Validation of the Haemophilia & Exercise Project-Test-Questionnaire (HEP-Test-Q)-An instrument for the assessment of subjective physical functioning in children with haemophilia.

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.

Prophylactic bypassing agent use before and during immune tolerance induction in patients with haemophilia A and inhibitors to FVIII.

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.

Target plasma factor levels for personalized treatment in haemophilia: a Delphi consensus statement.

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.

Haemarthrosis model in mice: BSS - Bleeding Severity Score assessment system.

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.

Association of peak factor VIII levels and area under the curve with bleeding in patients with haemophilia A on every third day pharmacokinetic-guided prophylaxis.

INTRODUCTION: We previously showed that pharmacokinetic-guided prophylaxis (PKP) allows the dosing interval to be extended while maintaining a specific trough level. However, the associations of peak factor VIII (FVIII) levels and area under the curve (AUC) with breakthrough bleeding have not been investigated. AIM: The aim of this study was to analyse data from the PKP arm to determine whether peak FVIII levels, AUC and time with FVIII levels in a haemostatically effective range are independent predictors of bleeding during prophylaxis. METHODS: Post hoc analysis of the association of FVIII levels and AUC with annualized bleeding rate in 34 patients on PKP. RESULTS: During 1 year of PKP, 131 bleeding episodes occurred in 24/34 patients. Average peak FVIII levels ranged from 24 to 168 IU dL(-1) , with higher values associated with a decreased risk for all bleeding (joint and non-joint; P < 0.01) and joint bleeding (P < 0.01). Following rFVIII infusion, median percent of time spent with FVIII levels >20 IU dL(-1) was 22%; median AUC was 1363. Both values were significantly associated with a lower ABR when targeting a 1% trough at 72 h. CONCLUSION: When PKP was administered every third day, higher peak FVIII levels, higher AUC and more time spent per week with FVIII levels >20 IU dL(-1) provided increased protection from joint and non-joint bleeding. These data highlight the potential impact of variability in individual pharmacokinetic and bleeding risk and support the need for high peak levels and AUC in some patients treated every third day. The findings do not necessarily apply to alternate-day or other prophylactic dosing regimens.

Health-related quality of life assessment in haemophilia patients on prophylaxis therapy: a systematic review of results from prospective clinical trials.

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.

US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors.

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.

Should anti-inhibitor coagulant complex and tranexamic acid be used concomitantly?

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.

Utility of a Paediatric Bleeding Questionnaire as a screening tool for von Willebrand disease in apparently healthy children.

UNLABELLED: 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.

Safety of radiation exposure after radiosynovectomy in paediatric patients with haemophilia.

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 (32) P 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.

The biological efficacy profile of BAX 855, a PEGylated recombinant factor VIII molecule.

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.

Considerations in individualizing prophylaxis in patients with haemophilia A.

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.

Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS): peering into the cup of Jamshid.

The complex process underlying the development of blood-induced joint disease remains mysterious. Novel technologies such as matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) to examine protein signatures may provide clues into the process.

Multicentre, randomized, open-label study of on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects.

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.

The first recombinant FVIII produced in human cells--an update on its clinical development programme.

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.

Towards personalizing haemophilia care: using the Haemophilia Severity Score to assess 178 patients in a single institution.

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.

Case studies in the management of refractory bleeding in patients with haemophilia A and inhibitors.

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.

The effect of cooling on coagulation and haemostasis: should "Ice" be part of treatment of acute haemarthrosis in haemophilia?

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.

Pharmacokinetic properties of IB1001, an investigational recombinant factor IX, in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis.

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 AUC(0-t) and AUC(0-∞) (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.