Primary prophylaxis implementation and long-term joint outcomes in Swedish haemophilia A patients.

INTRODUCTION: Primary prophylaxis is the gold standard in severe haemophilia A (SHA) but time to escalate the prophylaxis regimen varies. AIM: Assess prophylaxis implementation and long-term joint health outcomes in SHA with primary prophylaxis. METHODS: Adult male patients born after 1980, with SHA on primary prophylaxis, started before the age of 3 years and second joint bleed, and no history of FVIII inhibitors, were enrolled. Repeated joint-health examinations were performed with HJHS or HEAD-US; VERITAS-PRO assessed adherence. RESULTS: Thirty patients were enrolled with, at inclusion, median age 33.5 years, annualized bleed rate and joint bleed rate 0, and FVIII consumption 4232 IU/kg/year, respectively. The median age was 1.2 years, at prophylaxis start once weekly with a median FVIII dose of 47.7 IU/kg, and 1.7 years, by the time escalation to a final regimen had occurred, with a median infusion frequency of thrice weekly and FVIII dose 41.7 IU/kg, respectively. Older age correlated with later transition to escalated prophylaxis (p < .001). Longer time to escalated prophylaxis correlated to more bleeds (p < .001). Median HJHS increased slowly, reaching 4 at 35-40 years. HJHS at 15-20 years correlated with higher HJHS afterwards. Median total HEAD-US score was 1 and correlated with HJHS (p < .001). Median VERITAS-PRO score was 36, indicating good treatment adherence. CONCLUSION: Primary prophylaxis is effective but does not completely prevent the gradual development of arthropathy in SHA. Joint assessments with HJHS should start at an early age, as they correlate with arthropathy in later life. Prophylaxis escalation should proceed expeditiously to prevent bleeds.

Haemophilia A and B - evaluation of the Swedish prophylactic regimen by magnetic resonance imaging.

INTRODUCTION: Sweden has been a pioneer in the prophylactic treatment of haemophilia. Magnetic resonance imaging (MRI) can detect small changes in joints and can therefore give an indication of a risk of developing arthropathy. AIM: To use MRI to evaluate the outcome of the Swedish 'high-dose regimen' and correlate the findings to age, bleeds, joint score and physical activity. METHODS: The study group comprised 48 Swedish male patients, mean age 25 years (range 12-33 years), with severe or moderate haemophilia A or B. Data on the Haemophilia Joint Health Score (HJHS) were available and physical activity was evaluated by a self-reported questionnaire. RESULTS: MRI score was recorded in 188 joints. Twenty out of 48 patients had a score of ≥1 (range 1-13) in 31 joints of which 3/31 scores were in the knees and 28/31 in the ankles. No correlation was found between the number of recorded bleeds and the MRI score or between HJHS and MRI score. There was no correlation between the physical activity and the number of joint bleeds per se, but a trend (OR 3.0) that those most physically active (19/48; 39.6%), more frequently had an MRI score of ≥1 with an overweight for the right ankle. CONCLUSION: The Swedish prophylactic model offers protection against haemophilia joint arthropathy but will still not prevent osteochondral changes in some patients at young age. MRI of the ankles can signal risk of future arthropathy and indicate need to modify the prophylactic regimen.

No difference in quality of life between persons with severe haemophilia A and B.

INTRODUCTION: Good health-related quality of life (HRQoL) is an important goal in the treatment of persons with haemophilia B (PwHB). Studies focusing on this population are limited, however, and data are insufficient. AIM: To assess the HRQoL in PwHB and to compare this to data on persons with haemophilia A (PwHA), as well as to evaluate the impact of joint health on HRQoL and to identify areas of insufficient care. METHODS: The B-NORD study enrolled persons with severe haemophilia B and matched controls with haemophilia A. HRQoL was assessed using the EQ-5D-3L questionnaire and joint health using Haemophilia Joint Health Score 2.1 (HJHS). RESULTS: The EQ-5D-3L was completed by 63 PwHB and 63 PwHA. Mobility problems were reported by 46% of PwHB and 44% of PwHA, pain/discomfort by 62% and 56%, and anxiety/depression by 33% and 17%, respectively. No significant difference was observed between PwHA and PwHB in EQ-5D profiles, level sum score, EQ-5D index (PwHB mean .80, PwHA mean .83, p = .24), or EQ VAS score (PwHB: mean 70, PwHA: mean 77, p = .061). Linear regression adjusted for age demonstrated that an increase in HJHS score was associated with a significant decrease in both EQ-5D index (B -.003, R2 .22) and EQ VAS score (B -.37, R2 .17). CONCLUSION: Despite the majority of patients being treated with prophylaxis, impaired HRQoL was reported in both PwHB and PwHA. No differences in HRQoL were found between the two groups. Impaired joint health had a significant negative impact on HRQoL.

Accreditation model of European Haemophilia Centres in the era of novel treatments and gene therapy.

INTRODUCTION: The international certification of haemophilia centres in Europe is run by the European Association of Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) since 2013. The centres are designated as European Haemophilia Comprehensive Care Centres (EHCCC) or European Haemophilia Treatment Centres (EHTC), based on the specific requirements which evaluate centres' ability to provide care for patients with haemophilia and allied disorders. AIM: To establish the new protocol for accreditation of European Haemophilia Centres. METHODS: EAHAD, in collaboration with EHC, established Accreditation Working Group with the aim to define necessary measures to safeguard quality and improvement of bleeding disorders care throughout Europe and to build a novel model for accreditation of European Haemophilia Centres. RESULTS: The European guidelines for certification of haemophilia centres have been updated to guidelines for the accreditation and include all the requirements regarding facilities, laboratory and personnel needed for optimal management of novel treatment options, including the introduction of the hub-and-spoke model for delivery of gene therapy. A pilot project for the accreditation of haemophilia centres including on-site audit has been designed. CONCLUSION: Implementation of the novel accreditation protocol of the haemophilia treatment and haemophilia gene therapy centres has been made to further improve the quality of care for patients with haemophilia and other inherited bleeding disorders.

Surgical outcomes in patients with haemophilia A or B receiving extended half-life recombinant factor VIII and IX Fc fusion proteins: Real-world experience in the Nordic countries.

INTRODUCTION: Perioperative dosing recommendations vary across Nordic haemophilia treatment centres (HTCs) for extended half-life (EHL) factor concentrates in haemophilia A/B (HA/HB) patients. AIM: To summarise Nordic real-world surgical experiences with EHL recombinant factor VIII/IX Fc (rFVIIIFc/rFIXFc) fusion proteins using retrospective data from clinical records at four HTCs in Finland, Sweden and Norway. METHODS: Factor dosing and surgical outcomes were recorded from HA/HB patients who underwent surgery and were treated with rFVIIIFc/rFIXFc. Perioperative factor dosing regimens were clinician-determined based on local practises. RESULTS: Twenty five surgeries were performed on 20 patients, all covered by bolus injections except one minor HA surgery; eight minor surgeries were in paediatric patients. Median preoperative rFVIIIFc dose for major HA surgeries (n = 8) was 48 IU/kg (range: 35-57), with total consumption up to Day 14 of 427 IU/kg (196-568). For the two major HB surgeries (in one patient), preoperative rFIXFc doses were 50 IU/kg and 20 IU/kg; total consumption up to Day 14 was 130 IU/kg and 40 IU/kg. Median preoperative rFVIIIFc/rFIXFc bolus doses for minor HA (n = 10) and HB (n = 4) surgeries were 50 IU/kg (24-79) and 47 IU/kg (40-71), with total consumption up to Day 5 of 138 IU/kg (49-404) and 100 IU/kg (43-125), respectively. Intraoperative and postoperative haemostatic responses were rated as at least good/excellent for 24/25 surgeries, with bleeding episodes reported in only three surgeries. CONCLUSION: Nordic real-world experiences suggest that EHL products can be used safely and effectively for peri-operative haemostasis. Further research is required to develop local dosing guidelines for optimised treatment schedules.

Pain, depression and anxiety in people with haemophilia from three Nordic countries: Cross-sectional survey data from the MIND study.

INTRODUCTION: People with haemophilia (PwH) may experience symptoms of haemophilia-related pain, depression or anxiety, which can negatively impact health-related quality of life. AIM: To obtain the perspective of PwH and treaters from Sweden, Finland and Denmark on the management of haemophilia-related pain, depression and anxiety using cross-sectional survey data from the MIND study (NCT03276130). METHODS: PwH or their caregivers completed a survey about experiences of pain, depression and anxiety related to haemophilia, and the standard EQ-5D-5L instrument. Five investigators at haemophilia treatment centres (HTC) were sent a complementary survey containing questions about the management of pain and depression/anxiety. RESULTS: There were 343 PwH (mild: 103; moderate: 53; severe: 180; seven lacking severity information) and 71 caregiver responses. Experience of pain in the last 6 months was reported by 50% of PwH respondents and 46% of caregiver respondents. Anxiety/depression was reported by 28% of PwH respondents. Reporting of pain and anxiety/depression was associated with disease severity. Whilst 62% of PwH who had experienced pain at any time point (n = 242) felt this was adequately addressed and treated at their HTC, only 24% of those who had experienced depression/anxiety (n = 127) felt this was adequately addressed. Disease severity was negatively associated with EQ-5D-5L utility value (p < .001). In the HTC survey, 4/5 and 2/5 agreed that pain and depression/anxiety, respectively, are adequately addressed. CONCLUSIONS: Pain and depression/anxiety occur more frequently with increasing haemophilia severity, with negative impacts on health-related quality of life. PwH with depression/anxiety or unaddressed pain could benefit from improved management strategies.

Treatment outcomes in persons with severe haemophilia B in the Nordic region: The B-NORD study.

INTRODUCTION: Data on outcome in persons with haemophilia B (PwHB) are limited and mainly extrapolated from studies of haemophilia A (HA). AIM: To characterize treatment outcomes in persons with severe HB in the Nordic region, with a focus on joint health, compared with matched controls with HA. METHODS: PwHB attending haemophilia centres in Denmark, Finland, Norway and Sweden were enrolled and matched with controls with HA. Joint assessment using Haemophilia Joint Health Score (HJHS) and ultrasound according to Haemophilia Early Arthropathy Detection protocol (HEAD-US) was conducted. Adherence was evaluated using the Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS). RESULTS: Seventy-nine males with HB, with median age of 30 years (range 1-75), were enrolled. Eleven patients (14%) had a history of or current inhibitor. Twenty-nine PwHB (37%) reported joint bleeds during the prior year, and 35% had previously undergone joint surgery. Ninety-five per cent were on prophylaxis, and 70% used recombinant concentrates, with a median factor consumption of 3,900 IU/kg/year for standard half-life products. Only two patients had a VERITAS score corresponding to 'non-adherence'. Joint health, assessed with HJHS, showed a significant lower score among PwHB compared with HA controls, explained by a difference in the 18-49 age group, without observed differences in older or younger subgroups. The HEAD-US scores were overall low. CONCLUSION: The Nordic cohort of PwHB is well treated by prophylaxis, but the goal of zero bleeds for all is not reached. Our findings suggest that patients with severe HB suffer from a milder arthropathy than patients with severe HA.

Joint comorbidities among Swedish carriers of haemophilia: A register-based cohort study over 22 years.

BACKGROUND: A significant fraction of women with an impaired factor VIII or IX gene in the X chromosome, carriers of haemophilia, will have clotting factor activities corresponding to those seen in males with non-severe haemophilia, hence, experience an increased bleeding tendency. Data describing the long-term joint outcomes among carriers are limited. We compared the age at onset, frequency of joint-related diagnoses as well as joint surgery and related hospitalizations among carriers of haemophilia with sex- and birthdate-matched controls from the general population. METHODS: Carriers of haemophilia born 1941-2008 were identified through the haemophilia treatment centres' (HTCs) databases and the National Patient Register of Sweden. For each carrier, we included up to five individuals using the Swedish population register as comparisons. Data for the period 1987-2008 were obtained. RESULTS: Among 539 potential carriers identified, 213 had a known factor activity. Carriers with reduced factor activity and those with unknown factor activity had received their first joint-related diagnosis at a significantly earlier age than their comparisons. The same subgroups showed an overall 2.3- and 2.4-fold higher hazard for joint-related diagnoses compared with the general population. In addition, the hazards of joint-related outpatient hospitalization were 3.2-fold (95% CI: 1.2, 9.1) and 2.5-fold (95% CI: 1.6, 3.7). This was not observed for those with normal factor activity. CONCLUSION: Carriers of haemophilia suffer a significant risk for joint comorbidities. This risk seems to correlate to the factor activity. Our findings underline the importance of regular clinical follow-up of carriers at HTCs.

Platelet aggregation in healthy women during normal pregnancy - a longitudinal study.

Increased platelet activation is involved in obstetric complications such as preeclampsia and intrauterine growth retardation. It is of interest to study platelet aggregation during pregnancy, since increased aggregation theoretically could be a mechanism associated with placenta-mediated complications, which possibly could be prevented by drugs inhibiting platelet aggregation. There are, however, few robust studies describing platelet aggregation during normal pregnancy. The present longitudinal study was performed in order to study platelet aggregation during normal pregnancy resulting in a healthy child, during the puerperium and in nonpregnant, fertile women. Healthy, nonsmoking, pregnant women (n = 104), aged under 39 years and with BMI < 35, were followed during pregnancy and postpartum. Twenty-seven nonpregnant, non-puerperal, fertile women were studied for comparison. Platelet aggregation was determined with multiple electrode impedance aggregometry and analyzed at inclusion, 4 times during pregnancy and after at least 3 months postpartum. Platelet aggregation postpartum was compared with gestational weeks 8-15 and 37-40, respectively, and with nonpregnant, fertile women. Hemoglobin, leucocyte count, platelet count, prothrombin time, and activated partial thromboplastin time were determined at inclusion in order to verify normal hemostasis. Activation of platelets by arachidonic acid, adenosine diphosphate (ADP), and thrombin receptor activating peptide (trap-6) resulted in less aggregation during pregnancy, compared with postpartum (p < 0.03-< 0.001). Platelet aggregation following activation by collagen was unchanged. A minor increase in aggregation as pregnancy continued was found related to ADP (p < 0.021). Positive correlations were found between platelet counts and platelet aggregation. Postpartum platelet aggregation after activation with arachidonic acid, collagen, and trap-6 was lower than in the non-puerperal fertile state. Other hemostatic analyses were normal. In conclusion, there is a minor decrease in platelet aggregation after activation with arachidonic acid, trap-6, and ADP, measured with multiple electrode impedance aggregometry during normal pregnancy resulting in healthy babies, compared with the postpartum period. The small changes in platelet aggregation may be a consequence of a minor decrease in platelet count and probably lack clinical significance under normal conditions. Interindividual variations at certain time-points are substantial, which limits the usefulness of the multiple electrode impedance aggregometry for determining minor changes in platelet function.

Burden on parents of children with haemophilia: The impact of sociodemographic and child's medical condition.

AIMS AND OBJECTIVES: To describe the perceived burden on parents of children with severe or moderate haemophilia and the impact of sociodemographic aspects and the child's medical condition on this. BACKGROUND: Parents of children with haemophilia face a multitude of demands. The child needs frequent intravenous injections, hospital visits, extra supervision and care. The child's illness and related management might have psychosocial effects on the parents. DESIGN: A multicentre, cross-sectional study. METHODS: Caregiver burden was evaluated in 102 parents of children with haemophilia, using the HEMOCAB questionnaire which consists of 54 items divided into 13 domains which are to be answered on a 5-point Likert scale. To assess the impact of sociodemographic aspects and clinical data on parental burden, linear regression analyses were undertaken. The study followed the STROBE checklist throughout the research process. RESULTS: Greater burden was seen in parents of children with past or present inhibitors, in parents of younger children, if a family member administered the clotting factor and in parents of children with overweight/obesity. No significant differences in burden were observed for type of haemophilia, if the child had bleeding in the past 12 months, if the child self-infused, had another family member with haemophilia or if the parent had more children. CONCLUSIONS: Parental perceived burden can be negatively affected by the child's medical condition; our results underline that healthcare professionals need to be aware of increased parental burden if the child is young, has or had inhibitors and has overweight/obesity. RELEVANCE TO CLINICAL PRACTICE: More psychosocial support from the healthcare professionals needs to be directed towards parents of younger children and particularly the parents of young children with inhibitors, thus decreasing the parental burden. Parental burden may be reduced if healthcare professionals more actively treat overweight and refer children to appropriate specialists.

Effects of the oral, direct factor Xa inhibitor edoxaban on routine coagulation assays, lupus anticoagulant and anti-Xa assays.

Edoxaban is an oral direct factor Xa inhibitor for prophylaxis and treatment of thromboembolic disorders. The effects on common coagulation assays are clinically valuable information and in certain clinical situations a quick assessment of the anticoagulant is wanted. Our aim was to investigate the effect of edoxaban on routine coagulation methods and evaluate anti-Xa assays, commonly used for other direct factor Xa inhibitors, for estimation of the drug concentration. Edoxaban was spiked to plasma samples from healthy subjects in the concentration range 0-742 µg/L and analyzed using different reagents for activated partial thromboplastin time (APTT) and prothrombin time (PT). Assays for antithrombin, activated protein C resistance, lupus anticoagulant (LA) and chromogenic anti-Xa assays were also included. Edoxaban displayed similar effects in vitro to other oral direct Xa inhibitors. The concentration needed to double the coagulation time varied between assays and reagents; 539-758 µg/L for the APTT and between 329 and 2505 µg/L for the PT. Edoxaban gave false high antithrombin activities in assays based on Xa-inhibition. Two integrated assays for LA, both based on activation with dilute Russell's viper venom, displayed different results. Chromogenic anti-Xa assays displayed linear dose-response curves with edoxaban up to approximately 500 µg/L. In conclusion, therapeutic concentrations of edoxaban variably affect different coagulation assays, and even different reagents within an assay group. In comparison with other oral Xa-inhibitors, the in vitro effects of edoxaban were more similar to rivaroxaban than apixaban. For measurement of edoxaban concentration in plasma, it is possible to use the chromogenic anti-Xa assays.

Reaching Independence Through Forced Learning: Learning Processes and Illness Management in Parents of Children Affected by Hemophilia.

Hemophilia is a complex condition to manage, especially for parents to newly diagnosed children. This grounded theory study explores parents' learning processes and illness management in daily life during the first year after the start of their child's treatment. Using a longitudinal qualitative design, eight parents of four children were interviewed repeatedly during 12 to 14 months. The core category, reaching independence through forced learning, reflected the parents' learning process and their experiences of the challenges during the first year after start of treatment. Incentives for learning were characterized by a longing to reach independence and regain control of one's life situation. The emerging key incentive for learning was a desire to become independent of health care professionals. Early home treatment reduced the impact of the illness, and by supporting parents in different ways during the learning process, health care professionals can promote the parents' trajectory toward independency.

Self-reported activity and functioning in daily life; the perspective of persons with haemophilia living in Sweden.

OBJECTIVES: To investigate the self-estimated function, activity and participation in daily life of persons with severe or moderate haemophilia A and B (PWH) living in Sweden. The secondary aim was to explore the differences between participants with early treatment onset and later. METHODS: The Haemophilia Activity List (HAL), Arthritis Impact Measurement Scales (AIMS2) and Impact on Participation and Autonomy (IPA-S) were distributed by mail to 225 PWH with an invitation to participate in the study. The median and min-max are given for the different domains; a higher value indicates more disability. RESULTS: Eighty-four PWH (18-80 years) participated. The HAL indicated more problems in the legs [40 (0-100)] than in self-care [4 (0-92)] and household tasks [3 (0-87)]. The AIMS2 scores confirmed this (physical activity 12 (0-64.5) as well as somewhat reduced autonomy outdoors [IPA-S 17.5 (0-90)]. More limitations in daily life were reported by participants with later treatment onset. CONCLUSION: The PWH reported greater disability in the domains related to activities using the lower extremities compared to domains related to upper extremity. This study pointed out the need of using different questionnaires to capture patients own perspective and as useful supplement to other clinical assessment instruments.

Earlier detection of coagulopathy with thromboelastometry during pediatric cardiac surgery: a prospective observational study.

OBJECTIVE: Earlier detection of coagulopathy in pediatric cardiac surgery patients. AIM: To determine whether thromboelastometry (TEM) analysis before weaning from cardiopulmonary bypass (CPB) and hemoconcentration is predictive of post-CPB results and whether analysis of clot firmness already after 10 min yields reliable results. BACKGROUND: Cardiac surgery with CPB induces a coagulopathy that may contribute to postoperative complications. Earlier detection increases the possibility of initiating countermeasures. METHODS/MATERIAL: Fifty-six pediatric cardiac surgery patients were included in a prospective observational study. HEPTEM and FIBTEM clotting time (CT), clot formation time (CFT), and clot firmness after 10 min (A10) and at maximum (MCF) were analyzed during CPB and after CPB and ultrafiltration with modified rotational thromboelastometry (ROTEM). The analyses were compared, and correlations and differences were calculated. RESULTS: Hemoconcentration with modified ultrafiltration increased hematocrit from 28 ± 3 to 37 ± 4% (P < 0.001). Correlation coefficients of the TEM variables during and after CPB ranged from 0.61 to 0.82 (all P < 0.001). HEPTEM-CT and HEPTEM-MCF differed significantly but the differences were marginal. Both HEPTEM and FIBTEM A10 measurements during CPB were significantly less than MCF (P < 0.001 for both), but the correlations were highly significant (HEPTEM: r = 0.95, P < 0.001; FIBTEM: r = 0.96, P < 0.001), and the differences were predictable, with narrow confidence intervals (HEPTEM: -8.2 mm (-8.9 to -7.5); FIBTEM: -0.5 mm (-0.7 to -0.3). CONCLUSION: The results suggest that intraoperative TEM analyses can be accelerated by analyzing HEPTEM/FIBTEM on CPB before hemoconcentration and by analyzing clot firmness already after 10 min.

Monitoring of acetyl salicylic acid-induced platelet inhibition with impedance aggregometry in children with systemic-to-pulmonary shunts.

BACKGROUND: Shunt thrombosis after implantation of systemic-to-pulmonary shunts in paediatric patients is common. Acetyl salicylic acid is used for anti-thrombotic treatment; however, the effect is rarely monitored, although it is known that the response varies. The aim was to determine the effects of acetyl salicylic acid medication on platelet aggregation in children with systemic-to-pulmonary shunts. METHODS: A total of 14 children ­ median age 12 days; ranging from 3 to 100 days ­ were included in a prospective observational longitudinal study. All children were treated with oral acetyl salicylic acid (3­5 milligrams per kilogram once daily) after shunt implantation. Acetyl salicylic acid-dependent platelet aggregation in whole blood was analysed with impedance aggregometry (Multiplate®) after addition of arachidonic acid. Analyses were carried out before the primary operation, before and 5 and 24 hours after the first acetyl salicylic acid dose, and after 3­6 months of treatment. The therapeutic range for acetyl salicylic acid was defined as a test result less than 60 units. RESULTS: Acetyl salicylic acid reduced the arachidonic acid-induced platelet aggregation in all but one patient. Of the patients, 93% were in the therapeutic range 5 hours after acetyl salicylic acid intake, 86% were in the range after 24 hours, and 64% after 3­6 months. CONCLUSIONS: Acetyl salicylic acid reduces platelet aggregation after shunt implantation in paediatric patients, but a considerable percentage of the children are outside the therapeutic range. Monitoring of platelet aggregation has the potential to improve anti-platelet treatment after shunt implantation by identifying children with impaired acetyl salicylic acid response.

High use of pain, depression, and anxiety drugs in hemophilia: more than 3000 people with hemophilia in an 11-year Nordic registry study.

Background: Pain is a common feature of hemophilia, but prevalence of depression and anxiety is less studied. Registry data on prescription drugs can provide an objective measure of the magnitude of these complications. Objectives: To identify treatment patterns of prescribed pain, antidepressant, and antianxiety medications compared with those of matched controls in 4 Nordic countries. Methods: The MIND study (NCT03276130) analyzed longitudinal individual-level national data during 2007-2017. People with hemophilia (PwH) were identified from National Health Data Registers by diagnosis or factor replacement treatment and compared with population controls. Three subgroups were defined by the use of factor concentrates and sex (moderate-to-high factor consumption (factor VIII [FVIII] use of ≥40 IU/kg/week or FIX use of ≥10 IU/kg/week), low factor consumption, and women including carriers). Results: Data of 3246 PwH, representing 30,184 person-years, were analyzed. PwH (including children and adults) used more pain, depression, and anxiety medications compared with controls. This was most accentuated in the moderate-to-high factor consumption group and notably also observed in men with low factor consumption and women including carriers, usually representing a milder phenotype. A higher opioid use was observed across all age groups: 4- to 6-fold higher in the moderate-to-high factor consumption group and 2- to 4-fold higher in the low factor consumption group. Conclusion: The consistent higher use of pain, depression, and anxiety medications among PwH compared with population controls, regardless of age, sex, or factor consumption, in broad national data suggests a need for improved bleed protection and hemophilia care for all severities including mild hemophilia.

Infrastructural considerations of implementing gene therapy for hemophilia in the Nordic context.

Background: Despite improvements in hemophilia care, challenges remain, including treatment burden and impaired quality of life. Gene therapy may overcome these. However, its introduction presents a challenge. Objectives: To outline a function-based gene therapy working model describing critical milestones associated with gene therapy handling, administration, and follow-up to facilitate and implement an effective infrastructure for gene therapy introduction. Design: Literature review and consensus discussion among Hemophilia Comprehensive Care centers (HCCCs) in the Nordic region. Methods: Representatives from six HCCCs sought to pinpoint milestones and key stakeholders for site readiness at the pre-, peri-, and post-infusion stages, including authority and genetically modified organism (GMO) product requirements, awareness, medical eligibility, logistics and product handling for infusion, laboratory monitoring, and follow-up. Results: A gene therapy transit map was developed with key stakeholders identified. The approach to prepare the vector will differ between the Nordic centers, but the contracted pharmacy unit will be a key stakeholder. Therefore, a pharmacy checklist for the implementation of gene therapy was developed. For the future, Advanced Therapy Medicinal Product centers will also be implemented. Patients' expectations, commitments, and concerns need to be addressed repeatedly and education of patients and the expanded health-care professionals team will be the key to successful and optimal clinical management. Eligibility testing according to the product's summary of product characteristics and frequent follow-up and monitoring post-infusion according to the World Federation of Hemophilia chart will be crucial. Conclusion: The approach to deliver gene therapy in the Nordic region will differ partly between the hemophilia centers, but the defined road map with checklists for the implementation of this advanced therapy will be applicable to all. The map may also serve as a platform for the use of future GMO product options both within and outside the area of hemophilia.

Implementing gene therapy for hemophilia in the Nordic context Why was this study done? • Despite improvements in hemophilia care, challenges remain including treatment burden and impaired quality of life. • Gene therapy may overcome these challenges. • The introduction of gene therapy presents a challenge in many ways. What did the researchers do? • We, as representatives from six Hemophilia Comprehensive Care Centers in the Nordic region, sought to pinpoint milestones and key stakeholders for site readiness at the pre-, peri- and post-infusion stages, including authority and genetically modified organism (GMO) product requirements, awareness, medical eligibility, logistics and product handling for infusion, laboratory monitoring, plus follow-up. What did the researchers find? • We developed a gene therapy transit map and identified key stakeholders. • The approach to prepare the vector will differ between the Nordic centers, but the pharmacy unit will be a key stakeholder. We therefore developed a pharmacy checklist for the implementation of gene therapy. • For the future, Advanced Therapy Medicinal Product centers will be implemented. • Patients' expectations, commitments and concerns need to be addressed repeatedly. • Education of patients and the expanded health care professionals team will be the key to successful and optimal clinical management. • Eligibility testing according to the product's summary of product characteristics and close follow-up and monitoring post-infusion according to the World Federation of Hemophilia chart will be crucial. • Access to both chromogenic and one-stage factor activity assay results from a specialized coagulation laboratory with a short turn-around time is important. What do the findings mean? • The approach to delivering gene therapy in the Nordic region will differ partly between the hemophilia centers, but the defined road map with checklists for the implementation will be applicable to all. • The map may also serve as a platform for the use of future GMO product options both within and outside the area of hemophilia.