand; 9 items were reformulated. Pilot‐testing demonstrated good psychometric characteristics in terms of reliability (α = .94 Total Score) and validity. Convergent validity testing showed moderate correlations with the Haemo‐QoL (r = −.491), but low correlations with the Petrini Score (r = −.293). Known groups' validity revealed significant differences in clinical subgroups; chronic pain (P < .002) and target joints (P < .021). Field‐testing confirmed psychometric characteristics; Cronbach's alpha ranged from α = .80 ("endurance") to α = .94 (Total Score). The child‐adapted HEP‐Test‐Q showed moderate correlations with the PedHAL (r = .634, P < .0001) and the Haemo‐QoL SF (r = −.575, P < .0001). Known groups' validity testing proved that the HEP‐Test‐Q could discriminate between clinical subgroups. Conclusion: The child‐adapted HEP‐Test‐Q is a short, practical and acceptable instrument for the assessment of subjective physical functioning. Outcomes can be compared to adults because item concepts are identical to the adult version. [ABSTRACT FROM AUTHOR]

The development of high‐titre inhibitory antibodies (inhibitors) against factor VIII (FVIII) remains a challenge in the management of patients with haemophilia A (HA). Patients with high‐titre inhibitors are more likely to experience uncontrolled bleeding, physical disability from chronic arthropathy and premature death compared with those without this complication. Immune tolerance induction (ITI), utilizing repeated infusions of FVIII, is an effective therapeutic approach to eliminating inhibitory antibodies. This strategy can eradicate FVIII inhibitors, so that FVIII‐specific tolerance is induced. However, patients undergoing ITI are still vulnerable to the development of serious and/or repeated bleeding events. The efficacy of bypassing agents in preventing bleeding episodes has been widely proven in patients with HA and inhibitors to FVIII. Evidence suggests that reducing bleeding during ITI can also shorten the time to tolerance. There are concerns with the use of bypassing agents, including the cost of treatment, short half‐life, management of non‐responders and the risk of thrombosis. Despite these concerns, and the still limited evidence from prospective studies and consensus reports, the use of prophylaxis with bypassing agents during ITI has been gaining support. This review presents a rationale and current data supporting the use of prophylactic bypassing agents as effective and safe therapies to reduce the incidence of joint bleeding due to inhibitors and improve quality of life in patients with HA undergoing ITI. [ABSTRACT FROM AUTHOR]

Background Prophylactic replacement with factor concentrate is the optimal treatment for persons with severe haemophilia to avoid or minimize bleeding. This ultimately prevents or reduces joint disease and improves life expectancy and quality of life towards values matching those in the normal population. However, uncertainty still exists around the optimal regimens to be prescribed for prophylaxis. An increasing number of treating physicians and patients are showing interest in patient-tailored approaches to prophylaxis, which aim to harmonize the prophylaxis regimen with the patients' bleeding phenotype, levels of physical activity and a variety of other variables. Methods A modified Delphi technique was adopted to generate consensus. The expert panel met in person to set the objectives, be trained on the Delphi technique and agree on the desired level of consensus. Three iterations were used to identify the targets, the scenarios and their combinations. Results Twenty-eight scenarios and eight target levels were identified and used to issue recommendations. The panel reached the desired level of consensus on positive or negative recommendations. Areas where consensus was not reached were identified and proposed as areas for future research. Prospective assessment of the validity of most of the proposed targets is recommended. Conclusions We have generated, by expert consensus, target plasma levels of factor concentrate to be used to tailor treatment for persons with haemophilia. [ABSTRACT FROM AUTHOR]

Introduction The prophylactic administration of clotting factor concentrate is currently the most effective strategy for the prevention of joint bleeding. As new agents with different mechanisms of action and administration schedules are developed, it will be important to study them in relevant preclinical models. Aim The aim of this study was the standardization of a mouse haemarthrosis model in a haemophilia mouse and the development and validation of a comprehensive bleeding assessment system, the Bleeding Severity Score ( BSS). Methods and Results Four outcome measurements were assessed, two of which, the extra-articular bleeding score and intra-articular bleeding score, were determined to be the most reliable and were summarized into a BSS which was validated using a mouse haemarthrosis variability model. Conclusion Using this model, the haemostatic effect of prospective drugs can be assessed in a clinically relevant joint bleeding model and will significantly increase the value of preclinical studies. [ABSTRACT FROM AUTHOR]

Inhibitor development in haemophilia patients is challenging especially when undergoing surgical procedures. The development of an inhibitor precludes using factor VIII (FVIII) therapy thereby requiring a bypassing agent ( BPA) for surgical bleeding prophylaxis if the FVIII inhibitor titre >5 BU. Concomitant use of anti-inhibitor coagulant complex ( AICC) and tranexamic acid has been reported in the literature as a beneficial treatment for this population. Anti-inhibitor coagulant complex is known to cause an increase in thrombin generation and tranexamic acid inhibits fibrinolysis. Hence, the combined used of AICC and tranexamic acid has been limited due to safety concerns over possibilities of increased risk of thrombotic events and disseminated intravascular coagulation. However, the rationale for concomitant therapy is to obtain a potential synergistic effect and to increase clot stability. We conducted a literature review of past studies and individual case reports of concomitant use of AICC and tranexamic acid, which was extensively used during dental procedures. Evidence also exists for concomitant use of the combined therapy in orthopaedic procedures, control of gastrointestinal bleeding, epistaxis and cerebral haemorrhages. Some patients who received the combined therapy had failed monotherapy with a single BPA prior to combined therapy. There were no reports of thrombotic complications related to the concomitant therapy and haemostasis was achieved in all cases. Anti-inhibitor coagulant complex and tranexamic acid therapy was found to be safe, well-tolerated and effective therapy in haemophilia patients with inhibitors. Additional randomized controlled studies should be performed to confirm these findings. [ABSTRACT FROM AUTHOR]

von Willebrand disease ( VWD), an inherited bleeding disorder caused by deficiency or dysfunction of von Willebrand factor ( VWF) is diagnosed when a personal and often a family history of excessive mucocutaneous bleeding is present along with abnormal laboratory studies. An accurate assessment of haemorrhagic symptoms is key in suspecting VWD but presents a challenge especially in children due to overlap between normal and abnormal bleeding. Bleeding questionnaire ( BQ) scores have been validated in adults and have recently been validated in children with VWD for assessing bleeding severity. However, there are limited data supporting their use prospectively in healthy children with bleeding complaints. Aim The objectives of this study were to obtain normative data from children and validate a paediatric BQ (PBQ) to determine the discriminative ability of its total score and its individual components for identifying children likely to have VWD. Methods The PBQ was administered to 1281 multiethnic, healthy children between 30 days and 18 years of age presenting to a general paediatric office and to 35 children with VWD based on VWF antigen, activity and multimer pattern. Results When children with total BQ scores of 3 or more were predicted to have VWD, the sensitivity was 97.2%, the specificity was 97.1%, the positive predictive value was 48.6% and the negative predictive value was 99.9%. Conclusions The PBQ may help discriminate a significant bleeding history from trivial bleeding, may be integrated into the primary care algorithm for evaluating children suspected with VWD. [ABSTRACT FROM AUTHOR]

Introduction The development of anti-factor VIII (FVIII) antibodies (inhibitors) is the most serious treatment-related complication in patients with hemophilia A, rendering standard replacement therapy ineffective, heightening the risk for uncontrollable bleeding and morbidity, decreasing quality of life, and increasing healthcare costs. Aim Formulate evidence-based guidelines for optimizing immune tolerance induction (ITI) in patients with hemophilia A and inhibitors. Methods Results from the International ITI study and other available evidence were used to develop guidelines for ITI. Results Predictors of ITI success were identified and recommendations made for ITI with regard to candidates, timing, product, regimen, monitoring, defining success, concurrent immunomodulation, duration of treatment, and bleed management before and during ITI. Conclusion Evidence-based recommendations to guide treatment decisions may increase the likelihood of successful inhibitor eradication and the induction of FVIII tolerance in patients with hemophilia A who develop inhibitory antibodies. [ABSTRACT FROM AUTHOR]

Introduction Prophylaxis is effective in reducing the number of bleeding episodes in patients with severe or moderately severe haemophilia A and B, including those with inhibitors. However, data, predominantly from observational studies, suggest more equivocal effects on health-related quality of life ( HRQoL). Aim To examine the impact of prophylaxis on HRQoL from prospective clinical trials. Methods We performed a systematic literature review of clinical trials evaluating the efficacy of prophylaxis with factor VIII, FIX or bypassing agents. Trials assessing HRQoL via validated instruments were selected and summarized. Results Thirteen trials (haemophilia A [ n = 8]; haemophilia B [ n = 2]; inhibitors [ n = 3]) met all inclusion criteria. HRQoL instruments included the EQ-5D, SF-36, Haem-QoL-A, Haem-A-QoL, Haemo-QoL and CHO- KLAT. Improvements in HRQoL following prophylaxis were observed with the EQ- VAS, SF-36 and haemophilia-specific instruments in adult patients and were associated with reduced pain, fewer restrictions in physical activities and better general health. Prophylaxis led to statistically significant or clinically meaningful HRQoL improvement in six trials and non-significant improvement in four trials; two trials found no improvement and one reported no data. Despite study differences, consistent trends suggested that patients previously treated solely on-demand and those who experienced marked reductions in the frequency of bleeding with prophylaxis had a greater improvement in HRQoL. Conclusion Contrary to findings of observational studies, the results from the majority of prospective trials using validated instruments showed positive trends for improved HRQoL with prophylaxis in adults. [ABSTRACT FROM AUTHOR]

Introduction Central venous access devices ( CVADs) are frequently required as stable long-lasting venous access in children with haemophilia, especially those requiring immune tolerance induction ( ITI) for inhibitors. CVAD infection is one of the most frequently reported catheter-related complications in this patient population. Aim Detailed review of CVAD complications from the International ITI (I- ITI) study and analysis of potential risk factors for such complications. Methods Retrospective analysis of prospectively obtained data from the I- ITI study primarily focused on CVAD-related complications. Results A total of 115 children were recruited and 183 CVADs were placed in 99 subjects resulting in 121,206 CVAD-days observed on-study. A total of 124 CVAD infections were reported in 41 of 99 (41%) subjects with an overall infection rate of 0.94 per 1000 CVAD-days (interquartile ranges 0-1.7). A similar number of infections were observed in the two treatment arms (median: 2 and 3 in high dose and low dose respectively). Infections occurred more frequently in the presence of external catheters than with fully implanted catheters ( P = 0.026). Infected patients were significantly younger at the time of CVAD insertion (median age: 22 vs. 25 months, P = 0.020). Patients with Gram-positive infections were also significantly younger than those with Gram-negative infections (median age: 17 vs. 25 months, P < 0.0001). Conclusion CVAD infection was the most common complication observed in children with severe haemophilia and inhibitors in the frame of the I- ITI study. Younger age at CVAD insertion and external CVAD were associated with higher risk for infection. ITI outcome was unaffected by CVAD infections. [ABSTRACT FROM AUTHOR]

Many paediatric patients with haemophilia who might benefit from radiosynovectomy ( RS) for the control of synovitis do not undergo the procedure as there is controversy in the literature regarding the safety of radiation exposure after two cases of acute lymphocytic leukaemia in children with haemophilia treated with 32P RS were reported. The purpose of this review was to analyse the safety of RS in paediatric patients with haemophilia and provide a risk-benefit assessment, which practitioners could apply to their patients. Children undergoing knee RS receive a radiation dose of approximately 0.74 mSv (90 megabecquerels-MBq) and elbow and ankle RSs a dose of approximately 0.32 mSv (30-40 MBq). The radiation dose from natural sources is approximately 2 mSv and the recommended limit for patients (apart from natural sources) is 1 mSv per year. The lifetime cancer risk increases about 0.5% per 100 mSv per year. Considering the risks and benefits of RS, the authors recommend that clinicians consider this procedure in children with inhibitors or in patients without inhibitors when bleeding is recurrent and persistent despite aggressive factor replacement. [ABSTRACT FROM AUTHOR]

Prophylaxis prevents joint and other bleeding episodes in patients with haemophilia A. Development of new factor concentrates with longer circulating half-lives may encourage patients to start, continue or resume prophylaxis. The aim of this study was to compare the pharmacodynamic effect of a PEGylated full-length recombinant factor VIII ( rFVIII) concentrate with that of an unmodified rFVIII concentrate with respect to the duration of prophylactic efficacy in a murine model of haemophilic joint bleeding. Mice were pretreated with BAX 855 or unmodified rFVIII at specified times before right knee puncture to induce haemarthrosis; left knee joints served as controls. Joint bleeding was evaluated using a combination of visual and histological assessments. Administration of a single dose of unmodified rFVIII before joint puncture prevented haemarthrosis in mice up to 24 h, whereas pretreatment with BAX 855 protected the joint from bleeding up to 48 h. This pharmacodynamic study showed prolonged efficacy of BAX 855 compared to ADVATE in a haemophilia A mouse joint bleeding model. This finding supports the possibility of using BAX 855 to increase FVIII trough levels and/or extend the dosing interval in patients with haemophilia A on prophylaxis, which may potentially improve prophylactic efficacy and long-term adherence. [ABSTRACT FROM AUTHOR]

Neonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers ( HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% ( n = 64/159). Thirty-eight percent of respondents ( n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor ( n = 25; 39%) followed by the concern for bleeding ( n = 22; 34%) and issues related to vascular access in the neonate ( n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty-two percent ( n = 14) of respondents did not use more than one dose of factor replacement but 32% ( n = 21) used 1-2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3-5 (16%; n = 10) and 6-10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence-based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia. [ABSTRACT FROM AUTHOR]

Prophylaxis is considered optimal care for children and adults with severe haemophilia A because of its proven ability to reduce joint and other bleeding episodes. However, a ‘one size fits all’ approach to prophylaxis is not ideal, potentially leading to over-treatment in some individuals and under-treatment in others. Moreover, a generic plan fails to take into account a patient’s lifestyle and personal preferences. This article reviews the factors contributing to bleeding risk and joint damage and uses case studies to illustrate how these contributors can be weighed to individualize the prophylactic regimen, thereby increasing the likelihood of therapeutic success. [ABSTRACT FROM AUTHOR]

Few randomized studies have reported on the use of factor IX ( FIX) for secondary prophylaxis in haemophilia B patients. This study aimed to evaluate the efficacy and safety of two secondary prophylaxis regimens of recombinant coagulation FIX, nonacog alfa, compared with on-demand therapy. Male subjects aged 6-65 years with severe or moderately severe haemophilia B ( FIX:C ≤ 2, n = 50) and ≥12 bleeding episodes (including ≥6 haemarthroses episodes) within 12 months of study participation were enrolled in this multicentre, randomized, open-label, four-period crossover trial. The primary measure was the annualized bleeding rate ( ABR) of two prophylactic regimens vs. on-demand therapy. In the intent-to-treat group, mean ABR values were 35.1, 2.6 and 4.6 for the first on-demand period, the 50 IU kg−1 twice-weekly period, and the 100 IU kg−1 once-weekly period respectively. Differences in ABR between the first on-demand period and both prophylaxis regimens were significant ( P < 0.0001); no significant differences were observed between prophylaxis regimens ( P = 0.22). Seven serious adverse events occurred in five subjects, none related to study drug. Results demonstrated that secondary prophylaxis therapy with nonacog alfa 50 IU kg−1 twice weekly or 100 IU kg−1 once weekly reduced ABR by 89.4% relative to on-demand treatment. Both prophylaxis regimens demonstrated favourable safety profiles in subjects with haemophilia B. [ABSTRACT FROM AUTHOR]

Bleeding disorders, including haemophilia, von Willebrand disease, and platelet function abnormalities pose a substantial, ongoing management challenge. Patients with these disorders not only require treatment during bleeding events but also need effective management strategies to prepare for events ranging from minor dental procedures to major surgery and childbirth. Moreover, women with bleeding disorders often require ongoing treatment to prevent menorrhagia during childbearing years. Desmopressin ( DDAVP), a synthetic derivative of the antidiuretic hormone l-arginine vasopressin, has become a well-established tool for the management of patients with bleeding disorders in a variety of clinical settings. However, despite the widespread use of DDAVP, the available clinical evidence on its efficacy and safety in these settings is limited, and there has not been a recent comprehensive review of its role in the clinical management of patients with bleeding disorders. As such, this article provides a review of the mechanism of action and pharmacokinetic properties of DDAVP, followed by a concise summary of the available evidence for its use in the treatment and prevention of bleeding. [ABSTRACT FROM AUTHOR]

The development of inhibitors and the need for frequent venous access for FVIII injection are major challenges in current haemophilia treatment. Presently available recombinant FVIII (rFVIII) products produced in hamster cell lines are associated with inhibitor formation in up to 32% of previously untreated patients. The new human cell line-derived recombinant human FVIII (Human-cl rhFVIII) protein is the first native, unmodified truly human rFVIII product produced in a human cell line without additive animal proteins. The aim of using a human cell line for the production of rFVIII is the avoidance of non-human epitopes on rFVIII, thereby potentially reducing the rate of inhibitor development, avoiding allergic reactions and allowing personalized prophylaxis with the chance of fewer infusions. Studies to date show that prophylaxis with Human-cl rhFVIII prevents 96% of bleeding events in adults with severe haemophilia A when compared to on-demand treatment. Available pharmacokinetic data with a mean half-life of 17.1 h allow personalized prophylaxis with the chance of fewer infusions. Studies in previously treated children and adults indicate that Human-cl rhFVIII is efficacious and safe in the prevention and treatment of bleeding episodes and that none of the treated patients developed inhibitors or allergic reactions thus far. [ABSTRACT FROM AUTHOR]

The phenotypic variability in haemophilia is well documented; however, the biological basis beyond factor VIII and IX activities to explain the differing clinical pictures of the disease remains unclear. It has therefore been of interest to explore other modulators of the disease's variability. Furthermore, a scoring system that reflects the multiple facets of haemophilia symptoms would be useful to compare patients via a comprehensive assessment tool. To this end, Schulman et al., created a measure known as the Haemophilia Severity Score ( HSS) as one way to compare phenotypic severity. The aim of this study was to document the differing symptomatology of haemophilia patients using the HSS. Clinical data for 178 haemophilia patients without inhibitors were reviewed and annual incidence of haemarthrosis, orthopaedic joint scores and annual factor usage calculated. Each parameter was then entered into the formula to create the HSS for haemophilia A and B patients with mild, moderate and severe factor deficiencies. Variability in the HSS for patients with the same baseline level of factor was observed for all three deficiency levels and both haemophilia types. In addition, we found that moderate and severe haemophilic B patients tended to have more morbidity based on the above calculations than the haemophilic A counterparts. The HSS is a comprehensive tool that allows for easy numerical comparison of haemophilic patients and elucidates the variable clinical presentation of the disease. The HSS could be used to stratify patients via other possible modulators of haemophilia and discover other aetiologies of the disease. [ABSTRACT FROM AUTHOR]

In haemophilia patients with well-established high-titer inhibitors, even seemingly minor acute bleeding episodes or surgical procedures may become refractory to treatment and transform into limb- or life-threatening situations. In the absence of evidence-based treatment guidelines, this article presents 10 cases of difficult to control acute and surgical bleeding and offers consensus opinions regarding their management from a panel of experienced haemophilia treaters. [ABSTRACT FROM AUTHOR]

Prophylaxis may be beneficial for patients with severe haemophilia A who have developed inhibitors to factor VIII. The aim of this study was to determine physicians' preferences for medication attributes in the prophylactic treatment of this patient population. Haematologists from Europe ( EU) and the United States ( US) participated in a discrete choice exercise to explore their preferences for medication attributes (efficacy, cost, scientific evidence, dosing frequency and administration time) associated with prophylaxis for severe haemophilia A in patients with inhibitors to factor VIII. Physicians' preferences for medication attributes were assessed through completion of 25 trade-off tasks that included a choice between two hypothetical medications each comprised of one randomized level of each medication attribute. Participants also completed a sociodemographic questionnaire. Data were analysed using a random effects logit model. Participants ( N = 36: US = 19; EU = 17) were 80.6% men, had a mean of 19.8 years ( SD ± 8.1) [range 6-35] of practice experience. The physicians treated an average of 5.7 (±5.5) patients with severe haemophilia A and inhibitors per month and reported treating 36.2% of these patients prophylactically. The most important medication attributes for prophylactic treatment were efficacy [Relative Importance ( RI) = 35.0%] and scientific evidence ( RI = 34.1%), whereas treatment cost (12.0%), dosing frequency (10.8%) and administration time (8.2%) were less important. Results were similar across the EU and US. Efficacy and scientific evidence are the primary considerations for physicians' choice of prophylactic medications for use in this patient population. [ABSTRACT FROM AUTHOR]

Repeated haemarthroses and the consequences of blood in the joint contribute to blood induced joint disease ( BIJD) in people with haemophilia ( PWH). Prevention of bleeding, through medical management, is the standard of care in developed countries, but is not universally available due to financial and other barriers. Ice application, as part of R.I.C.E. (Rest, Ice, Compression, Elevation) or alone, is commonly recommended as an adjunct treatment to decrease bleeding, pain, tissue metabolism, oedema, and inflammation. This article will review evidence regarding local cooling by commonly used ice application methods, to decrease the temperature of the skin and intra-articular ( IA) joint space and the resultant effects on haemostasis and coagulation. The general literature was reviewed for articles in English describing temperatures achievable in the skin and IA space using clinically relevant ice protocols, and the effect of cooling on haemostasis and coagulation. The literature demonstrates that typical methods of ice application can cool both the skin and IA space. Published, general literature studies have also consistently demonstrated that experimental cooling of blood and/or tissue, both in vitro and in vivo in humans and in animal models, can significantly impair coagulation and prolong bleeding. In PWH with acute haemarthrosis, ice application has potential to increase haemorrhage morbidity by further impairing coagulation and haemostasis. Ice has not been shown to improve overall outcome, stop bleeding nor swelling from haemarthrosis. Although ice can help manage acute, haemarthrosis-related pain, there are other available interventions that will not impair coagulation and haemostasis. [ABSTRACT FROM AUTHOR]

Since the 1980s, major surgical interventions in patients with congenital haemophilia with inhibitors have been performed utilizing bypassing agents for haemostatic coverage. While reports have focused on perioperative management and haemostasis, the US currently lacks consensus guidelines for the management of patients with inhibitors during the surgical procedure, and pre- and postoperatively. Many haemophilia treatment centres ( HTCs) have experience with surgery in haemophilia patients, including those with inhibitors, with approximately 50% of these HTCs having performed orthopaedic procedures. The aim of this study was to present currently considered best practices for multidisciplinary care of inhibitor patients undergoing surgery in US HTCs. Comprehensive haemophilia care in the US is provided by ~130 federally designated HTCs staffed by multidisciplinary teams of healthcare professionals. Best practices were derived from a meeting of experts from leading HTCs examining the full care spectrum for inhibitor patients ranging from identification of the need for surgery through postoperative rehabilitation. HTCs face challenges in the care of inhibitor patients requiring surgery due to the limited number of surgeons willing to operate on this complex population. US centres of excellence have developed their own best practices around an extended comprehensive care model that includes preoperative planning, perioperative haemostasis and postoperative rehabilitation. Best practices will benefit patients with inhibitors and allow improvement in the overall care of these patients when undergoing surgical procedures. In addition, opportunities for further education and outcomes assessment in the care of this patient population have been identified. [ABSTRACT FROM AUTHOR]

IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double-blind, non-inferiority, cross-over study conducted in participants aged ≥12 years weighing ≥40 kg, with severe or moderately severe haemophilia B (FIX activity ≤2 IU dL−1). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4-18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8-59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg−1 or nonacog alfa. The lower limit of the one-sided 95% confidence interval for the ratio of AUC0-t and AUC0-∞ (IB1001/nonacog alfa) was 0.90, establishing non-inferiority. Terminal phase half-lives were similar (29.7 ± 18.2 h for IB1001 and 33.4 ± 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non-inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B. [ABSTRACT FROM AUTHOR]

. Blood in the joint causes a number of physiological and pathological events that eventually lead to haemophilic arthropathy. Animal models show that blood in the joint induces inflammation that continues long after blood has been cleared [1]. TNF-alpha, IL-1beta and IL-6 are inflammatory mediators that increase following haemarthrosis in haemophilic mice [2]. Conventional anti-inflammatory drugs have failed to demonstrate a lasting effect in preventing haemophilic arthropathy. A new TNF-alpha antagonist has shown promising results in haemophilic mice [3]. Similarly, the use of cyclo-oxygenase-2 inhibitors may reduce angiogenesis associated with the healing process following bleeding and the associated tissue damage [4]. Animal models are useful for studying the pathophysiology of haemarthropathy, however, when applying results from animals to humans, the differences in matrix turnover rate, thickness of cartilage and joint biomechanics must be kept in mind [5]. In people with haemophilia, there is a variable response to haemarthrosis as demonstrated by magnetic resonance imaging (MRI). Up to 30% of subjects have normal MRI despite having three or more haemarthroses into the same joint [6]. Once bone damage is present, little can be done to restore anatomic integrity. Several molecules, including members of the bone morphogenic protein subfamily, have been injected into bone defects in non-haemophilic subjects with some evidence of benefit [7]. To achieve the primary goal of reducing blood in the joint and the negative sequelae, it is questionable to use ice to treat haemarthrosis. Indeed low temperature is associated with impairment of coagulation enzyme activity and platelet function [8]. [ABSTRACT FROM AUTHOR]

. Acute haemorrhage treatment in patients with congenital haemophilia with inhibitors (CHwI) has transitioned to home. Patient/caregiver perceptions of bleeding symptoms and reasons for starting/stopping treatment were investigated. Frequently bleeding CHwI patients (≥4 episodes in 3 months) prescribed recombinant factor VIIa (rFVIIa) as first-line therapy, or their caregivers, completed daily diaries for 3-6 months capturing bleeding symptoms and treatment decisions. Thirty-eight patients reported 131 joint, 19 muscle and 44 other bleeding events. Symptoms (all/joint/muscle haemorrhages) included pain (78.9%/90.1%/89.5%), joint swelling (44.8%/65.6%/5.3%), decreased mobility (41.2%/48.9%/68.4%), local warmth (21.1%/26.0%/15.8%), other swelling (16.0%/6.9%/47.4%), irritability (14.9%/16.8%/10.5%), visible bleeding (12.4%/7.6%/5.3%) and redness (10.3%/6.1%/10.5%). Most patients/caregivers recognized when bleeds started (58.4%/58.0%), but were less clear when bleeds stopped (43.5%/33.3%). Medication was commonly started by patients/caregivers when bleeds were identified (73.7%/47.4%) or when concerned bleeds might start (32.9%/27.6%). Common reasons for delays in starting medication by patients included 'I thought it might not be a bleed' (48.9%), 'I wanted to see if the bleed progressed' (46.8%) and 'I thought it was just joint pain' (44.7%). Common reasons for caregivers were: 'I wanted to see if it progressed' (37.9%), 'I didn't have medication' (20.7%) and 'I thought it might not be a bleed' (17.2%). Reasons for stopping medication for patients/caregivers were pain cessation/stabilization (93.9%/54.7%), arrest of swelling progression (60.6%/46.9%) and improved mobility (50.0%/35.9%). Patients/caregivers have difficulty in determining bleed onset and particularly resolution, both quite necessary for treatment decisions and clinical trials. Caregivers' inability to assess resolution in children may lead to longer treatment duration seen in the Dosing Observational Study in Haemophilia (DOSE). [ABSTRACT FROM AUTHOR]

. Advances in therapy have improved life expectancy and quality of life of patients with haemophilia A. Due to the chronic and complex management of this disease, particularly, the development of inhibitors, little is known about their health resource utilization in the real-life setting over time. The aim was to assess the distribution and trend of healthcare resource utilization among US haemophilia A patients with and without inhibitors. The MarketScan® Database, was queried to identify individuals with ≥1 year continuous enrolment, two medical diagnoses of haemophilia A and claims for factor VIII or bypassing agent (to infer inhibitor status) during 2001-2007. Haemophilia-related cost was estimated from inpatient, outpatient and pharmacy claims. Annual cost differences were assessed by age and over a 4-year period for those with continuous enrolment. Among 51 million covered lives, 1044 haemophilia patients were identified, of whom 981 (94%; mean age = 21.2 years) did not have an inhibitor. The median haemophilia-related cost for these patients was $63,935 per patient per year. When normalized by weight, annual cost was stable (no statistically significant differences) among 312 non-inhibitor patients (mean age = 21.8 years) with 4-year continuous data. While there was a wide distribution of haemophilia-related cost among the 63 individuals with an inhibitor (mean age = 15.4 years), only 0.6% of the total haemophilia patients had costs exceeding $1 million per patient per year. This study indicated that most haemophilia A patients were inhibitor-free with relatively stable annual costs over time. There was a wide distribution of haemophilia-related cost for inhibitor patients, while the proportion of patients who incurred extreme high cost was low. [ABSTRACT FROM AUTHOR]

. Haemophilia has been recognized as the most severe among the inherited disorders of blood coagulation since the beginning of the first millennium. Joint damage is the hallmark of the disease. Despite its frequency and severity, the pathobiology of blood-induced joint disease remains obscure. Although bleeding into the joint is the ultimate provocation, the stimulus within the blood inciting the process and the mechanisms by which bleeding into a joint results in synovial inflammation (synovitis) and cartilage and bone destruction (arthropathy) is unknown. Clues from careful observation of patient material, supplemented with data from animal models of joint disease provide some clues as to the pathogenesis of the process. Among the questions that remain to be answered are the following: (i) What underlies the phenotypic variability in bleeding patterns of patients with severe disease and the development of arthropathy in some but not all patients with joint bleeding? (ii) What is the molecular basis underlying the variability? (iii) Are there strategies that can be developed to counter the deleterious effects of joint bleeding and prevent blood-induced joint disease? Understanding the key elements, genetic and/or environmental, that are necessary for the development of synovitis and arthropathy may lead to rational design of therapy for the targeted prevention and treatment of blood-induced joint disease. [ABSTRACT FROM AUTHOR]

Summary. von Willebrand disease (VWD) is the most common inherited bleeding disorder. Treatment guidelines recommend the use of von Willebrand factor/factor VIII (VWF/FVIII) concentrate for VWD patients with type 2 or 3 VWD undergoing surgery, and type 1 patients undergoing surgery who are unresponsive, or for whom desmopressin acetate is contraindicated. This prospective, open-label, multinational study evaluated the safety, efficacy and optimal dosing of a VWF/FVIII concentrate (Humate-P) in subjects with VWD undergoing elective surgery. Dosing was based on VWF ristocetin cofactor (VWF:RCo) and FVIII pharmacokinetic assessments performed before surgery. Pharmacokinetic assessments were completed in 33 adults and 9 children. Haemostatic efficacy was assessed on a 4-point scale (excellent, good, moderate/poor or none). Overall effective haemostasis was achieved in 32/35 subjects. Median terminal VWF:RCo half-life was 11.7 h, and median incremental in vivo recovery was 2.4 IU dL−1 per IU kg−1 infused. Major haemorrhage occurred after surgery in 3/35 cases despite achieving target VWF and FVIII levels. Median VWF/FVIII concentrate loading doses ranged from 42.6 IU VWF:RCo kg−1 (oral surgery) to 61.2 IU VWF:RCo kg−1 (major surgery), with a median of 10 (range, 2-55) doses administered per subject. Adverse events considered possibly treatment-related ( n = 6) were generally mild and of short duration. The results indicate that this VWF/FVIII concentrate is safe and effective in the prevention of excessive bleeding during and after surgery in individuals with VWD. [ABSTRACT FROM AUTHOR]

Patients with congenital haemophilia with inhibitors are at risk of peri-operative bleeding complications, since replacement of the missing coagulation factor is ineffective, presenting a therapeutic challenge in elective or emergency surgery. Therefore, the management of peri-operative bleeding requires the use of bypassing agents, such as recombinant activated FVII (rFVIIa, NovoSeven). This article presents an updated evaluation of the safety and effectiveness of rFVIIa in the treatment of peri-operative bleeding in this patient population. Surgical and other medical procedures managed with rFVIIa from two randomized clinical trials, the Hemophilia Research Society/Hemophilia and Thrombosis Research Society (HRS/HTRS) registry databases and the medical literature were analysed. There were 395 rFVIIa-treated procedures (261 surgical, 89 dental and 45 other medical procedures) reported for 263 congenital haemophilia patients with inhibitors. In trials, initial rFVIIa dosing was 35-90 mcg kg bolus injection or 50 mcg kg h continuous infusion. Dosing in the registries and literature was more variable. Recombinant FVIIa effectiveness was comparable across data sources, with an overall rate of 84% (333/395). The incidence of thrombotic events was very low (0.4% of patients and 0.025% of procedures). Prior to the US approval of rFVIIa in 1999, surgical procedures in congenital haemophilia patients with inhibitors were often considered too risky. Recombinant FVIIa has consistently demonstrated effectiveness in treatment of bleeding in these patients during such procedures. Thrombotic events were rare. This analysis confirms the value of corroborating clinical trial results with post-marketing surveillance registries to assess small patient populations with clinically challenging management decisions. [ABSTRACT FROM AUTHOR]

Postauthorization safety surveillance of factor VIII (FVIII) concentrates is essential for assessing rare adverse event incidence. We determined safety and efficacy of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method, (rAHF-PFM)] during routine clinical practice. Subjects with differing haemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on-demand therapy. Among 408 evaluable subjects, 386 (95%) received excellent/good efficacy ratings for all on-demand assessments; the corresponding number for subjects with previous FVIII inhibitors was 36/41 (88%). Among 276 evaluable subjects receiving prophylaxis continuously in the study, 255 (92%) had excellent/good ratings for all prophylactic assessments; the corresponding number for subjects with previous FVIII inhibitors was 41/46 (89%). Efficacy of surgical prophylaxis was excellent/good in 16/16 evaluable procedures. Among previously treated patients (PTPs) with >50 exposure days (EDs) and FVIII ≤2%, three (0.75%) developed low-titre inhibitors. Two of these subjects had a positive inhibitor history; thus, the incidence of de novo inhibitor formation in PTPs with FVIII ≤2% and no inhibitor history was 1/348 (0.29%; 95% CI, 0.01-1.59%). A PTP with moderate haemophilia developed a low-titre inhibitor. High-titre inhibitors were reported in a PTP with mild disease (following surgery), a previously untreated patient (PUP) with moderate disease (following surgery) and a PUP with severe disease. The favourable benefit/risk profile of rAHF-PFM previously documented in prospective clinical trials has been extended to include a broader range of haemophilia patients, many of whom would have been ineligible for registration studies. [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]

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.

The emergence of a population of relatively healthy adults with severe haemophilia A presents a unique challenge for haemophilia care in the 21st century. Understanding how best to continue, restart, initiate or modify prophylaxis in younger and older adult patients is essential to optimizing their care. To elucidate practice and outcome data, a survey was sent to 23 US hemophilia treatment centers (HTCs); 10 centers responded, providing data concerning up to 145 adults (mean age of 34 years). Forty-eight patients (33%) were on regular prophylaxis when first seen at the HTC; the prophylactic regimen was modified for 22/48 (46%), often because of breakthrough bleeding. Five of 21 patients (24%) for whom data were available discontinued prophylaxis. Three of those five patients (60%) experienced increased bleeding episodes and the other two (40%) subsequently resumed regular prophylactic infusions because of the increased bleeding. Of the 77 patients not initially receiving prophylaxis for whom data were available, prophylaxis was started or resumed in all. The prophylactic regimen was modified in 57/77 patients (74%) at some point during treatment, often because of breakthrough bleeding. Of the 55 patients whose prophylactic regimens were modified for whom data were available, 22 (40%) discontinued prophylaxis. Thirteen of 20 patients (65%) for whom data were available experienced an increase in bleeding episodes and 7/18 patients (39%) who had discontinued prophylaxis and for whom data were available subsequently resumed regular prophylactic infusions because of bleeding. These findings suggest that prophylaxis prevents bleeding in adults with severe haemophilia A and that discontinuation of the prophylactic regimen is associated with increased bleeding events. [ABSTRACT FROM AUTHOR]

The article presents a meeting report on the application of factor eight inhibitor in patients with haemophilia A. The panel of clinicians are indicated to accomplish goals such as knowledge examination on the bypassing activity of factor eight inhibitor as FEIBA VH for prophylaxis and the formulation of investigational and clinical recommendations. An overview of FEIBA and its effectivity in haemophilia patients with inhibitors are also being discussed.

The development of an inhibitor represents one of the most challenging complications in patients with haemophilia A. Optimal management is immune tolerance induction (ITI), typically through the administration of high doses of factor VIII (FVIII) concentrate. Among 12 patients who underwent ITI using Advate, a third-generation recombinant FVIII product that is free of animal and human protein additives, tolerance was achieved in nine (75%), including seven of 10 patients (70%) with high-titre inhibitors. ITI is ongoing in two patients and not yet successful; immune tolerance failed in the third patient. The median time to success was 4.0 months for group as a whole and for patients with high-titre inhibitors. Treatment was well tolerated, and no adverse events were observed. Advate was found to be equivalent to other FVIII products with regard to both ITI success rates and the incidence of adverse effects when used in these immune tolerance regimens. [ABSTRACT FROM AUTHOR]

Prophylactic infusion of factor concentrates is a safe, effective intervention for preventing arthropathy in patients with haemophilia; on-demand treatment is insufficient to prevent the orthopaedic complications and subsequent haemophilic arthropathy that stem from recurrent joint haemorrhages. The usefulness of prophylaxis in haemophilia patients without inhibitors suggests that patients with haemophilia and inhibitors could derive similar benefits. In patients with haemophilia and high-titre (>5 BU mL−1) inhibitors, bleeding episodes are treated with bypassing agents such as activated prothrombin complex concentrates (APCCs) and recombinant activated factor VII (rFVIIa, NovoSeven®; Novo Nordisk A/S, Bagsvaerd, Denmark). It is possible to administer bypassing therapy regularly to prevent haemorrhages, with the goal of limiting arthropathy and serious life- and limb-threatening bleeding. The data evaluating the efficacy and safety of this approach in patients with inhibitors are limited, consisting of results from one prospective trial and retrospective case reports. This report describes our experience with the prophylactic use of the APCC Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA™; Baxter AG, Vienna, Austria). Data from patients at one treatment centre were retrospectively evaluated. Case records of six patients with haemophilia A or B and high-titre inhibitors were identified. When APCC was administered regularly, most patients exhibited a reduction in the numbers of haemorrhages, an improvement in orthopaedic status, and an improvement in quality of life. Prophylaxis with APCC can reduce haemorrhages and halt further joint deterioration in patients with haemophilia and inhibitors. [ABSTRACT FROM AUTHOR]

Preservation of normal joint function in patients with haemophilia is a goal of modern therapy. Regular injections of anti-haemophilic factor concentrate reduce the risk of joint bleeding, the optimal regimen for which remains under investigation. The goals of the experiment described here are: (i) to assess the capacity of a murine model of severe haemophilic arthropathy to predict the likelihood of success of a test product to prevent joint bleeding and the complications that follow and (ii) to compare the effectiveness of recombinant human activated factor VII (rFVIIa) to recombinant human factor VIII (rFVIII) to prevent acute joint bleeding in the mouse model of haemarthrosis. Mice lacking expression of FVIII received a single intravenous injection of human rFVIII (280 U kg−1), rFVIIa (10 mg kg−1) or vehicle prior to blunt trauma injury to the knee joint. Mice receiving rFVIII and rFVIIa developed less injury-induced joint bleeding, swelling and loss of range of motion compared to mice pretreated with vehicle. Despite the reduction in clinical symptoms, synovial hyperplasia was evident in all groups after 7 days although less pronounced in mice receiving rFVIII and rFVIIa. The data under these experimental conditions demonstrate: (i) that this model can be used to evaluate novel therapies designed to prevent joint bleeding (prophylaxis) and (ii) both rFVIII and rFVIIa reduced acute haemarthrosis but did not completely prevent synovitis, the sequelae of blood induced joint injury. [ABSTRACT FROM AUTHOR]

Prophylaxis is defined as the regular administration of clotting factor concentrates to prevent bleeding. Extensive data from observational studies and a recent randomized controlled trial (have established that early prophylactic treatment prevents bleeds and arthropathy in boys with severe haemophilia. The initiation of prophylaxis in young children remains challenging. To prevent arthropathy, prophylaxis should be started early, before the onset of joint damage. Alternative strategies of starting include starting before the age of 2 years, or starting before the third joint bleed. Dose and frequency vary between the original Swedish regime of 20–40 IU kg−1 three times per week and lower dosed and step up regimes starting with 50 IU kg−1 once weekly and rapidly increasing dose and frequency in case of bleeds. In the second decade, most patients on prophylaxis learn self-infusion. Self-management warrants confirmation of adequate knowledge of the disease. Increasing self-management concurring with major physical and psychological changes may cause reduced adherence. The challenge is to promote adherence and continue to prevent bleeds during this important period of rapid growth. The third decade of life often represents a change in lifestyle. Patients may get a job and periods of physical activity may be more confined. About two thirds of patients experiment with discontinuing prophylaxis in their early twenties, and 20–30% with mild bleeding patterns switch to on-demand treatment for prolonged periods or even permanently. The challenge is to optimize efficiency by individualizing prophylactic dose and frequency according to lifestyle and bleeding pattern. Inhibitors may develop in up to 30% of patients with severe haemophilia. Especially those with high titre inhibitors are at increased risk of developing target joints and severe arthropathy. The use of prophylactic treatment with bypassing agents in inhibitor patients is increasing. Early studies report in a significant reduction of bleeds, including intracranial bleeds, and improvement in quality of life. Data on results of primary prophylaxis in patients with inhibitors to prevent arthropathy are not yet available. [ABSTRACT FROM AUTHOR]

Haemophilic arthropathy, which shares some clinical and biological injury characteristics with rheumatoid arthritis, is characterized by two main features: chronic proliferative synovitis and cartilage destruction. It is the consequence of repeated extravasation of blood into joint cavities, but its exact pathogenesis, particularly with regard to early changes in the joint, is still incompletely understood. This review presents recent findings obtained in experiments performed in vitro and using animal models, which have improved our knowledge of the pathogenesis of haemophilic arthropathy. These experimental studies show that haemophilic arthropathy is a multifactorial event in which the deposit of iron in the joints appears to exert a central role. First, iron may promote the apoptosis of chondrocytes by catalysing the formation of oxygen metabolites; this may explain the fact that intra-articular blood exerts a directly harmful effect on cartilage before, and independent of synovial changes. Secondly, iron may also act on the synovial membrane by favouring its proliferation through the induction of proto-oncogenes involved in cellular proliferation and stimulation of inflammatory cytokines as well as abrogation of apoptosis. These two processes, one degenerative and cartilage-mediated, the other inflammatory and synovium-mediated could occur in parallel or sequentially. Overall, it may be expected that these experimental results will yield new therapeutic strategies capable of effectively preventing the occurrence of this still serious and common complication in patients with severe haemophilia. [ABSTRACT FROM AUTHOR]

Recurrent haemarthrosis results in chronic synovitis and destructive arthropathy. The long-term effect of a single haemorrhage is not known. To investigate the histopathological changes following a single, but major joint haemorrhage, an animal model of massive haemarthrosis without mechanical trauma was developed and is described in this manuscript. The knee joint capsule of mice deficient in coagulation factor VIII or IX and non-haemophilic wild type mice was punctured to induce a one time, but massive haemorrhage. The single joint puncture resulted in acute haemarthrosis in both types of haemophilic mice but not in wild type mice. Subsequent to injury, the changes in the knee joints were analysed using gross, histological and radiographic assessments and compared with the uninjured knee. In addition, a novel imaging modality, micro-computed tomography, was used to document the structural damage to the joint. Our results indicate that the long-term changes classically observed in patients with advanced haemophilic arthropathy are evident following a single massive haemarthrosis. This model will allow a thorough investigation of the pathobiology of blood-induced joint disease and will be useful to test the efficacy of innovative therapeutic strategies to prevent haemophilic synovitis and arthropathy. [ABSTRACT FROM AUTHOR]

Haemophilia is a congenital disorder that commonly results in musculoskeletal bleeding and orthopaedic complications. After an acute joint haemorrhage, an increase in intra-articular pressure and inflammation cause pain, swelling and limited motion. Blood in the joint space provokes a proliferative disorder known as haemophilic synovitis. Overgrowth of the synovial membrane causes mechanical dysfunction. Eventually, there is destruction of the articular surface and underlying bone. The aim of this project was to test the hypothesis that a minimum number of haemarthroses negatively impacts on joint function and that this would be reflected by decreased physical performance of experimental animals. Mice deficient in factor VIII coagulant activity were trained to ambulate on a rotating rod then injured three times at weekly intervals. Their ability to walk was then compared to a group of uninjured mice. Cohorts of mice were killed after 1, 2 or 3 months and the knee joints examined by gross and histological methods. The results supported the following conclusions: (i) haemophilic mice can be trained to ambulate on a rotating rod; (ii) acute hemarthrosis temporarily impairs their ability to ambulate and (iii) following recovery from acute injury, mice developing synovitis demonstrated inferior physical ability compared to mice not developing synovitis. This is the first description of a quantitative assay to monitor joint function in experimental animals and should be useful to evaluate the efficacy of new therapies developed to prevent and treat bleeding and to test strategies to counter the devastating effects of synovitis. [ABSTRACT FROM AUTHOR]

The article reports on optimizing outcomes for patients with severe hemophilia A in the U.S. It states that prophylaxis is the most effective strategy for optimizing outcomes in patients with severe hemophilia A. Primary prophylaxis can prevent the development of arthropathy, protect against other serious bleeding events, and allow patients to live full, active lives.

Prophylaxis is paramount to try to avoid the development of haemophilic synovitis. The best treatment for synovitis in patients with inhibitors is radioactive synoviorthesis (rhenium for ankle and elbows, yttrium for knees). With both methods (prohylaxis and radioactive synoviorthesis), we can delay the development of severe haemophilic arthropathy, that eventually will require major orthopaedic surgery. [ABSTRACT FROM AUTHOR]

Hemarthrosis is a common manifestation of haemophilia, and joint arthropathy remains a frequent complication. Even though the exact mechanisms related to blood-induced joint disease have not yet been fully elucidated, it is likely that iron deposition in the synovium induces an inflammatory response that causes not only immune system activation but also stimulates angiogenesis. This process ultimately results in cartilage and bone destruction. Investigating the processes that occur in the early stages of blood-induced joint disease in humans has been very limited. Therefore, the use of haemophilic animal models is critical to augment the understanding of this phenomenon. This article discusses three cellular regulators (p53, p21 and TRAIL) induced in synovial tissue that are important for iron metabolism. A cartilage remodelling programme induced by the release of cytokines and growth factors that result in articular damage is also discussed. Full elucidation of the pathogenesis of haemophilic joint disease is required to identify new avenues for prevention and therapy. [ABSTRACT FROM AUTHOR]

Recurrent spontaneous haemarthrosis are commonly seen in patients affected by haemophilia. The knee and the elbow are most commonly affected and both are amenable to arthroscopic treatment. Arthroscopic synovectomy is indicated after failure of appropriate medical management with recurrent bleeding. Many patients also demonstrate motion loss and functional deterioration. The benefits of arthroscopic synovectomy include the ability to perform adequate synovial debridement, but also concomitant lysis of adhesion and capsular release to regain range of motion. Results of arthroscopic synovectomy demonstrate a significant decrease in episodes of haemarthrosis, and significant improvement in pain, range of motion and function. The primary predictor of outcome is degree of pre-existing degenerative changes within the joint. In more severe cases, the results of arthroscopic synovectomy are unpredictable and serious consideration should be given to primary arthroplasty. [ABSTRACT FROM AUTHOR]

Arthropathy remains a major cause of morbidity in patients with haemophilia. Frequent bleeding into the joints leads to joint damage with resultant contractures, joint deformities and arthritis. This in turn leads to muscle atrophy, limited physical activity, osteoporosis and disability. Even though several studies of prophylactic factor replacement for persons with severe haemophilia demonstrate improved joint function, this therapy is still not readily available to most people with haemophilia around the world and a universal treatment protocol has not been used. In this article, we discuss key issues in the treatment of severe haemophilia: the optimal timing of initiation and termination of therapy, dosing options and goals of therapy. The options for countries where prophylaxis is not readily available are also discussed. Most studies are small and not randomized making consensus treatment recommendations difficult to formulate. Randomized, clinical trials are needed to provide the answers regarding the optimal treatment of patients with severe haemophilia. [ABSTRACT FROM AUTHOR]

Orthopaedic complications are among the most disabling sequelae occurring in patients with haemophilia and inhibitors. Recurrent or refractory joint bleeds can lead to joint damage, limiting mobility and causing permanent disability. Activated prothrombin complex concentrates (aPCCs) are effective in controlling acute, intraoperative and postoperative bleeding in patients with haemophilia and inhibitors. The relatively long, dosing interval and safety profile distinguish aPCCs as a well-suited option for prophylaxis. Therefore, it is postulated that long-term routine aPCC administration will decrease the frequency of recurrent bleeds, prevent damage to normal joints, and slow the progression of existing joint disease in patients with inhibitors. To test this hypothesis, a retrospective chart audit was performed. In four treatment centres, five patients were identified who received aPCC [Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex (FEIBA®); Baxter AG, Vienna, Austria] prophylactically for ≥6 months to prevent or reduce further joint deterioration, reduce bleeding and prevent postsurgical bleeding. Median treatment duration was 15 months and included administration of >1300 doses of aPCC. Dosages ranged from 50 to 75 U kg−1 three times per week in four patients; one patient received 100 U kg−1 daily. Orthopaedic status was maintained in four patients and improved in one; the frequency of bleeding episodes was reduced in all patients. No adverse events or thrombotic complications were reported. This case series demonstrates that routine aPCC administration may be used safely and effectively to reduce the occurrence of bleeding episodes and to maintain or improve clinical joint status in some patients. [ABSTRACT FROM AUTHOR]