Peri-operative desmopressin combined with pharmacokinetic-guided factor VIII concentrate in non-severe haemophilia A patients.

INTRODUCTION: Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated. AIM: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients. METHODS: Non-severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri-operative combination treatment. In the single-arm DAVID study intravenous desmopressin (0.3 µg/kg) once-a-day was, after sampling, immediately followed by PK-guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK-guided combination treatment (intervention arm) or PK-guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL. RESULTS: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C > 1.00 IU/mL. CONCLUSION: Peri-operative combination treatment with desmopressin and PK-guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption.

Transition readiness among adolescents and young adults with haemophilia in the Netherlands: Nationwide questionnaire study.

INTRODUCTION: Care for adolescents with haemophilia is transferred from paediatric to adult care around the age of 18 years. Transition programs help to prepare adolescents for this transfer and prevent declining treatment adherence. Evaluating transition readiness may identify areas for improvement. OBJECTIVE: Assess transition readiness among Dutch adolescents and young adults with haemophilia, determine factors associated with transition readiness, and identify areas of improvement in transition programs. METHODS: All Dutch adolescents and young adults aged 12-25 years with haemophilia were invited to participate in a nationwide questionnaire study. Transition readiness was assessed using multiple-choice questions and was defined as being ready or almost ready for transition. Potential factors associated with transition readiness were investigated, including: socio-demographic and disease-related factors, treatment adherence, health-related quality of life, and self-efficacy. RESULTS: Data of 45 adolescents and 84 young adults with haemophilia (47% with severe haemophilia) were analyzed. Transition readiness increased with age, from 39% in 12-14 year-olds to 63% in 15-17 year-olds. Nearly all post-transition young adults (92%, 77/84) reported they were ready for transition. Transition readiness was associated with treatment adherence, as median VERITAS-Pro treatment adherence scores were worse in patients who were not ready (17, IQR 9-29), compared to those ready for transition (11, IQR 9-16). Potential improvements were identified: getting better acquainted with the adult treatment team prior to transition and information on managing healthcare costs. CONCLUSIONS: Nearly all post-transition young adults reported they were ready for transition. Improvements were identified regarding team acquaintance and preparation for managing healthcare costs.

Validation of the pedHALshort and HALshort in Dutch children and adults with haemophilia.

INTRODUCTION: The Haemophilia Activities List (HAL) and paediatric HAL assess self-reported limitations in various daily activities. To reduce patient burden, shorter versions of the pedHAL (22 items) and HAL (18 items) have been developed. AIM: This study aimed to determine the agreement between the pedHAL/HALfull and pedHAL/HALshort and construct validity and internal consistency of the pedHAL/ HALshort in persons with haemophilia (PWH). METHODS: A cross-sectional secondary analysis of the Hemophilia in the Netherlands-6 national survey was performed. Adult and paediatric PWH completed the original pedHAL/HALfull , from which pedHAL/ HALshort were derived. Score differences between the original and short versions were calculated. Construct validity was studied by testing hypotheses regarding the relationship of the pedHAL/HALshort with the pedHAL/HALfull , Haemophilia & Exercise Project Test-Questionnaire (HEP-Test-Q), Canadian Haemophilia Outcomes-Kids' Life Assessment Tool (CHO-KLAT) and RAND 36-item Health Survey (RAND-36) (convergent/discriminant validity) as well as its ability to discriminate between subgroups (known-group validity). Internal consistency was assessed with Cronbach's α. RESULTS: We included 113 children (median 10y [range 4-17], 53% severe haemophilia) and 691 adults (median 51y [range 18-88], 35% severe). Scores of the pedHAL/HALfull and pedHAL/HALshort were similar with high correlations (>0.9). Construct validity was confirmed for the pedHAL/HALshort . The HALshort was able to discriminate between different disease severities and ages. Cronbach's α of the pedHAL/HALshort was 0.95-0.97. CONCLUSION: This study confirmed the agreement between the pedHAL/HALfull and the pedHAL/HALshort and the construct validity of the pedHAL/HALshort . The next step is to study construct validity of the pedHAL/HALshort when administered as short forms.

A tailored intervention for illness acceptance improves adherence and quality of life in adults with haemophilia using prophylaxis.

INTRODUCTION: Adherence to prophylactic treatment (prophylaxis) in persons with haemophilia is challenging and has been reported at only ±50%. Acceptance problems are one of the main reasons for non-adherence in haemophilia. An evidence-based intervention was developed based on an acceptance and commitment therapy (ACT) approach. AIM: To evaluate a tailored intervention focused on illness acceptance in adults with haemophilia who were prescribed prophylaxis. METHODS: A pre-post study was executed in adults with haemophilia who were prescribed prophylaxis. A series of 8 2-hour group trainings were held, including 3-8 participants/series. Adherence (VERITAS-Pro, optimum 0), health-related quality of life (HRQoL, SF-36, optimum 100) and illness perception (BIPQ, optimum 0) were measured at start, after six months and 12 months and analysed using Wilcoxon signed-rank test. RESULTS: Twenty-four patients (median age 47 years, range 27-74) were included. After 12 months, adherence improved in 68% of patients, quality of life in 48% and illness perception in 31%. Adherence (total score) improved from 35 to 25 (P<0.01). HRQoL showed clinically relevant improvement in domains of social-functioning (P = 0.04), role-emotional, physical-functioning, role-physical and bodily pain. Illness perception improved statistically significant on domains of affect (P = 0.01), concern (P = 0.01) and understanding (P = 0.04). Patients evaluated the training useful, an eye-opener, a personal enrichment and insightful. CONCLUSION: The tailored group intervention resulted in significant improvement of adherence, quality of life and illness perception. Based on our current experience, we have implemented it in clinical practice and collaborate with the patient association to make it available for all Dutch people with haemophilia.

A qualitative study on the experiences of haemophilia carriers before, during and after pregnancy.

INTRODUCTION: Haemophilia carriers (HCs) face considerable haemostatic and psychological challenges during reproduction. AIM: To explore the perspectives of HCs on healthcare in the current standard of haemophilia treatment during all reproductive phases: preconception, pregnancy, childbirth and the postpartum period. In addition, we examined the psychological impact of haemophilia during these phases. MATERIAL AND METHODS: Focus group discussions (FGDs) and semi-structured interviews were conducted with HCs in January/February 2020 until data saturation was reached. All sessions were recorded, transcribed verbatim and analysed by two independent researchers through thematic content analysis using MAXQDA® software. The results were then discussed within the research team until consensus was reached. The constructed themes were shared with and reviewed by the HCs. RESULTS: Fifteen HCs were included in three FGDs and four interviews. Five central themes were constructed: (1) communication by healthcare professionals, (2) lack of knowledge, (3) feeling insecure, (4) autonomy and (5) family experiences with haemophilia. Desired improvements in care mainly concerned counselling during preconception and pregnancy. This included timely access to comprehensive information during each consecutive phase, acceptance of HCs' choices by healthcare providers and healthcare tailored to the HC's family experience with haemophilia. CONCLUSIONS: In recent years, haemophilia treatment has seen major advances, which could impact general and reproductive care for HCs. HCs indicated that reproductive care would benefit from a more personal and informative approach. Healthcare professionals could use these insights to adapt their consultations to meet the needs of these women when they are preparing for having children.

Similar sports participation as the general population in Dutch persons with haemophilia; results from a nationwide study.

INTRODUCTION: Although sports participation is advocated in people with haemophilia (PWH), detailed data concerning sports participation in Dutch PWH is lacking. AIM: to assess sports participation in Dutch PWH (6-65 years) compared to the Dutch general population (GP). METHODS: Data from a nationwide, cross-sectional study in PWH were analysed. Sports participation (type, duration, frequency) was assessed by the Modifiable Activities Questionnaire (MAQ), limitations in activities using the (Paediatric) Haemophilia Activities List ((Ped)HAL). Sports in the two highest categories according to the National Hemophilia Foundation classification were considered high-risk sports. Groups were compared using Chi-square testing. RESULTS: A total of 524 Adult PWH (median age: 45 (IQR: 30-55); 37% severe) and 126 paediatric PWH (median age: 11 (IQR: 8-14); 52% severe) were included. Sports participation was higher in adults (70%) than the GP (58%) and similar to the GP in children (PWH: 68%, GP: 72%). High-risk sports participation decreased with age in PWH: from 65% (6-12 years) to 17% (50-65 years), which was also observed in the GP. Sports participation in children was independent of severity (non-severe: 67% vs. severe: 65%; P = 0.97), but not in adults (non-severe: 75%, severe: 62%; P < 0.01). Non-severe PWH played more high-risk sports than severe PWH: children at 65% vs. 48% (P = 0.05), adults at 25% vs. 15% (P = 0.07). DISCUSSION: These results suggest that sports participation in PWH was comparable to the GP. Sports participation was dependent of haemophilia severity in adults. Children were more involved in high-risk sports than adults. More studies on sports-related injury-risk are needed for adequate counselling.

Validation of a perioperative population factor VIII pharmacokinetic model with a large cohort of pediatric hemophilia a patients.

AIMS: Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively. METHODS: A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03-15.2) and body weight of 14 kg (4-57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation. RESULTS: The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL-1 . Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03-77.6) and body weight of 30 kg (4-111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h-1  68 kg-1 , 2930 mL 68 kg-1 , 1810 mL 68 kg-1 , and 172 mL h-1  68 kg-1 , respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL-1 . CONCLUSIONS: This study emphasizes the importance of external validation of population PK models using real-life data.

Toward Personalized Care and Patient Empowerment and Perspectives on a Personal Health Record in Hemophilia Care: Qualitative Interview Study.

BACKGROUND: To enable personalized treatment and shared decision-making in chronic care, relevant health information is collected. However, health information is often fragmented across hospital information systems, digital health apps, and questionnaire portals. This also pertains to hemophilia care, in which scattered information hampers integrated care. We intend to co-design a nationwide digital personal health record (PHR) for patients to help manage their health information. For this, user perspectives are crucial. OBJECTIVE: This study aims to assess patients' and health care providers' perspectives regarding the use of a PHR in hemophilia care in the Netherlands, required functionalities, and expectations and concerns. METHODS: In this semistructured interview study, 19 pediatric and adult persons with hemophilia, parents, and women with other inherited bleeding disorders, as well as 18 health care providers working within and outside of hemophilia treatment centers, participated. Perspectives of patients and providers were explored separately. To explore requirements, participants were asked to prioritize functionalities. RESULTS: Participants expected a PHR would increase the transparency of health information, improve patients' understanding of their illness, and help the coordination of care between health care providers and institutions. Prioritized functionalities included the integration of relevant health information and patient-entered data. Formulated expectations and concerns focused on 4 themes: usability, safety, inclusiveness, and implementation. While patients expressed worries over medicalization (ie, more confrontational reminders of their illness), providers were concerned about an increased workload. CONCLUSIONS: People with hemophilia, their parents, and health care providers welcomed the development of a PHR, as they expected it would result in better coordinated care. Formulated expectations and concerns will contribute to the successful development of a PHR for persons with hemophilia, and ultimately, for all persons with a chronic condition.

Framework for Multistakeholder Patient Registries in the Field of Rare Diseases: Focus on Neurogenetic Diseases.

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.

[Personal health records: a promising tool?] / Persoonlijke gezondheidsomgeving.

Currently, nearly all health care institutions in the Netherlands employ patient portals to help engage and empower patients. Yet, the fragmented landscape of incompatible portals hampers patient engagement. The implementation of national personal health records (PHRs) could help to resolve this. PHRs are websites or apps in which all relevant medical data of all health care providers involved are collected. PHRs are managed by patients. The Netherlands has adopted a free-market model, in which private companies develop PHRs and the government acts as a controlling body. Although PHRs can ultimately aid shared-decision making and patient participation, several challenges have to be overcome. How are safety and privacy taken into consideration? How will PHRs change the communication between patients and health care providers? Can we standardize and integrate all relevant patient information? And finally, how can we make PHRs understandable and easy-to-use for all patients, especially those with lower health literacy?

Patients' and health care providers' perspectives on quality of hemophilia care in the Netherlands: a questionnaire and interview study.

Background: Hemophilia care has improved greatly because of advances in treatment options and comprehensive care. In-depth insight into the perspectives of persons with hemophilia and health care providers on their care may provide targets for further improvements. Objectives: To assess satisfaction of the hemophilia population with their care, to explore factors determining care satisfaction, and to identify areas for potential health care improvements, including digital health tools. Methods: First, to assess care satisfaction and factors determining satisfaction and health care improvements, data from a nationwide, cross-sectional questionnaire among 867 adult and pediatric Dutch persons with hemophilia A or B were analyzed. This included the Hemophilia Patient Satisfaction Scale questionnaire, Canadian Hemophilia Outcomes Kids' Life Assessment Tool satisfaction questions, a visual analog scale satisfaction score, and open questions. Second, to further explore factors determining satisfaction and health care improvements, semistructured interviews were conducted with 19 persons with hemophilia or their parents and 18 health care providers. Results: High care satisfaction was found, with an overall median Hemophilia Patient Satisfaction Scale score of 12 (IQR, 6-21). Participants in the interviews reported that patient-professional interactions, availability of care, and coordination of care were major factors determining satisfaction. Suggested health care improvements included improved information provision and coordination of care, especially shared care with professionals not working within comprehensive care centers. Participants suggested that digital health tools could aid in this. Conclusion: Satisfaction with hemophilia care is high among persons with hemophilia in the Netherlands, although several potential improvements have been identified. Accentuating these is especially relevant in the current era of treatment innovations, in which we might focus less on other aspects of care.

Desmopressin in nonsevere hemophilia A: patient perspectives on use and efficacy.

Background: Desmopressin increases plasma factor VIII and von Willebrand factor levels in persons with nonsevere hemophilia A. Patients' perspectives on desmopressin are relevant to increase and optimize its suboptimal use. However, patients' views on desmopressin are not reported. Objectives: To evaluate the perspectives of persons with nonsevere hemophilia A on desmopressin use, barriers for its use, side effects, and their knowledge about desmopressin's efficacy and side effects. Methods: Persons with nonsevere hemophilia A were included in a cross-sectional, national, multicenter study. Questionnaires were filled out by adult patients and children aged ≥12 years themselves. Caretakers filled out questionnaires for children aged <12 years. Results: In total, 706 persons with nonsevere hemophilia A were included (544 mild, 162 moderate, [age range, 0-88 years]). Of 508 patients, 234 (50%) patients reported previous desmopressin use. Desmopressin was considered as at least moderately effective in 171 of 187 (90%) patients. Intranasal administration was the modality of choice for 138 of 182 (76%) patients. Flushing was the most reported side effect in 54 of 206 (26%) adults and 7 of 22 (32%) children. The most frequently reported advantage and disadvantage were the convenience of intranasal, out-of-hospital administration by 56% (126/227) and side effects in 18% (41/227), respectively. Patients' self-perceived knowledge was unsatisfactory or unknown in 28% (63/225). Conclusion: Overall, desmopressin was most often used intranasally and considered effective, with flushing as the most common side effect. The most mentioned advantage was the convenience of intranasal administration and disadvantage was side effects. More information and education on desmopressin could answer unmet needs in patients with current or future desmopressin treatment.

Socioeconomic participation of persons with hemophilia: Results from the sixth hemophilia in the Netherlands study.

Background and objectives: Treatment availability and comprehensive care have resulted in improved clinical outcomes for persons with hemophilia. Recent data on socioeconomic participation in the Netherlands are lacking. This study assessed participation in education, in the labor market, and social participation for persons with hemophilia compared with the general male population. Methods: Dutch adults and children (5-75 years) of all hemophilia severities (n = 1009) participated in a questionnaire study that included sociodemographic, occupational, and educational variables. Clinical characteristics were extracted from electronic medical records. General population data were extracted from Statistics Netherlands. Social participation was assessed with the PROMIS Ability to Participate in Social Roles and Activities short form, with a minimal important difference set at 1.0. Results: Data from 906 adults and children were analyzed. Participation in education of 20 to 24 year olds was 68% (general male population: 53%). Educational attainment was higher compared with Dutch males, especially for severe hemophilia. Absenteeism from school was more common than in the general population. The employment-to-population ratio and occupational disability were worse for severe hemophilia than in the general population (64.3% vs. 73.2% and 14.7% vs. 4.8%, respectively), but similar for nonsevere hemophilia. Unemployment was 5.4% (general male population: 3.4%). Absenteeism from work was less common (38% vs. 45.2%). Mean PROMIS score was similar to or higher than in the general population (54.2; SD 8.9 vs. 50; SD 10). Conclusion: Socioeconomic participation of persons with nonsevere hemophilia was similar to the general male population. Some participation outcomes for persons with severe hemophilia were reduced.

Informed consent for neonatal trials: practical points to consider and a check list.

Obtaining informed consent from parents of critically ill neonates can be challenging. The parental decision-making process is influenced by the severity of the child's condition, the benefit-risk balance, their emotional state and the quality of the relationship with the clinical team. Independent of local legislation, parents may prefer that consent is sought from both. Misconceptions about the absence of risks or unrealistic expectations about benefits should be openly addressed to avoid misunderstandings which may harm the relationship with the clinical team. Continuous consent can be sought where it is unclear whether the free choice of parental consent has been compromised. Obtaining informed consent is a dynamic process building on trusting relationships. It should include open and honest discussions about benefits and risks. Investigators may benefit from training in effective communication. Finally, involving parents in neonatal research including the development of the informed consent form and the process of obtaining consent should be considered standard practice.

Patient Perspectives on Novel Treatments in Haemophilia: A Qualitative Study.

BACKGROUND AND OBJECTIVE: New treatments for haemophilia are under development or entering the market, including extended half-life products, designer drugs and gene therapy, thereby increasing treatment options for haemophilia. It is currently unknown how people with haemophilia decide whether to switch to a new treatment. Therefore, the objective of this study was to explore what factors may play a role when Dutch patients and parents of boys with moderate or severe haemophilia make decisions about whether to switch to a different treatment, and how disease and treatment characteristics may affect these decisions. This may aid clinical teams in tailored information provision and shared decision making. METHODS: We conducted interviews among adults with moderately severe or severe haemophilia and parents of young boys with severe haemophilia. We aimed to include participants from a variety of backgrounds in terms of involvement in the haemophilia community, age, treatment centre and treatments. Participants were recruited through the Netherlands Haemophilia Society and a haemophilia treatment centre. Semi-structured interviews were recorded and transcribed verbatim. Thematic content analysis was used to analyse the data. RESULTS: Twelve people with haemophilia and two mothers of boys with haemophilia were included. In general, participants reported to be satisfied with their current treatment. However, they considered ease of use of the medication (fewer injections, easier handling, alternative administration) an added value of new treatments. Participants were aware of the high cost of coagulation factor products and some expressed their concern about the Netherlands Haemophilia Society's long-term willingness to pay for current and novel treatments, especially for increased usage due to high-risk activities. Participants also expressed their concerns about the short- and long-term safety of new treatments and believed the effects of gene therapy were not yet fully understood. Participants expected their treatment team to inform them when a particular new treatment would be suitable for them. CONCLUSIONS: With the number of treatment options set to increase, it is important for healthcare providers to be aware of how patient experiences shape patients' decisions about new therapies.

The experiences and attitudes of hemophilia carriers around pregnancy: A qualitative systematic review.

BACKGROUND: Hemophilia carriers (HCs) face specific psychosocial challenges related to pregnancy, caused by their inherited bleeding disorder. Optimal support from healthcare providers can only be realized by exploring medical and psychological healthcare requirements. OBJECTIVE: To review all published evidence on the experiences and attitudes of HCs regarding reproductive decision-making, prenatal diagnosis, pregnancy, childbirth, and puerperium to provide an accessible overview of this information for health care providers. STUDY SELECTION: Cochrane library, PubMed/MEDLINE, EMBASE, CINAHL, and PsycINFO were searched for original qualitative data. Two authors performed study selection, risk-of-bias assessment, data extraction, and data analysis through meta-summary. The extracted themes were discussed within the research team. FINDINGS: Fifteen studies with an overall moderate quality were included. The following findings were identified: (a) Quality of life of family members with hemophilia influences reproductive decision-making; (b) Genetic counselling is generally considered useful; (c) The development of a specialized carrier clinic is considered valuable; (d) HCs describe prenatal diagnosis as beneficial yet psychosocially challenging; and (e) noninvasive prenatal diagnosis and preimplantation genetic diagnosis are predominantly considered beneficial. These findings are limited by the overall moderate quality of included studies and the possibly partly outdated results in the current era of hemophilia treatment. CONCLUSIONS: Available qualitative literature on HCs around pregnancy focuses on genetic counselling and prenatal diagnosis. Future studies are needed on the experiences and needs of HCs through pregnancy and puerperium as well as in light of emerging hemophilia diagnosis and treatment options.

Desmopressin treatment combined with clotting factor VIII concentrates in patients with non-severe haemophilia A: protocol for a multicentre single-armed trial, the DAVID study.

INTRODUCTION: Haemophilia A is an inherited bleeding disorder characterised by factor VIII (FVIII) deficiency. In patients with non-severe haemophilia A, surgery and bleeding are the main indications for treatment with FVIII concentrate. A recent study reported that standard dosing frequently results in FVIII levels (FVIII:C) below or above FVIII target ranges, leading to respectively a bleeding risk or excessive costs. In addition, FVIII concentrate treatment carries a risk of development of neutralising antibodies. An alternative is desmopressin, which releases endogenous FVIII and von Willebrand factor. In most patients with non-severe haemophilia A, desmopressin alone is not enough to achieve FVIII target levels during surgery or bleeding. We hypothesise that combined pharmacokinetic (PK)-guided administration of desmopressin and FVIII concentrate may improve dosing accuracy and reduces FVIII concentrate consumption. METHODS AND ANALYSIS: In the DAVID study, 50 patients with non-severe haemophilia A (FVIII:C ≥0.01 IU/mL) with a bleeding episode or undergoing surgery will receive desmopressin and FVIII concentrate combination treatment. The necessary dose of FVIII concentrate to reach FVIII target levels after desmopressin administration will be calculated with a population PK model. The primary endpoint is the proportion of patients reaching FVIII target levels during the first 72 hours after start of the combination treatment. This approach was successfully tested in one pilot patient who received perioperative combination treatment. ETHICS AND DISSEMINATION: The DAVID study was approved by the medical ethics committee of the Erasmus MC. Results of the study will be communicated trough publication in international scientific journals and presentation at (inter)national conferences. TRIAL REGISTRATION NUMBER: NTR5383; Pre-results.

The "OPTI-CLOT" trial. A randomised controlled trial on periOperative PharmacokineTIc-guided dosing of CLOTting factor concentrate in haemophilia A.

Haemophilia A is an X-linked inherited, rare bleeding disorder, caused by a deficiency of coagulation factor VIII (FVIII). Previous studies in prophylactic dosing have demonstrated that FVIII consumption can be significantly reduced by individualising dosing based on combined analysis of individual pharmacokinetic (PK) profiling and population PK data (Bayesian analysis). So far, no studies have been performed that address perioperative concentrate consumption using iterative PK-guided dosing based on a PK population model. The "OPTI-CLOT" trial is an open-label, prospective, multicentre randomised controlled superiority trial (RCT), aiming to detect a 25 % difference in perioperative FVIII concentrate consumption with iterative Bayesian PK-guided dosing in comparison to the standard dosing procedure. Sixty haemophilia A patients ≥ 12 years of age, with FVIII plasma levels ≤ 0.05 IUml(-1) will be included requiring FVIII replacement therapy administered either by continuous or bolus infusion for an elective, low or medium risk surgical procedure. The proposed study aims to investigate a novel perioperative iterative PK-guided dosing strategy, based on a recently constructed perioperative PK population model. This model will potentially decrease underdosing and overdosing of clotting factor concentrate and is expected to overall reduce FVIII consumption by minimally 25 %. Moreover, participating hospitals will gain experience with PK-guided dosing, facilitating future implementation of this intervention which is expected to optimise current care and reduce costs of treatment.

B plexins activate Rho through PDZ-RhoGEF.

Plexins are receptors for the repulsive axon guidance molecules semaphorins. Previously, we have shown that plexin-B1 binds activated Rac, but that clustering of plexin-B1 causes Rho activation, resulting in stress fiber formation. Using the yeast two-hybrid system, we found that the C-terminus of B plexins interacted directly with Rho-specific exchange factors, via their PDZ domain. Mutation of the carboxy-terminal amino acids of plexin-B1 or coexpression of a dominant negative PDZ-RhoGEF abrogated the ability of plexin-B1 to cause stress fiber formation. Our results demonstrate a role for PDZ-RhoGEF in B plexin-mediated activation of Rho/Rho kinase signaling, implicated in the regulation of axon guidance and cell migration.